Adjuvant radiation therapy for women with newly diagnosed, non-metastatic breast cancer

INTRODUCTION — Globally, breast cancer is the most frequently diagnosed and the leading cause of cancer death in women. For women with newly diagnosed, non-metastatic breast cancer, treatment consists of a multidisciplinary approach that involves input from surgery, radiation oncology, and medical oncology.

The objective of adjuvant radiation therapy (RT) is to eradicate any tumor deposits remaining following surgery for patients treated by either breast-conserving surgery or mastectomy [1]. Doing so reduces risk of locoregional recurrence and improves breast cancer-specific and overall survivals.

This topic will review the role of adjuvant RT. Other aspects of the management of women with newly diagnosed, non-metastatic breast cancer are covered separately. (See "Overview of the treatment of newly diagnosed, invasive, non-metastatic breast cancer".)

PATIENTS TREATED WITH BREAST-CONSERVING SURGERY

Approach — For most women treated with breast-conserving surgery, we administer whole-breast RT (WBRT). This includes women treated with neoadjuvant therapy, even if they experienced a complete response to treatment.

As discussed below, adjuvant WBRT reduces the risks of recurrence and breast cancer death. (See 'Whole-breast RT' below.)

There are few exceptions to this approach:

●For older women (typically defined as ≥65 years) with node-negative, stage I and early node-negative, stage II (with primary tumors up to 3 cm) [2], hormone receptor-positive breast cancer who are treated with endocrine therapy, exclusion of RT may be a reasonable option, depending on the values and preferences of the patient. (See 'Possible omission of RT for select ER-positive, HER2-negative cancers' below.)

●For certain women with small (≤3 cm), hormone receptor-positive, lymph node-negative tumors who are ≥50 years old, accelerated partial-breast irradiation (APBI) may be a reasonable alternative to WBRT. (See 'Accelerated partial-breast irradiation' below.)

For most women receiving WBRT, we also offer an RT boost to the tumor bed to further reduce the risk of in-breast tumor recurrence (IBTR). Possible exceptions include patients ≥60 years old with small, low-grade, hormone receptor-positive tumors resected with negative margins. (See 'RT boost to the tumor bed' below.)

For women who have involved lymph nodes and high-risk primary tumors, regional nodal RT may also be indicated. (See 'Indications for regional nodal irradiation' below.)

Patients treated with neoadjuvant therapy receive WBRT regardless of their pathologic response. Regional nodal irradiation may also be indicated. (See 'Patients who received neoadjuvant therapy' below.)

Technical aspects of delivering RT are covered separately. (See "Radiation therapy techniques for newly diagnosed, non-metastatic breast cancer".)

Whole-breast RT — For most women treated with breast-conserving surgery, we administer WBRT. Exceptions are discussed elsewhere. (See 'Approach' above.)

Rationale — WBRT following breast conservation therapy reduces the locoregional recurrence rate and risk of breast cancer death. These benefits of WBRT are demonstrated by the 2011 meta-analysis performed by the Early Breast Cancer Trialists' Collaborative Group (EBCTCG), which included over 10,000 women (known to be either pathologically node-negative or positive) in 17 trials [1]. The main results of the meta-analysis were that WBRT resulted in:

●A nearly 50 percent reduction in the 10-year risk of any first recurrence compared with breast-conserving surgery alone (19 versus 35 percent, respectively; relative risk [RR] 0.52, 95% CI 0.48-0.56). The reduction in recurrence rate associated with RT was due to a decrease in locoregional rather than distant recurrences.

●A reduction in the 15-year risk of breast cancer death (21 versus 25 percent; RR 0.82, 95% CI 0.75-0.90).

Risks and toxicities — WBRT is associated with acute toxicities that involve the area treated (eg, skin, muscle, and internal organs), although these complications are relatively uncommon. WBRT can also result in long-term complications, including cardiotoxicity, lung injury, and second malignancies [3], which can occur many years after treatment has been completed. However, improvements in RT techniques over time have likely reduced long-term toxicities. Further discussion of specific late toxicities is found elsewhere. (See "Overview of long-term complications of therapy in breast cancer survivors and patterns of relapse" and "Cardiotoxicity of radiation therapy for breast cancer and other malignancies".)

As an example of frequency of early toxicities, among 294 patients treated with surgery and RT at one institution, 29 patients (9.9 percent) had grade 2 or higher complications at one year [4]. These included arm edema (4 percent), breast skin fibrosis (4 percent), decreased range of motion (1 percent), and pneumonitis (0.6 percent). One patient each experienced fat necrosis and rib fracture.

Management of these issues may require ongoing care beyond the completion of RT. Physical therapy may assist in management of decreased range of motion associated with scarring and fibrosis. One trial found that six months of treatment with pentoxifylline and vitamin E reduced skin fibrosis compared with placebo [5]. Further discussion of evaluation and management of lymphedema is found elsewhere. (See "Clinical features and diagnosis of peripheral lymphedema", section on 'Radiation therapy' and "Clinical staging and conservative management of peripheral lymphedema".)

Conventional versus hypofractionated schedules — Historically, most women have received conventionally dosed WBRT, which is delivered to the entire breast in 1.8 to 2 Gy daily fractions over 4.5 to 5 weeks to a total dose of 45 to 50 Gy. However, another option is a shorter fractionation ("hypofractionated") schedule, which has been associated with equivalent tumor control and fewer toxicities, and is now preferred for many patients. In general, a hypofractionated regimen delivers more radiation per dose, but the overall treatment duration is shorter (typically 40 to 42.5 Gy in approximately three to five weeks without or with a boost, respectively, although one study has evaluated 30 Gy in weekly fractions for five weeks [6,7]). We agree with the American Society for Radiation Oncology (ASTRO) that use of hypofractionated RT should be encouraged in all women with invasive breast cancer or ductal carcinoma in situ (DCIS) for whom the intent is to treat only the whole breast without an additional field to cover the regional lymph nodes, provided that dose homogeneity goals can be achieved (dose homogeneity of >7 percent and the volume of breast tissue receiving >105 percent of the prescription dose should be minimized) [8,9]. This is independent of any age, stage, or use of systemic therapy. Importantly, however, there is insufficient evidence to support hypofractionation when regional RT is indicated (table 1). (See 'Indications for regional nodal irradiation' below.)

Cosmetic and disease outcomes have been equivalent between hypofractionated and conventional schedules. The efficacy of a hypofractionated schedule was shown in a 2016 meta-analysis of nine randomized trials (n = 8228 women) that compared it with conventionally scheduled WBRT [10]. Shorter fractionation resulted in:

●No difference in breast cancer-specific survival (RR 0.91, 95% CI 0.78-1.06)

●No difference in 10-year mortality (RR for mortality 0.91, 95% CI 0.80-1.03)

●No difference in breast appearance (RR 0.90, 95% CI 0.81-1.01)

●No difference in late RT subcutaneous toxicity (RR 0.93, 95% CI 0.83-1.05)

●A decrease in acute RT toxicity (RR 0.32, 95% CI 0.22-0.45)

Ten-year follow-up of two of the trials (START-A and START-B) included was analyzed in a separate meta-analysis and also suggests that there was no significant difference between the shorter fractionation and conventionally dosed RT schedules [11]. This was irrespective of age, type of primary surgery, axillary node status, tumor grade, administration of adjuvant chemotherapy, or the use of a tumor-bed boost RT [11].

Schedules as short as one week have also been explored for WBRT, with similar results. In a subsequent randomized trial of over 4000 breast cancer patients, the five-year incidence of ipsilateral breast tumor relapse was 2.1 percent with the standard 40 Gy in 15 fractions over three weeks versus 1.4 percent with 26 Gy in five fractions over one week (5.2 Gy per fraction; hazard ratio [HR] 0.67, 95% CI 0.38-1.16) and 1.7 percent with 27 Gy in five fractions over one week (5.4 Gy per fraction; HR 0.86, 95% CI 0.51-1.44) [12].

In regards to toxicities, cosmesis results have been somewhat mixed with hypofractionated versus standard schedules and likely depend at least in part on the specific schedule used. Other long-term toxicities appear to be similar:

●In ten-year follow-up of the FAST trial, there were no significant differences in normal tissue effects for the standard 50 Gy in 25 fractions schedule versus a once-weekly schedule for five weeks totaling 28.5 Gy, but normal tissue effects were higher with a weekly schedule for five weeks totaling 30 Gy (odds ratio relative to standard radiation 2.12, 95% CI 0.55-2.89) [7]. Similarly, in the trial discussed above evaluating five fractions over one week, moderate or marked tissue effects in the breast or chest wall were more common among patients receiving 27 Gy (15 percent) than either 40 Gy (10 percent) or 26 Gy (12 percent), but differences between the 40-Gy and 26-Gy groups were not statistically different [12].

●By contrast, a separate randomized trial showed similar or better cosmetic outcomes among patients receiving a hypofractionated schedule (40 Gy in 15 fractions) compared with standard fractionation (50 Gy in 25 fractions), among over 1800 patients with node-negative breast cancer or DCIS (246 patients) [13]. Radiation-associated cardiac and lung disease were comparable between the groups.

●In a multicenter, retrospective cohort of 8700 patients receiving adjuvant radiation for breast cancer (approximately half of whom received standard versus hypofractionated schedules), moderate or severe breast pain was reported in 29 percent of those receiving hypofractionation and 46 percent of those receiving standard fractionation, while frequent bother from at least one breast symptom was reported in 41 versus 61 percent, respectively [14]. Severe fatigue was reported by 19 percent after hypofractionation and 27 percent after standard fractionation.

Overall, several caveats apply in interpretation of data regarding hypofractionation [15]:

●Additional studies are needed to more fully evaluate both efficacy and toxicity in certain subgroups, particularly for those with more advanced tumors (T-size >5 cm); postmastectomy, with or without reconstruction; or in patients with positive nodes, although available evidence suggests good tolerability of hypofractionated RT [16,17]. (See 'Indications for regional nodal irradiation' below.)

●More studies are needed before hypofractionation can be recommended for those in whom regional RT is indicated.

●Additional studies are also needed to more fully evaluate both the efficacy and toxicity of hypofractionated irradiation for treating primary breast cancers with rare histologies, in patients with breast augmentation, and in patients with collagen vascular disease.

●There are insufficient data to evaluate the tolerability of shorter fractionation when used with other therapies (ie, chemotherapy or monoclonal antibodies).

RT boost to the tumor bed — RT boost to the tumor bed is intended to decrease locoregional recurrence rates. While RT to the tumor bed following breast-conserving surgery and WBRT is recommended in younger women, its routine use in older women is less clear. A common practice, which we support, is that all patients receive an RT boost after WBRT, except for selected women aged 60 and older with stage 0 to I luminal phenotypes resected with negative margins, for whom it is optional. The degree of benefit and the associated potential skin toxicities following a boost in patients who had received hypofractionated RT are unclear. The decision to give a boost in these patients should be made after a discussion between the patient and the treating radiation oncologist.

If an RT boost is administered, 10 to 14 Gy in either 2 Gy or 2.5 Gy fractions is usually administered, with boost dose, in part, dependent upon the dose and fractionation delivered to the whole breast. Technical aspects of delivering an RT boost, including simultaneous integrated versus concurrent boost, are covered separately. (See "Radiation therapy techniques for newly diagnosed, non-metastatic breast cancer".)

Two trials that evaluated the impact of an RT boost suggest that it results in a lower rate of recurrences and as a result, a lower rate of subsequent mastectomies; however, there is no appreciable benefit in overall survival (OS) [18,19]. In the largest trial that included women with stage I or II breast cancer undergoing WBRT, patients were randomly assigned to an RT boost or no further treatment [19-21]. Of note, the majority of patients (95.5 percent) in this trial had negative resection margins. With 17.2-year median follow-up, among women with a negative resection margin (n = 5318), an RT boost resulted in [22]:

●A significant reduction in the local recurrence rate (9 versus 13 percent in those who did not receive a boost; HR 0.65, 95% CI 0.52-81). This proportional reduction in the risk of local recurrence was comparable in all age groups. However, the absolute magnitude of the reduction was greatest in younger women (≤50 years) with DCIS present (15 versus 31 percent among such women who did not receive a boost; HR 0.37, 95% CI 0.22-0.62) [23].

●A lower rate of mastectomy as first salvage for those with in-breast tumor recurrence (75 versus 79 percent).

●No difference in OS, breast cancer mortality, or disease-free survival (DFS) at 20 years.

●A higher rate of severe fibrosis (5.2 versus 1.8 percent).

Use of a boost has also shown improvements in local recurrence rates in DCIS. In a randomized trial in 1608 patients with non-low risk DCIS, those assigned to receive a boost to the surgical bed experienced five-year free from local recurrence rates of 97 percent versus 93 percent in the no boost group (HR 0.47, 95% CI 0.31–0.72) [24]. The boost group had higher rates of grade ≥2 breast pain (14 versus 10 percent) and induration (14 versus 6 percent). Patients in this trial had at least one of the following markers for increased local recurrence risk: younger age (<50 years), symptomatic presentation, palpable tumor, microscopic tumor size ≥15 mm, multifocal disease, intermediate or high nuclear grade, central necrosis, comedo-histology, or a radial surgical margin <10 mm.

A gene expression-based classifier assay has been shown to identify patients at particularly high risk of locoregional recurrence, who are thus more likely to benefit from tumor-bed boost, and possibly regional nodal RT [25]. However, we await prospective validation prior to routine clinical use.

Accelerated partial-breast irradiation — APBI refers to the use of limited, focused RT as a more convenient alternative to conventional WBRT for women following breast-conserving surgery. Compared with WBRT, APBI delivers a higher dose of RT per day to a limited volume of tissue, encompassing the lumpectomy bed with margin over a shorter period of time and leading to potentially fewer breast symptoms and late skin side effects [26,27]. It may be reasonable in select patients, as discussed below.

Technical aspects of APBI delivery are discussed separately. (See "Radiation therapy techniques for newly diagnosed, non-metastatic breast cancer".)

Patient selection — We agree with ASTRO, the American Society of Breast Surgeons (ASBS), and the American Brachytherapy Society (ABS) that properly selected patients who meet all of the following criteria are potential candidates for APBI (table 2) [28-30]:

●≥50 years of age

●Diagnosed with a small (≤2 cm), node-negative breast cancer

●Tumor excised to negative surgical margins (>2mm)

We caution against the use of APBI in others due to limited outcomes data, including those with any of these features:

●Multicentric breast cancer

●Evidence of pathologic involvement of lymph nodes

●Primary tumor >3 cm

●The presence of lymphovascular space invasion

●Breast cancer during pregnancy

Other features that may also make patients less than optimal candidates for APBI include women with [28-32]:

●Invasive lobular carcinoma (ILC) or grade III DCIS

●Triple-negative breast cancers

●Human epidermal growth factor receptor 2 (HER2)-positive breast cancers

●Hereditary breast cancer (BRCA1/2 mutation), especially if they are less than 50 years old

Benefits and risks — APBI offers a shorter course of treatment than WBRT (eg, five days versus several weeks) and may have similar disease outcomes, particularly among those with low-risk disease. However, trials have yielded differing results regarding acute and late toxicities and cosmesis for APBI versus WBRT [33-45].

●Cancer outcomes – In a systematic review including 15 randomized trials and six observational studies with over 17,000 patients, the differences in ipsilateral breast recurrence were not statistically significant between APBI and WBRT (4.0 versus 3.1 percent at 10 years; RR 1.29, 95% CI 0.87-1.91) [46].

The meta-analysis included several large randomized trials including the RAPID trial, the Italian intensity-modulated RT-Florence study, the GEC-ESTRO trial, the Budapest trial, and the IMPORT-LOW trial, which all demonstrated comparable breast tumor recurrence and OS rates, with equivalent or fewer late normal-tissue adverse effects [38,40-42,47-50].

However, results from one trial have suggested that although the efficacy of APBI may be similar to WBRT, it may not be equivalent. In NSABP-B39, among approximately 4200 patients who had recently received a lumpectomy and had up to three positive axillary nodes, the incidence of IBTR at 10 years after treatment was 4.6 percent among those who received APBI versus 3.9 percent among those who received WBRT, differences that were not statistically significant but did not meet the criteria for equivalence [51]. The 10-year relapse-free interval rate was worse with APBI than WBRT (91.8 versus 93.4 percent, respectively).

●Toxicities and cosmesis – Trials have shown differing results regarding toxicity cosmesis with APBI versus WBRT. As examples, in the RAPID trial, discussed above, there was less radiation dermatitis and breast swelling associated with APBI [52]. Similarly, at longer-term follow up of the IMRT-Florence and GEC-ESTRO trials of more than 10 years, APBI demonstrated less acute and late toxicity. By contrast, a separate trial (IRMA) suggested increased rates of late moderate soft tissue and bone toxicities [45].

Cosmesis was reported to be worse with APBI in the RAPID and IRMA trials compared with the IMRT-Florence and GEC-ESTRO trials, in which cosmetic outcome (as evaluated by both clinician and patient) was the same or improved compared with WBRT [44,48]. This is likely due to differing radiation doses used in the trials (eg, APBI delivered as 38.5 Gy in 10 fractions twice daily in the RAPID and IRMA trials versus 30 Gy in 5 fractions once daily with the IMRT-Florence trial).

We await full reporting of the trials discussed above, including long-term disease outcomes and subset analyses, to further refine our approach.

Indications for regional nodal irradiation

Approach — For women who are found to have pathologically positive lymph nodes at the time of breast-conserving surgery through sentinel lymph node biopsy (SLNB), there are two main decisions. The first is whether axillary dissection versus axillary RT should be performed for control of disease in the axilla. This is discussed elsewhere. (See "Overview of sentinel lymph node biopsy in breast cancer", section on 'Management after sentinel lymph node biopsy'.)

The second decision is whether regional nodal RT (to the infra- and supraclavicular nodes and internal mammary nodes) should be performed. While regional RT may reduce the risk of locoregional recurrences, the added toxicities (potential lymphedema, fibrosis, etc.) may outweigh potential benefits for patients with a lower absolute risk for recurrence. Therefore, our approach is to utilize regional RT for patients with higher-risk disease, for whom the absolute risk reduction is greater. Indications for regional RT are discussed below:

●Lymph node involvement – While experts agree that for women with more than three involved lymph nodes, regional RT should be delivered, there is some controversy in regards to patients with one to three involved lymph nodes. Our approach is to deliver regional RT to patients with one or more macroscopically involved lymph nodes based on the progression-free survival (PFS) benefits observed in the MA.20 and European Organisation for Research and Treatment of Cancer (EORTC) studies discussed below [53,54]. (See 'Involved lymph nodes' below.)

●T3 or T4 primary lesion – (See 'High-risk features of the primary tumor' below.)

●T2 lesion with other high-risk features – These include women who had fewer than 10 axillary nodes removed and whose tumors also have at least one of the following: high-grade histology, ER negativity, or lymphovascular invasion. (See 'High-risk features of the primary tumor' below.)

RT to the regional nodes includes treatment of the supraclavicular and infraclavicular nodes. We also typically include RT to the axilla, with exceptions sometimes made for patients who underwent complete axillary dissection. In such women, axillary bed RT has been associated with lymphedema in approximately 25 percent of cases [55]. Additionally, we generally include the internal mammary nodes, although an individualized approach is necessary. (See 'RT of internal mammary nodes' below.)

In a meta-analysis, absolute improvements in breast cancer recurrence and mortality from regional node radiotherapy in eight trials from the 1990s to 2000s were greatest for patients at highest risk for recurrence: the absolute reductions in 15-year breast cancer mortality were 1 to 2 percent among those with no positive axillary lymph nodes, 2 to 3 percent among those with one to three positive nodes, and 4 to 5 percent for those with four or more positive nodes [56]. However, no mortality benefits were observed in eight older trials evaluating regional node radiotherapy from the 1960s to 1970s. The difference may be due to refinement in radiation techniques over time.

There is observational evidence that patients with node-positive, hormone receptor-positive, HER2-negative breast cancer and intermediate or high recurrence score (RS) on the Oncotype DX test experience higher rates of locoregional recurrence than those with lower scores (ten-year locoregional recurrence rates of 17 versus 10 percent for those with RS ≥18 versus <18, in one study [57]). Too few events were included to address the predictive role of RS for RT. However, in a separate study, RS was not found to be predictive of benefit from RT, suggesting that other genetic signatures may be necessary to identify those most likely to benefit from RT [25]. In the setting of evolving data, we continue to offer regional nodal RT to those with any positive lymph nodes, given the observed PFS benefits, unless future randomized trials demonstrate that it is safe to omit it. We await results from the ongoing TAILOR RT trial, which uses RS for randomization to regional nodal RT to further inform our approach.

Involved lymph nodes — For women who have had breast-conserving therapy and have any number of macroscopically involved lymph nodes, we suggest addition of RT to the regional nodes to standard WBRT. RT to the regional nodes typically includes treatment of the supraclavicular and infraclavicular nodes, and, if axillary dissection has not been performed, also to the axilla. For women with extensive involvement of the lymph nodes (eg, extensive extracapsular extension or axillary tissue involvement [58]; or large number of involved lymph nodes [sometimes considered as >50 percent of the dissected lymph nodes]), we offer axillary RT even if lymph node dissection has been performed. Approach to patients with micrometastatic disease in the lymph nodes is discussed elsewhere. (See 'Exception for micrometastatic nodal disease' below.)

Support for locoregional RT in women with involved lymph nodes comes from the National Cancer Institute of Cancer Clinical Trials Group (NCIC-CTG) MA.20 and EORTC 22922 trials. Both of these trials show decreased risk of recurrence, although OS is not improved [53,54].

●In the NCIC-CTG MA.20 trial, over 1800 women who had undergone breast-conserving therapy (approximately 90 percent of whom had node-positive disease) were randomly assigned to receive regional RT or not in addition to WBRT [54]. The addition of regional RT resulted in:

•Improvement in 10-year DFS compared with WBRT alone (82 versus 77 percent, respectively; HR 0.76, 95% CI 0.61-0.94)

•No improvement in 10-year OS compared with WBRT alone (82.8 versus 81.8 percent; HR 0.91, 95% CI 0.72-1.13)

●In a similar trial coordinated by the EORTC (EORTC 22922/10925), approximately 4000 women (over half of whom had node-positive disease and the rest of whom had central or medial tumors and node-negative disease) underwent WBRT and were randomly assigned to additional regional RT to the internal mammary and medial supraclavicular nodes (IM-MS) or not [53]. At a median follow-up of 10.9 years, the addition of RT to the IM-MS nodes resulted in:

•Significantly improved breast cancer mortality rate compared with no additional treatment (12.5 versus 14.4 percent; HR 0.82, 95% CI 0.7-0.97)

•A trend toward improved OS (82.3 versus 80.7 percent; HR 0.87, 95% CI 0.76-1.00)

•An improved DFS (72 versus 69 percent; HR 0.89, 95% CI 0.80-1.00, p = 0.04)

Locoregional RT did increase the risk of adverse events, including pneumonitis, lymphedema, and pulmonary fibrosis [53,54]. Reporting of results at longer follow-up (median, 15.7 years) suggests no statistically significant overall, disease-free, or distant-metastases-free survival benefit with IM-MS RT, but breast cancer mortality was reduced (19.8 versus 16.0 percent; 95% CI 0.70-0.94), as was the probability of breast cancer recurrence within the first 15 years (27.1 versus 24.5 percent; 95% CI 0.77-0.98 percent) [59]. (See "Clinical features and diagnosis of peripheral lymphedema", section on 'Radiation therapy' and "Clinical staging and conservative management of peripheral lymphedema" and "Overview of long-term complications of therapy in breast cancer survivors and patterns of relapse" and "Radiation-induced lung injury".)

While there is agreement regarding regional RT for patients with more than three macroscopically involved lymph nodes, some controversy exists for patients with one to three involved lymph nodes because of some studies that suggest excellent outcomes in these patients without RT [60,61]. However, for this population, we generally recommend locoregional RT in order to maximize the opportunity to reduce the risk of recurrence and potentially improve disease-specific survival. In the MA.20 trial, 85 percent of the approximately 1800 women in the overall study had one to three positive nodes (all of whom underwent breast-conserving therapy). The EORTC study included more women overall (approximately 4000), but only 43 percent had one to three positive nodes (and only 76 percent of the entire group received breast-conserving therapy). In these studies, among women with one to three positive nodes, there were nonsignificant trends toward improved OS and DFS with the additional RT [53,54].

Exception for micrometastatic nodal disease — For women with micrometastatic disease to one to two lymph nodes, we do not add regional RT in the absence of other high-risk features (irrespective of whether the lymph nodes were removed via sentinel or axillary nodal dissection). However, regional RT may be added in patients with micrometastatic lymph node disease if other high-risk features are present. (See 'High-risk features of the primary tumor' below.)

Typical WBRT fields cover a large portion of the axilla, and as such, are likely to provide adequate treatment for most women with micrometastatic disease in the absence of other high-risk features. Trials have suggested that minimal involvement of the sentinel lymph node may be managed appropriately following SLNB with WBRT alone and any indicated systemic treatments [60,62]. While these studies examined axillary lymph node dissection (ALND), not regional RT, as the intervention for managing minimally involved axillary lymph nodes, they are relevant because patients who did not receive ALND had excellent outcomes with WBRT alone following their SLN dissection.

●In the IBCSG 23-01 trial, over 900 patients who initially presented with a breast cancer tumor ≤5 cm in size and clinically non-palpable axillary nodes were randomly assigned to a completion or no further axillary surgery [62,63]. Over 90 percent of patients received breast-conserving surgery as their surgical treatment. Eligibility included patients with one or more sentinel nodes harboring micrometastatic tumor deposits (≤2 mm) only; patients with macrometastatic axillary node involvement were not included. With a median follow-up of five years, locoregional recurrences were 2 to 3 percent in both arms. Additionally, at a median follow-up of 9.7 years, there were no differences in DFS, axillary recurrence rates, or OS [63]. Median number of nodes with micrometastatic involvement in the trial was one.

●In the ACOSOG Z0011 trial, approximately 900 women with no apparent nodal disease on clinical exam but with positive nodes on SLNB (up to two positive sentinel nodes) were randomly assigned to undergo a full axillary node dissection or no further surgery. Per protocol, all patients were to be treated with WBRT with standard tangent fields, and regional RT was not allowed [60,61]. Locoregional recurrence-free survival at five years was 97 percent (95% CI, 95-99 percent) in the SLNB-alone group and 96 percent (95% CI, 94-98 percent) in the ALND group. Further analyses suggested that incidental axillary irradiation with standard whole-breast tangential fields may have played an important role in ensuring the good outcomes observed among patients assigned to WBRT alone, although the trial has been criticized because up to one-fifth of patients may also have received regional nodal irradiation despite the study protocol [64]. A further limitation is that the trial was closed prematurely for slow accrual.

Together, these data support our approach of utilizing WBRT without additional dedicated regional RT for patients with micrometastatic nodal disease.

High-risk features of the primary tumor — Given the results of the EORTC and MA.20 trials discussed above, both of which included subsets of node-negative patients, our approach is to offer regional RT in addition to WBRT to women with high-risk, node-negative disease [53,54]. In accordance with the MA.20 entry criteria, we include in this category women with T3 or T4 disease, as well as those with T2 tumors who have undergone limited axillary dissection (<10 lymph nodes) and also have other risk factors, including high-grade histology, ER negativity, or lymphovascular invasion [54]. RT to the regional nodes includes treatment of the supraclavicular and infraclavicular nodes and, if axillary dissection has not been performed, also to the axilla. Additionally, we generally include the internal mammary nodes, although an individualized approach is necessary. (See 'RT of internal mammary nodes' below.)

In both of these trials, there were trends towards improved DFS with regional RT among patients with node-negative disease. In the EORTC study, among almost 1800 patients with node-negative disease (treated with either mastectomy or breast conservation therapy), the DFS in patients receiving regional RT was 76 percent versus 72 percent in patients not receiving regional RT (HR 0.85, 95% CI 0.70-1.02) [53]. In MA.20, among 177 patients with high-risk, node-negative disease treated with breast-conserving therapy, 10-year DFS was 84 percent among those receiving regional RT in addition to WBRT versus 72 percent among those receiving WBRT alone (HR 0.55, 95% CI 0.28-1.09) [54].

Additional considerations

Patients who received neoadjuvant therapy — For patients who receive neoadjuvant therapy and proceed with breast-conserving surgery, we give postoperative WBRT regardless of response to treatment. Our approach for patients with residual nodal disease and for those who presented with stage III disease (regardless of response) is to treat the regional nodes. This approach is based on retrospective data suggesting these patients are at a higher risk for locoregional recurrence [65]. For patients presenting with stage II disease who have a complete response to therapy, we adopt an individualized approach regarding the radiation of the regional nodes, weighing risk factors of the presenting tumor. Although some prospective observational data suggest that de-escalation of radiotherapy would be possible in this subgroup [66], we await reporting of the NSABP B-51 trial to further inform our approach (NCT01872975).

Possible omission of RT for select ER-positive, HER2-negative cancers

Those >65 years with small, node-negative cancers — It may be a reasonable option to avoid RT in selected older women with estrogen receptor (ER)-positive, HER2-negative breast cancer [67-72]. Specifically, this includes women aged 65 years or older with clinically node-negative, small (T size <3 cm) breast cancer who are willing to initiate and continue the prescribed course of adjuvant endocrine therapy. Nevertheless, many older patients may prefer to do radiation to minimize their risk of local recurrence, particularly if they are good candidates for APBI or are uncertain whether they can tolerate adjuvant endocrine therapy or are not willing to receive hormonal therapy for five years [73]. We also recognize that chronologic age may differ from "biological age," and that some women who are older than 65 with good baseline health may have a higher likelihood of benefit from RT than a younger patient with significant comorbidities. (See 'Patient selection' above.)

The option to omit RT in patients with ER-positive, node-negative, small breast cancers is supported by a 2014 meta-analysis that included five trials of mostly postmenopausal women, all of whom received systemic therapy (the majority of whom received tamoxifen) [74]. Most women had T1, node-negative tumors and were older than 65 years, with 39 percent aged 70 years or older. At five years, RT resulted in:

●A lower absolute risk of locoregional recurrence compared with no RT (2.2 versus 6.5 percent, respectively). This corresponded to a number needed to treat of 24 to prevent one recurrence.

●No difference in the absolute risk of a distant recurrence (2.7 versus 2.3 percent) or death from all causes (7.7 percent in both study arms).

As an example of one of the trials included in the meta-analysis, among over 600 women age ≥70 years with clinical stage I, ER-positive breast cancer, the addition of RT to tamoxifen decreased locoregional recurrences at 10 years (2 versus 10 percent, with and without RT), but resulted in similar OS [70]. Similarly, a subsequent randomized trial, the PRIME 2 study, confirmed a reduction in recurrence rate with RT that did not translate into a survival benefit [2,75]. In this study, approximately 1300 women age ≥65 years with node-negative breast cancers <3 cm were randomly assigned to RT versus no RT. After a median follow-up of 9.1 years, the 10-year rate of local breast cancer recurrence was lower in women assigned to RT (0.9 versus 9.5 percent; HR 10.4, 95% CI 4.1-26.1) [75]. No differences in OS, regional recurrence, distant metastases, contralateral breast cancers, or new breast cancers were noted between the two groups.

The impact of adjuvant RT on the need for a subsequent mastectomy for recurrence in women older than 70 years is not clear, as data are conflicting. One study suggested that the rate of subsequent mastectomy was not significantly different with or without RT (4 versus 2 percent, respectively) [70], but in another study, adjuvant RT resulted in a lower risk (3 versus 6 percent; HR 0.33, 95% CI 0.22-0.48). In both studies, as has been observed in other trials, OS was similar, despite higher rates of locoregional failure [76].

Thus, while RT may reduce breast cancer recurrences, some older adult women with small, node-negative, hormone receptor-positive tumors may opt to avoid RT given a lack of overall survival benefit. Other factors to consider, in addition to patient age and size of tumor, include high tumor grade, lymphovascular invasion, or low intensity of ER expression, all of which increase the rates of local failure and may make RT more desirable. Ultimately, the decision to omit RT should take into account potential comorbidities and tumor features that could affect long-term survival. Patients should understand that without RT, the rate of in-breast recurrence may be higher over time and the rate of requiring subsequent mastectomy may be higher. Moreover, compliance with endocrine therapy is a critical aspect of treatment, particularly for those in whom RT was omitted. Given these considerations, older adult patients with hormone receptor-positive cancers should be referred to a radiation oncologist to discuss the pros and cons of endocrine therapy alone versus endocrine therapy plus RT. If RT is preferred, more tolerable courses of RT, including partial breast irradiation or hypofractionated schedules, may be an appropriate option. (See 'Conventional versus hypofractionated schedules' above and 'Accelerated partial-breast irradiation' above.)

Investigational omission in other settings — Trials are investigating whether some patients at low risk for local recurrence may safely omit radiation.

●One trial has suggested that omission of radiation in patients ≥55 years of age with small, luminal breast cancers may be possible, although this is not standard practice. The LUMINA trial [NCT01791829] included 500 females ≥55 years with T1N0, grade 1 or 2, luminal A-breast cancer treated with breast-conserving surgery and endocrine therapy alone (no radiation), the incidence of local recurrence at five years was low (2.3 percent) [77]. Breast cancer occurred in the contralateral breast at a comparable rate of 1.9 percent. Recurrence of any type occurred in 2.7 percent. In this trial, luminal A was defined as ER ≥1 percent and progesterone receptor >20 percent, negative HER2, and Ki67 ≤13.25 percent.

●Separately, a prospective study found that patients ≥50 years with non-triple negative cT1N0 breast cancer that was unifocal on preoperative magnetic resonance imaging, and pT1N0 or N1mi at the time of surgery, could safely omit adjuvant radiation and experience a low ipsilateral invasive recurrence rate (1 percent at five years) [78]. Further data and longer follow-up are needed.

●Ongoing clinical trials (eg, the IDEA [NCT02400190], and PRECISION [NCT02653755] trials) are evaluating whether genetic assays such as the Oncotype recurrence score or PAM50 risk of recurrence score may identify other women in whom RT may be omitted without meaningfully increasing the risk of recurrence. Trials are also underway comparing adjuvant APBI versus aromatase inhibitors in older patients [79].

Although these data are provocative, they are preliminary and should not be incorporated into routine clinical care.

Caution with intraoperative RT — Ongoing research is aimed at exploring other modalities of RT that will minimize toxicities without reducing effectiveness. An example of this is intraoperative RT (IORT), which condenses the entire therapeutic dose into a single fraction, permitting surgery and RT to be completed in one day. At this time, however, in accordance with guidelines by ASTRO, we suggest that use of IORT be limited to a clinical trial or a registry because the available data suggest an association with a higher risk of IBTR. For patients in whom the duration of therapy required for standard WBRT is a concern, hypofractionated WBRT or APBI in one-week schedules are a viable option. (See 'Conventional versus hypofractionated schedules' above.)

Two trials, the TARGIT-A and ELIOT trials, suggest that IORT is associated with an increased risk of IBTR compared with WBRT (absolute increase of approximately 4 percent at five years, 7 percent at 10 years, and 10 percent at 15 years) [80-82]. In women with high-risk breast cancers (eg, grade 3, ER-negative, or triple-negative), the absolute increased risk was on the order of 15 to 20 percent. Although at longer follow-up of the TARGIT-A trial, the local recurrence rate at 10 years was not significantly different between the arms (HR 1.13, 95% CI 0.91-1.41), it was unexpectedly high (approximately 20 percent in each arm) [83]. Mastectomy-free survival, distant DFS, OS, and breast cancer mortality were also similar between the groups [84].

PATIENTS TREATED WITH MASTECTOMY — Postmastectomy RT (PMRT) has two potential benefits: a decrease in the rate of locoregional recurrence, and an increase in long-term breast cancer-specific and overall survivals for certain patient populations. These benefits have been consistently reported in multiple studies [85-87]. Decisions on who should receive PMRT depend on the baseline risk for recurrence.

PMRT fields — In our practice, we deliver postmastectomy RT (PMRT) to both the chest wall and to the regional nodes. These include the supraclavicular and infraclavicular nodes. We also include RT to the axilla except in some patients who underwent complete axillary dissection. Additionally, we generally include the internal mammary nodes, although an individualized approach is necessary. (See 'RT of internal mammary nodes' below.)

For women who undergo a complete axillary dissection, we typically administer RT to a more limited field (ie, omitting a full axillary field and instead radiating the level III axilla only and the supraclavicular/infraclavicular regions, with or without internal mammary nodes). This approach is taken to limit the risk of subsequent lymphedema, which in one series approached 40 percent following axillary RT, but may be reduced by limiting the regional RT fields [55,88-90]. However, as in the case of women being treated with breast-conserving therapy, if high-risk features are present, we administer level I and II axillary RT even if an axillary dissection was performed. Examples of high-risk features include extensive extracapsular extension, large number of involved lymph nodes (sometimes considered as >50 percent of the dissected lymph nodes), perinodal fat invasion, or foci of invasive cancer invading the axillary fat. (See "Radiation therapy techniques for newly diagnosed, non-metastatic breast cancer", section on 'Regional node RT'.)

PMRT is typically administered using a conventional treatment schedule. Although in one trial of women with high-risk breast cancer, a hypofractionated PMRT schedule demonstrated non-inferior outcomes and similar toxicities as conventional fractionated radiotherapy, more study is required before such an approach becomes standard practice [91]. In particular, additional studies are needed to more fully evaluate both the efficacy and toxicity of hypofractionation for PMRT in the setting of immediate reconstruction (with or without an implant or tissue expander).

Indications for patients who did not receive neoadjuvant therapy

Involved lymph nodes — Node-positive disease is associated with a higher risk of recurrence. In general, we favor PMRT for women with positive lymph nodes. The magnitude of the benefit and the strength of the recommendation depends upon the number of nodes involved. For women with more than three involved lymph nodes, we administer PMRT to the chest wall and regional nodes. PMRT is the subject of some debate when there are one to three involved axillary lymph nodes (N1 disease). We generally proceed with PMRT for these women in order to maximize the opportunity to reduce the risk of recurrence and potentially improve disease-specific survival. However, given that the absolute magnitude of benefit derived depends on the baseline risk of locoregional failure, we recommend an individualized approach taking into account patient preference and high-risk features, in accordance with society guidelines [92].

Rationale for this approach comes from the 2005 Early Breast Cancer Trialists' Collaborative Group (EBCTCG) meta-analysis, which included 8500 patients with mastectomy, axillary dissection, and node-positive disease enrolled in trials of radiotherapy (generally to the chest wall and regional lymph nodes) versus no radiotherapy [85]. For women with node-positive disease, PMRT resulted in improved breast cancer-specific survival (54.7 versus 60.1 percent with no RT) and reduced local recurrence at 15 years (7.8 versus 29 percent with no RT).

While the 2005 EBCTCG meta-analysis discussed above supports PMRT for node-positive disease, detailed results for women with one to three involved nodes were not provided [85]. Data in support of PMRT for these patients come from a 2014 EBCTCG meta-analysis of trials between 1964 and 1986 [93]. This analysis included approximately 1300 women with one to three involved lymph nodes receiving mastectomy and axillary dissection, and demonstrated that radiotherapy to the chest wall and regional nodes reduced locoregional recurrence (3.8 versus 20.3 percent), overall recurrence (34 versus 45.7 percent; rate ratio [RR] 0.68, 95% CI 0.57-0.82), and breast cancer mortality (42 versus 50 percent; RR 0.80, 95% CI 0.67-0.95). However, these data must be cautiously interpreted, as they were taken from trials where either no systemic therapy was given or less than contemporary systemic regimens were used. Therefore, the outcomes were worse in the control groups compared with what are currently observed. Additional data come from the European Organisation for Research and Treatment of Cancer (EORTC) 22922/10925 trial discussed above, which included almost 1000 patients who had undergone a mastectomy, the majority of whom had fewer than four involved lymph nodes [53], as well as the British Columbia series, in which PMRT improved breast cancer-free survival among premenopausal women with node-positive disease, regardless of whether they had four (RR 0.59, 95% CI 0.38-0.91) or one to three involved nodes (RR 0.64, 0.42- 0.97) [87].

Retrospective data suggest that among patients with one to three involved lymph nodes, there may be some who are less likely to benefit from PMRT. An observational study from the National Cancer Database (NCDB) and the Surveillance, Epidemiology, and End Results (SEER) program, which included over 90,000 patients who underwent mastectomy for tumors smaller than 5 centimeters with one to three involved lymph nodes, suggested that PMRT improved mortality among patients with three involved lymph nodes, as well as those with two involved lymph nodes and a primary tumor larger than 2 cm (hazard ratio [HR] 0.86, 95% CI 0.81-0.91). No beneficial effect was observed in patients with one involved lymph node, or in those with two involved lymph nodes and a primary tumor smaller than 2 cm [94]. In the absence of prospective data to confirm these observations, however, we continue to treat patients with N1 disease with PMRT, regardless of whether they have one or more involved lymph nodes.

Observational data suggest that patients with node-positive, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative breast cancer and intermediate or high recurrence scores (RS) on the Oncotype Dx assay (≥18) have higher rates of local recurrence than those with lower scores (<18), even among patients who undergo mastectomy [57]. Too few events were included to address the predictive role of RS for RT. However, in a separate study, RS was not found to be predictive of benefit from RT, suggesting that other genetic signatures may be necessary to identify those most likely to benefit from RT [25]. In the setting of evolving data, we continue to offer regional nodal RT to those with positive lymph nodes, given the observed survival benefits, unless future randomized trials demonstrate that it is safe to omit it. We await results from the ongoing TAILOR RT trial, which uses RS for randomization to postmastectomy RT (or regional nodal RT, for those who underwent breast-conserving therapy), to further inform our approach.

Exception for micrometastatic nodal disease — Data are limited in regards to PMRT for micrometastatic disease to the lymph nodes. We typically approach micrometastatic disease to the lymph nodes similarly to node-negative disease, with RT decisions based on the presence of other high-risk features. (See 'Other high-risk features' below.)

Other high-risk features — For most women who have node-negative disease, adjuvant PMRT is not indicated. However, some exceptions exist. We suggest PMRT (to the chest wall and regional nodes) for those with node-negative disease and the following tumor features:

●T4 disease.

●Select cases of positive margins at mastectomy with other poor prognostic features (eg, age ≤50 years, T2 or higher primary lesions, triple-negative histology, high grade, or lymphovascular invasion [95]).

●Select cases of T2 and T3 disease with other poor prognostic features (eg, age ≤50 years, triple-negative histology, high grade, or lymphovascular invasion) [86,96,97].

The Danish Breast Cancer Cooperative Group (DBCG) 82 b and c trials addressed the question of whether PMRT (including the axillary, supra/infraclavicular, and ipsilateral internal mammary nodes) improved breast cancer outcomes in pre- and postmenopausal patients, respectively [86,96,97]. These studies included node-positive as well as high-risk, node-negative disease (defined as tumors that were >5 cm or invaded the skin or fascia) and demonstrated improved disease-free and overall survival (OS) associated with RT among women treated with RT after mastectomy [96,97]. It should be noted that the number of patients with node-negative disease was small in these studies (approximately 130 women in each Danish study).

Studies have evaluated which patients with node-negative disease are most likely to benefit from PMRT. As an example, in a meta-analysis of 5 trials enrolling almost 9000 patients with tumors 5 cm or larger, treated with mastectomy and without PMRT, the 10-year locoregional failure rate was 10 percent (of which about three-quarters were isolated locoregional failures) [98]. This low rate of locoregional failure argues that not all patients with larger tumors need PMRT, though the predictive features to identify which patients should receive it are not clearly understood.

Separately, in an observational study of approximately 94 women with T1-T2, N0 breast cancers with positive margins after mastectomies, higher relapse rates among those who had not received PMRT were associated with age ≤50 years, T2 tumor size, and grade III disease, but not among those who had received it [95].

The limited data that exist for PMRT in triple-negative disease suggest a benefit to treatment; however, these data require independent confirmation before PMRT is uniformly administered to women with triple-negative breast cancer who lack other high-risk features. In a randomized trial of 681 women with triple-negative breast cancer treated with mastectomy (82 percent node-negative) and adjuvant chemotherapy with or without PMRT, at a median follow-up of 86 months, women who received postmastectomy chest wall RT had significantly better five-year relapse-free survival (88 versus 75 percent) and OS (90 versus 79 percent) compared with those who received chemotherapy alone [99].

Indications for patients who received neoadjuvant therapy — We treat patients with any degree of residual macroscopic nodal disease after neoadjuvant chemotherapy with PMRT, based on retrospective evidence suggesting a higher rate of recurrence in such patients [100]. We also offer PMRT to patients with residual breast disease, though our threshold to omit treatment in such patients is lower than for patients with residual nodal disease. In the absence of prospective data to guide our approach to patients with a complete response to neoadjuvant treatment, we treat patients who presented with stage III disease with PMRT, regardless of response. For patients presenting with stage II disease, we evaluate pretreatment risk factors as well as the patient’s response to neoadjuvant therapy, with a lower threshold to omit treatment for those patients who have a complete response.

Retrospective data in women with stage III disease suggest that postoperative RT improves local control even for patients who have a pathologic complete response (pCR) to neoadjuvant chemotherapy [101-107]. As an example, in one retrospective study that included over 670 women treated with neoadjuvant chemotherapy followed by mastectomy, PMRT was associated with a significantly lower rate of locoregional recurrence at 10 years (22 versus 11 percent) and a lower risk of death from breast cancer (HR 0.5, 95% CI 0.34-0.71) [103]. Among the 46 patients who presented with stage III or IV disease and achieved a pCR with neoadjuvant chemotherapy, PMRT was associated with a reduced 10-year rate of locoregional recurrence (3 versus 33 percent among patients not receiving PMRT).

By contrast, other observational data suggest that certain lower-risk patients who achieve a pCR with neoadjuvant chemotherapy (NACT) have low rates of locoregional recurrence following mastectomy without the use of PMRT [66,108,109]. For example, a large retrospective study of 3000 women treated with mastectomy with or without PMRT found that PMRT was associated with a modest reduction in 10-year locoregional recurrence rates (10.3 versus 12.6 percent among patients who did not receive PMRT), with predictors of recurrence being clinical node involvement prior to neoadjuvant chemotherapy, residual cancer in the breast or lymph nodes after neoadjuvant therapy, and presenting tumor size >5 cm [109]. Patients lacking these features were at low risk of locoregional recurrence.

Higher-quality evidence is needed to better inform recommendations for RT after neoadjuvant therapy. To that end, two prospective trials are ongoing and will prospectively evaluate the benefit of RT in patients treated with neoadjuvant therapy (NSABP B-51/RTOG 1304 and A011202).

Risks and toxicities — In general, the toxicities of PMRT are similar to those associated with whole-breast and regional node RT. (See 'Risks and toxicities' above and "Overview of long-term complications of therapy in breast cancer survivors and patterns of relapse" and "Cardiotoxicity of radiation therapy for breast cancer and other malignancies" and "Radiation dermatitis" and "Clinical manifestations, prevention, and treatment of radiation-induced fibrosis" and "Radiation-induced lung injury".)

Considerations when RT is given after immediate reconstruction — In women undergoing immediate reconstruction of the breast for whom PMRT is indicated, placement of a temporary tissue expander at the time of mastectomy may be necessary until after adjuvant RT is completed. This is because RT can be damaging to either a permanent implant or to an autologous tissue breast reconstruction, and it is therefore preferable to delay these procedures until after RT. These issues are discussed in more detail elsewhere. (See "Overview of breast reconstruction", section on 'Integrating radiation therapy and breast reconstruction'.)

RT OF INTERNAL MAMMARY NODES — For women receiving adjuvant regional RT, either after breast-conserving surgery or with postmastectomy RT (PMRT), we generally include RT of the internal mammary nodes (IMN). However, an individualized approach is necessary that takes into account the patient's risk for IMN involvement, her anatomy, and the ability of the treating radiation oncologist to ensure that critical structures (eg, the heart) are excluded from the treatment field.

Like the axillary lymph nodes, the IMN receive lymph drainage from all quadrants of the breast, although the risk for IMN involvement is highest with medially located breast cancers. In addition, among patients who have pathologically node-negative axillary disease, up to 10 percent may harbor regional metastases to the IMN. This risk rises to almost 40 percent if patients have axillary node-positive breast cancers, especially if the primary tumor is located in the inner or central breast. (See "Overview of management of the regional lymph nodes in breast cancer", section on 'Internal mammary lymph nodes'.)

However, whether the IMNs should be included in the RT field is controversial, as data are limited and conflicting. However, the sum of the data suggests a benefit of IMNRT in patients with a high risk of recurrence, and it is therefore our approach to include the IMNs in our adjuvant RT fields.

●A prospective, observational, cohort study evaluated IMNRT in over 3000 women, approximately one-half of whom received IMNRT after surgery (breast-conserving surgery or mastectomy, with axillary dissection for either case). Patients with right-sided disease were allocated to IMNRT, whereas patients with left-sided disease were assigned to no IMNRT because of the risk of RT-induced heart disease. At a median follow-up of 14.8 years, IMNRT was associated with improved 15-year overall survival (OS) rates (60 versus 55 percent), decreased breast cancer mortality (32 versus 34 percent), and decreased risk of distant metastasis (36 versus 39 percent; HR 0.88, 95% CI 0.79-0.99) [110].

●These results are supported by a previous retrospective study of almost 400 patients undergoing mastectomy (80 percent with >3 pathologic nodes involved), in which addition of IMNRT to PMRT was associated with improvement in disease-free survival and a trend towards improved OS at 10 years [111]. Additionally, the MA.20 and European Organisation for Research and Treatment of Cancer (EORTC) 22922 studies discussed above that demonstrate a benefit of regional nodal RT after breast-conserving surgery or mastectomy also lend indirect support for IMNRT, which was included as part of the standard RT field [53,54]. The improvement in locoregional control with regional RT may have been at least in part a result of the inclusion of the IMN, particularly in axillary node-positive disease. (See 'Involved lymph nodes' above.)

●By contrast, IMNRT was not associated with improved outcomes in a trial that included over 1400 women with invasive breast cancer (majority with T1 to T2 tumors) treated with a modified radical mastectomy and chest wall plus supraclavicular node RT; these women were randomly assigned to additional treatment with IMNRT or not [112]. After a median of 11 years, there was no difference in survival outcomes with or without IMNRT. However, subgroup analysis suggested that women with positive axillary nodes and inner-quadrant, central-breast tumors may benefit from IMNRT.

This study was likely underpowered to detect a difference in outcomes, particularly due to the inclusion of node-negative patients (approximately 25 percent of those who participated). In addition, the use of two-dimensional treatment planning may have underestimated the coverage to the IMNs in the control arm.

RT of internal mammary nodes is associated with greater toxicity, for example cardiotoxicity, particularly when used in conjunction with anthracyclines. These issues are discussed elsewhere. (See "Cardiotoxicity of radiation therapy for breast cancer and other malignancies", section on 'Modified RT techniques' and "Risk and prevention of anthracycline cardiotoxicity", section on 'Risk factors'.)

TIMING OF RT RELATIVE TO SYSTEMIC THERAPY — Trials have demonstrated reductions in risk of recurrence at local and distant sites in patients receiving both systemic therapy and RT compared with RT alone. Therefore, in patients who are candidates for adjuvant systemic therapy, strategies are needed to sequence systemic therapy and RT [113-115].

There are minimal data with which to inform the optimal timing of RT relative to systemic therapy [116-118]. Therefore, the sequencing of RT and systemic therapy is based on institutional standards of practice. A reasonable approach takes into account the type of systemic therapy being administered:

●For patients who have been recommended to receive adjuvant chemotherapy, RT is generally administered following the completion of chemotherapy as no study has demonstrated an advantage of delivering RT immediately after surgery. (See "Selection and administration of adjuvant chemotherapy for HER2-negative breast cancer", section on 'Timing of chemotherapy and radiation'.)

●For those patients with estrogen receptor (ER)-positive disease who have been recommended to initiate endocrine therapy, it is acceptable to initiate endocrine therapy either concomitantly with RT or following completion of RT. Our approach is to sequence endocrine therapy after RT because when administered concurrently, side effects of endocrine therapy such as joint aches and hot flashes may make it more difficult for patients to remain stationary on the treatment table during RT treatments. Data regarding survival and toxicity outcomes of the two approaches are discussed in detail elsewhere. (See "Adjuvant endocrine and targeted therapy for postmenopausal women with hormone receptor-positive breast cancer", section on 'Timing of endocrine therapy'.)

●For patients with breast cancers that overexpress the human epidermal growth factor 2 (HER2) receptor, we administer RT concomitantly with adjuvant trastuzumab and pertuzumab. This approach was utilized in clinical trials evaluating the role of trastuzumab and pertuzumab in the adjuvant setting and does not appear to result in an increased complication rate [119-121]. (See "Adjuvant systemic therapy for HER2-positive breast cancer".)

CONSIDERATIONS FOR SPECIFIC POPULATIONS

Women with a BRCA gene mutation — Women with a breast cancer susceptibility gene 1 or 2 (BRCA1 or BRCA2) mutation who undergo surgery and RT for breast cancer have been shown to have similar rates of RT-associated complications as patients without BRCA1/2 mutations. Although preclinical studies suggest that women with breast cancer and a BRCA1 or BRCA2 gene mutation might be sensitive to the toxicity of RT [122-124], this has not been demonstrated in clinical studies to date [125,126]. (See "Overview of hereditary breast and ovarian cancer syndromes".)

Women with a connective tissue autoimmune disorder — Although only few and low quality data are available, the weight of evidence suggests that women with breast cancer and systemic or discoid lupus erythematosus or scleroderma are at an increased risk for RT-related toxicities, particularly late effects [127-130]. For patients with other forms of collagen vascular disease (CVD), including rheumatoid arthritis, dermatomyositis/polymyositis, polymyalgia rheumatic/temporal arteritis, and mixed connective tissue disorders, there may also be increased risk of late effects from RT, though one study suggests that late toxicities are severe only for patients with systemic lupus erythematosus or scleroderma [128]. Patients with active CVD prior to or during RT may be at a higher risk for toxicity relative to those with controlled disease [130]. Although CVD is not an absolute contraindication to RT, decisions about RT should take into account the severity of the CVD in order to determine the relative benefits and risks of RT for the treatment of breast cancer. In particular, women with CVD should be educated regarding their increased risk for late toxicities associated with RT.

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".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Beyond the Basics topics (see "Patient education: Breast cancer guide to diagnosis and treatment (Beyond the Basics)" and "Patient education: Surgical procedures for breast cancer — Mastectomy and breast-conserving therapy (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●Introduction – The purpose of adjuvant radiation therapy (RT) is to eradicate any tumor deposits remaining following surgery. Doing so reduces risk of locoregional recurrence and improves breast cancer-specific and overall survivals. Recommendations on adjuvant RT depend on the type of surgery received, extent of disease, and other patient factors. (See 'Patients treated with breast-conserving surgery' above and 'Patients treated with mastectomy' above.)

●Women treated with breast-conserving surgery

•For most women treated with breast-conserving surgery (BCS), we recommend adjuvant RT as part of local treatment, rather than surgery alone (Grade 1B) (see 'Whole-breast RT' above):

-However, for women ≥65 years old with node-negative, hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-negative primary tumors up to 3 cm for whom endocrine therapy is planned, omission of RT may be an option, given a lack of overall survival benefit. However, women in this subset who wish to minimize the risk of recurrence may reasonably opt for RT. Therefore, women should discuss the pros and cons of RT with a radiation oncologist prior to making a decision for omission. (See 'Possible omission of RT for select ER-positive, HER2-negative cancers' above.)

-For most patients receiving radiation after BCS, we suggest whole breast radiation therapy (WBRT) (Grade 2C). However, some women with small ≤2 cm, hormone receptor-positive, node-negative tumors who are ≥50 years old may reasonably opt instead for accelerated partial-breast irradiation, given the shorter schedule and improved toxicities. (See 'Accelerated partial-breast irradiation' above.)

•For most women receiving WBRT after breast-conserving surgery, we suggest RT boost to the tumor bed to further reduce the risk of in-breast tumor recurrence (Grade 2B). Possible exceptions include patients ≥60 years old with small, low-grade, hormone receptor-positive tumors resected with negative margins. (See 'RT boost to the tumor bed' above.)

•For women who have >3 involved lymph nodes, we recommend regional nodal RT (Grade 1B). For those with 1 to 3 involved lymph nodes or high-risk primary tumors, we also suggest regional nodal RT (Grade 2B).

-Our approach to regional nodal RT includes treatment of the supraclavicular and infraclavicular nodes as well as the internal mammary nodes.

-We also include RT to the axilla except for some patients who underwent complete axillary dissection. The rationale for avoiding axillary RT in those who underwent dissection is to avoid excess toxicity. However, we do treat some women who underwent axillary dissection with axillary radiation, if there are other high-risk features (eg, extensive extracapsular extension, large number of involved lymph nodes [sometimes considered as >50 percent of the dissected lymph nodes], perinodal fat invasion, foci of invasive cancer invading the axillary fat) with axillary RT even if they have undergone axillary dissection. (See 'Indications for regional nodal irradiation' above.)

•For women lacking indications for regional nodal RT, we suggest a hypofractionated rather than conventional schedule (Grade 2B). (See 'Conventional versus hypofractionated schedules' above.)

•For patients who received neoadjuvant chemotherapy, we treat with WBRT, regardless of response. For patients with residual nodal disease and for those who presented with stage III disease (regardless of response), we additionally treat the regional nodes. For patients presenting with stage II disease who have a complete response to neoadjuvant therapy, an individualized approach toward regional nodal irradiation based on pretreatment risk factors is necessary. (See 'Patients who received neoadjuvant therapy' above.)

●Women treated with mastectomy

•For women who have >3 involved lymph nodes, we recommend regional nodal RT (Grade 1B). For those with 1 to 3 involved lymph nodes or high-risk primary tumors, we also suggest regional nodal RT (Grade 2B). (See 'Indications for patients who did not receive neoadjuvant therapy' above.)

•Among women receiving neoadjuvant therapy, we suggest postmastectomy RT (PMRT) for patients with residual nodal disease, residual breast disease, or stage III disease on presentation (Grade 2C). For patients presenting with stage II disease who have a complete response to neoadjuvant therapy, an individualized approach based on pretreatment risk factors is necessary. (See 'Indications for patients who received neoadjuvant therapy' above.)

•We deliver PMRT to both the chest wall and to the regional nodes. These include the supraclavicular and infraclavicular nodes as well as the internal mammary nodes. We also typically include RT to the axilla, except for most patients who underwent complete axillary dissection.

-However, as in the case of women being treated with breast-conserving therapy, if high-risk features are present, we administer axillary RT even if an axillary dissection was performed. Examples of high-risk features include extensive extracapsular extension, large number of involved lymph nodes (sometimes considered as >50 percent of the dissected lymph nodes), perinodal fat invasion, and foci of invasive cancer invading the axillary fat. (See 'PMRT fields' above.)

●Timing of RT

•For patients in whom adjuvant chemotherapy is indicated, RT is generally administered after its completion. For patients in whom adjuvant endocrine therapy is indicated, RT can be given concurrently or prior to its initiation. For patients in whom trastuzumab with or without pertuzumab is indicated, RT is given concurrently. (See 'Timing of RT relative to systemic therapy' above.)

ACKNOWLEDGMENTS — The editorial staff at UpToDate would like to acknowledge Lori J Pierce, MD, and Jennifer F De Los Santos, MD, who contributed to an earlier version of this topic review.