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Purpose of Review Inflammatory breast cancer (IBC) is a biologically aggressive subtype with a high risk for rapid local progression and early distant metastasis. We review the updated data for optimal locoregional management of IBC, including areas of active controversy. Recent Findings Advancements in tri-modality therapies have improved survival among IBC patients in recent years; however, the risk of locoregional and distant recurrence remains high, particularly in triple-negative IBC. Data to support de-escalation of surgery or radiotherapy is limited, and the recommended treatment approach for non-metastatic IBC remains preoperative systemic therapy (PST), modified radical mastectomy (MRM), and adjuvant radiotherapy in all patients. For patients with de novo metastatic disease, locoregional intervention may be appropriate. Summary Optimal locoregional management of IBC remains PST followed by MRM and adjuvant radiotherapy. With increas- ingly effective systemic therapies, research to identify a subset of patients who may benefit from de-escalation of locoregional therapies is warranted. . . Keywords Inflammatory breast cancer Locoregional therapy Inflammatory carcinoma Introduction rates of 55–71% at 2–5 years [6–12]. This success largely reflects the rapid evolution of our understanding of breast Inflammatory breast cancer (IBC) is a distinct, biologically cancer biology and subsequent treatment. While the tri- aggressive subtype of breast cancer, characterized by rapid modality treatment approach for IBC is comparable to that disease progression and a propensity for early distant metas- of locally advanced breast cancers (LABC), IBC remains a tases . While rare, it has a high mortality rate; representing unique therapeutic challenge. This report highlights key con- only 2–3% of breast cancers diagnosed annually in the USA, siderations and optimal treatment strategies for current-day IBC accounts for 8–10% of breast cancer-related deaths [1, 2]. management of this biologically distinct breast cancer Historically, the prognosis of IBC has been dismal, and at- subtype. tempts at local therapy have been futile, with early local failure in most patients and a median overall survival (OS) of only 1.2 years [3–5]. However, advances in systemic therapy, sur- gery, and radiotherapy have yielded substantial improvements Locoregional Management: Historical in clinical outcomes, with contemporary series reporting OS Perspective In the prechemotherapy era, attempts at locoregional manage- This article is part of the Topical Collection on Local-Regional ment of IBC were unsuccessful, resulting in a uniformly fatal Evaluation and Therapy outcome. In 1943, Haagenson and Stout reported outcomes of 20 cases of IBC treated with radical mastectomy alone with a * Maggie L. DiNome mean survival of 15.5 months and no patient surviving 5 years firstname.lastname@example.org . The use of radiotherapy as the sole treatment for IBC was equally ineffective with studies demonstrating early Department of Surgery, University of California Los Angeles, 10833 Le Conte Avenue, CHS 72-215, Los Angeles, CA 90095, USA locoregional recurrence (LRR), dismal survival, and a high incidence of radiation-induced complications [3, 13, 14]. Department of Radiation Oncology, University of California Los Angeles, Los Angeles, CA, USA With the introduction of adriamycin-based chemotherapy in Curr Breast Cancer Rep (2020) 12:326–335 327 the 1970s, however, 5-year OS rates were noted to increase to or re-imaging if there is a concern for progression on systemic 30–40% [15–17]. therapy, as the window for locoregional control may close Surgery and radiation, in conjunction with systemic thera- quickly [24�� ]. py, were subsequently recognized as critical components for the treatment of patients with IBC; extent and sequencing of locoregional treatment, however, continued to evolve Presentation and Diagnosis [18–20]. In a series of 308 IBC patients treated with curative intent in the era of anthracycline-based chemotherapy, local The presentation of IBC is driven by rapid evolution of skin relapse-free survival (LRFS) was improved when mastectomy erythema and breast swelling, secondary to lymphedema was performed after chemotherapy, compared to prior to che- caused by tumor emboli within dermal lymphatics . This motherapy or not at all (10-year LRFS was 62.8% vs 58.6% vs edema causes exaggeration of hair follicle pits, creating the 34.4%, respectively) . Among 178 women with IBC treat- classic “peau d’orange” (orange peel) appearance of the skin. ed with preoperative systemic therapy (PST) at MD Anderson In many cases, there is no discrete palpable mass on clinical Cancer Center from 1974 to 1993, LRR at 5 years was 16.3% breast exam, and in up to 19% of patients, there may be no in patients treated with mastectomy plus radiotherapy, com- clinical findings in the breast besides skin erythema . pared to 35.7% in patients treated with radiotherapy alone The diagnosis of IBC requires a tissue confirmation of . Patients with a partial response to PST were noted to malignant cells in an underlying associated mass in the breast benefit the most from the addition of mastectomy. parenchyma or dermal tumor cells in a punch biopsy of the Importantly, improved local control was associated with im- skin. Despite its distinct clinical behavior, a pathognomonic proved disease-free, overall, and cause-specific survival [18, molecular signature for IBC has not yet been identified [30, 21, 22]. 31]; distinguishing IBC from non-inflammatory breast cancer is based on clinical presentation. The most recent staging man- ual (AJCC 8th ed) requires diffuse erythema and edema of at Locoregional Management: Modern least 1/3 of the breast with rapid onset of symptoms over a 3- Perspective to 6-month time period or less . The time of symptom development is the key criterion differentiating IBC from International expert consensus panels and the National non-inflammatory locally advanced breast cancer (LABC) Comprehensive Cancer Network (NCCN) currently recom- that may present with secondary erythema and skin involve- mend a tri-modality treatment approach for IBC. This regimen ment. While the presence of dermal lymphatic invasion on includes PST, a modified radical mastectomy (MRM), and skin biopsy is usually present, it can be missed in up to 25% post-mastectomy radiotherapy (PMRT). If there is marginal of patients related to skip regions within the breast, and there- response or clinical progression on PST, additional systemic fore is not required for diagnosis [33, 34]. therapy and/or preoperative radiotherapy are considered, with All IBC cases are defined as cT4d regardless of the pres- further local or systemic treatment individualized to subse- ence or size of an associated breast mass, and thus, all patients quent response [23–27]. with IBC are at least stage III at diagnosis. It is important to Table 1 describes outcomes in non-metastatic IBC patients realize that 25–30% of patients will present with de novo treated with modern therapy. Five-year OS rates range from metastatic disease. Among patients without distant disease at 55 to 69% [6–10], with the worst survival noted in triple- presentation, over 80% have clinical involvement of the re- negative patients (5-year OS 44%) and the highest survival gional lymph nodes [10, 35, 36]. The relative breakdown of in HER2-positive patients treated with anti-HER2-targeted biological subtypes differs slightly from non-IBC tumors, therapy (5-year OS 74%) [10�� ]. However, LRR remains high with a greater proportion of HER2-enriched and triple- with 3- to 5-year cumulative rates ranging from 17 to 21% [6, negative tumors in IBC. In recent series, 38–39% of IBC were 8]. The use of tri-modality therapy is consistently an indepen- ER+/HER2-, 32–35% were HER2 enriched, and 25–28% dent predictor of improved survival when compared to the use were triple-negative [10, 11]. of only 1 or 2 treatment modalities [9, 28]. The involvement of multidisciplinary consultants at the time of diagnosis is crucial for optimal management, as vari- Imaging for Treatment Planning ous disciplines play a role during all stages of therapy. For example, the radiation oncologist and surgeon should examine The optimization of locoregional treatment relies on clearly the patient prior to the initiation of systemic therapy to ensure defining the extent of local, regional, and distant disease prior that all pretreatment imaging necessary for locoregional treat- to the initiation of systemic therapy. The goals of initial imag- ment planning has been performed. There should be immedi- ing are to define the extent of disease in the breast parenchyma ate re-consult with a surgeon or radiation oncologist for exam and skin, to evaluate for chest wall invasion, and to identify 328 Curr Breast Cancer Rep (2020) 12:326–335 Table 1 Locoregional recurrence and overall survival in selected IBC studies in modern cohorts of non-metastatic IBC patients treated with tri- modality therapy Study Date Database N median follow-up LRR Survival outcomes Romanoff et al. 2018 2006–2016 Retrospective; N =117 5-year cumulative LRR 17% 5-year OS 71% single Institution Median f/u 5-year isolated LRR 4.8% 5-year DRFS 63% 3.4 years Rosso et al. 2017 2007–2015 Prospective; N =114 5-year LRR 3.5% 5-year OS 69.4% single Institution Median f/u 3.6 years Warren et al. 2015 1997–2011 Retrospective; N =132 3-year cumulative LRR 5-year OS 58.1% single Institution Median f/u 3.3 years 21.3% Van Uden et al. 2019 2006–2015 Population based; N =1061 Not examined 5-year OS 55.6% Netherlands Cancer Registry Median f/u 2.4 years Kuptas et al. 2019 2010–2015 Population based; N = 4068^ Not examined 5-year OS 62.2% National Cancer Database Median f/u not provided *When possible, data represents only the subgroup analysis of stage III IBC patients in whom tri-modality therapy was completed in each study. In studies where all patients did not receive tri-modality therapy, details are noted ^19.6% of patients did not receive radiation therapy areas of regional lymph node involvement at diagnosis, as considered optional; however, recent data suggest that well as to monitor response during and after PST. PET/CT may be superior in evaluating for regional nodal Diagnostic imaging starts with bilateral mammography and involvement and can reveal distant metastases not seen by ultrasound. While data supporting the routine use of breast conventional imaging. For example, in two studies, PET/ MRI for IBC involve small, retrospective studies, it appears CT detected disease not seen on conventional cross- to be the most accurate imaging modality for detecting a pri- sectional imaging in up to 23% of patients and supported mary breast lesion and defining the extent of skin involve- changes in radiotherapy planning in 18–19% [39, 40]. ment. For example, mammography reveals an underlying Prior to treatment with locoregional therapy, re-staging breast lesion in only 68% of patients with IBC, while MRI imaging with PET/CT is preferred or at minimum a CT will detect a primary breast lesion in up to 98% (Fig. 1). chest, abdomen, and pelvis and bone scan [24�� ]. For these reasons, most experts recommend MRI at diagnosis Clinical photography is also recommended to document and after systemic therapy to assess treatment response [24�� ]. extent of skin involvement prior to initiation of systemic ther- Given the high rate of de novo metastatic disease, stag- apy. Photographs are a useful adjunct to conventional breast ing studies should be considered in all IBC cases. Current imaging in directing surgical resection and radiation treatment NCCN guidelines recommend staging for distant metasta- planning [7, 24]. Photography is especially important in cases ses to include a diagnostic CT of the chest, abdomen, and where the surgeon or treating radiation oncologist is not able pelvis and bone scan . The use of PET/CT is to examine the patient prior to chemotherapy. Fig. 1 Mammogram (a)and MRI (b) imaging on the same patient with extensive underlying non-mass enhancement measuring 10.9 × 9.8 × inflammatory left breast cancer. Only mild skin thickening is noted on 8.4 cm (AP by ML by SI) throughout superior and central breast (thick diagnostic mammogram (thin arrow), whereas MRI demonstrates arrow) with nipple retraction Curr Breast Cancer Rep (2020) 12:326–335 329 Systemic Therapy for Locoregional Control molecular aberrations and biomarkers specific to IBC to elu- cidate potential targeted therapies (i.e., targeting angiogenesis, The role of preoperative systemic therapy in locoregional tumor micro-environment, inflammation/immunity) remains management of IBC cannot be over-emphasized. an active area of research . Locoregional control is not simply a function of disease bur- den but heavily dependent on biologic subtype and response to primary systemic therapy . This finding was observed Surgery in the earliest chemotherapy trials, where 5-year LRR was 11% vs 34% vs 67% in IBC patients who experienced com- The guideline-concordant surgical management of IBC is plete, partial, or no clinical response to chemotherapy, respec- MRM, including clearance of level 1 and level 2 axillary tively . Risk of LRR and OS varies according to biologic lymph nodes. Breast mound reconstruction is considered pri- subtype, with triple-negative IBC fairing the worst, and pa- marily as a delayed procedure, occurring at least 6 months tients with HER2 overexpressing IBC having the lowest LRR after completion of PMRT [24, 27]. Wide skin resection is and highest OS [6, 9, 12]. performed at the time of mastectomy (including all skin in- The incidence of pathologic complete response (pCR) volved prior to initiation of chemotherapy) to achieve negative varies by subtype, and achieving a pCR is a significant pre- margins. Punch biopsies of the skin (taken in clinic prior to dictor of favorable OS and freedom from recurrence [9, 10, surgery or intra-operatively) may help guide resection when 12, 42]. Among 4000 non-metastatic IBC patients treated with the extent of skin involvement is not clear based on exam and PST from 2010 to 2015 in the NCDB, 20.1% achieved pCR in imaging alone. In some cases, resecting the extent of skin both the breast and axilla, including 38.8% in HER2-positive, disease will require chest wall coverage with reconstructive 19.1% in triple-negative, and 6.2% in HR+/HER2-negative techniques (i.e., skin grafting or myocutaneous flap closures), tumors [10�� ]. Patients who achieved total pCR had a 5-year with latissimus dorsi flap reconstruction being a simpler and OS of 82.9%, and absence of total pCR was the strongest therefore preferred method [7� ]. However, in rare cases where predictor of worsened survival (HR 3.23, p <0.001). the amount of skin necessary does not allow for primary clo- Achieving a pCR is associated with a low risk for LRR. In a sure of the latissimus donor site, autologous reconstruction recent series of cT4 patients treated at Memorial Sloan with an abdominal donor site may need to be considered. Kettering Cancer Center (including 117 patients with IBC), Skin-sparing mastectomy and breast-conserving therapy are 5-year LRR was 0% in patients with pCR compared to 15% currently contraindicated given the skin involvement with when pCR was not achieved [6� ]. IBC. Preoperative systemic therapy for IBC is tailored according Positive surgical margins have consistently resulted in in- to biological subtype, and largely extrapolated from studies creased LRR and have been associated with lower survival involving non-IBC patients, given the limited number of stud- . In a recent series in which negative margins were ies specifically evaluating IBC patients. The mainstay of che- achieved at surgery following tri-modality therapy, the 5- motherapy remains anthracycline- and taxane-based regi- year LRR rate was 3.5% [7� ]. This rate is considerably lower mens. Improvement in outcomes with the use of intense than the 17–21% LRR reported at 3–5 years in other modern dose-dense administration compared with conventionally series where margin status was not provided [6, 8] and sup- scheduled chemotherapy in IBC has been studied with mixed ports the continued use of aggressive surgical resection in results [43, 44]; regardless, dose-dense regimens are common- patients with IBC. ly utilized [24�� ]. For HER2-positive IBC, anti-HER2- Historically, IBC was considered a relative contraindica- directed therapies have significantly improved outcomes. In tion to breast reconstruction due to concerns about positive the NOAH study, a significant improvement in 5-year event- margins, a high risk of LRR, and poor survival outcomes. free and overall survival was identified in a subgroup analysis The NCCN recommends against immediate breast reconstruc- of HER2-positive IBC patients who received neoadjuvant and tion (IBR) for the reasons previously mentioned and the ne- adjuvant trastuzumab (5-year OS 74% vs 44%) . The cessity to proceed to PMRT without potential delay from sur- NeoSphere study demonstrated slightly higher rates of pCR gical complications. However, as outcomes from tri-modality when trastuzumab was combined with pertuzumab , treatment improve and the benefits of undergoing reconstruc- supporting dual anti-HER2-directed therapy in the neoadju- tion after mastectomy are increasingly recognized, patients vant setting. Adjuvant systemic therapies are given according with IBC can be considered for delayed reconstruction. to treatment response to PST and according to biologic sub- Chang et al. compared 59 IBC patients who underwent mostly type, including endocrine therapy for estrogen receptor- delayed autologous reconstruction to IBC patients who did positive cancer. not undergo reconstruction and demonstrated improved OS Inflammatory breast cancer behaves as a biologically dis- in the reconstructed group . The survival advantage no tinct entity from other invasive breast cancers. A search for doubt reflects a highly select patient population who did not 330 Curr Breast Cancer Rep (2020) 12:326–335 experience early recurrence and remained eligible for delayed with IBC does not negatively impact survival [49, 54–56]. reconstruction (at average 18.6 months after PMRT). Chin et al. compared 23 IBC patients who underwent mostly However, it supports the consideration of breast reconstruc- autologous reconstruction (14 in the IBR setting) to non- tion in the delayed setting for patients who respond favorably reconstructed historical controls and found no difference in to treatment. disease-free or OS . Another small, single institution study by Simpson et al. compared IBC patients who had undergone IBR, mostly with tissue expander-based reconstruction, to Controversies in Surgical Management those who had no reconstruction and found no difference in OS . A SEER-Medicare study performed by Patel et al. With advances in chemotherapy and targeted therapies, rates found that among 1472 patients who underwent mastectomy of pCR are increasing in patients, especially in those with for IBC between 1991 and 2009, 3% had IBR, and IBR was HER2-positive disease. A valid consideration is whether less not associated with an increased risk of breast cancer-specific aggressive breast surgery or less invasive axillary staging pro- mortality, even after accounting for competing risk of death cedures can be considered in these patients who achieve an from other causes [56�� ]. While supportive, these studies are excellent response to PST. However, currently, insufficient limited by small numbers and an implicit selection bias. data exists to support a tailored surgical approach for patients Beyond oncologic concerns, the feasibility of IBR in IBC with IBC. Herein, we review the limited data available on the is limited by practical concerns. Given the diffuse skin in- controversial use of breast conservation surgery (BCS), IBR, volvement, it is typically necessary to resect a significant por- and sentinel lymph node biopsy (SLNB) in IBC. tion of the skin, which precludes immediate non-autologous reconstruction. Additionally, even if IBR is considered in se- Safety of Breast Conservation Surgery lect patients, autologous reconstruction would be preferred to replace volume and skin and to better withstand the impact of Some groups are considering the use of BCS for IBC. In a PMRT [49, 57–59]. Lastly, the aforementioned Simpson consensus panel statement by the UK Inflammatory Breast study demonstrated that IBC patients who undergo IBR expe- Cancer Working Group, the use of BCS is considered accept- rience significantly more post-operative complications than able if clear margins are obtained. However, this recommen- those who undergo delayed or no reconstruction; however, dation is given in the absence of data to support the safety of these complications did not significantly delay receipt of BCS in IBC . PMRT . Their findings are supported by data from the Indeed, studies evaluating the use of BCS in IBC are ret- non-IBC population where IBR does modestly increase time rospective and have small sample sizes and inherent selection from surgery to receipt of chemotherapy but not receipt of biases [51–53]. Brzezinska et al. reviewed 35 IBC patients PMRT [60� ] and does not appear to be clinically relevant. treated with BCS between 1999 and 2013, reporting a 5-year OS and locoregional recurrence-free survival of 70.3% and 87.5%, respectively, with a median follow-up of 37 months Considerations in Surgical Management of the Axilla . Importantly, all patients presented with a localized mass, which is a rare presentation of IBC; additionally, the high OS A recent study of 3471 IBC patients treated with tri-modality in a pre-HER2-targeted therapy study period is incongruent therapy in the NCDB between 2010 and 2014 found that more with historical controls. Both findings caution extrapolation of extensive axillary surgery (> 10 nodes removed vs < 10) for these study results to IBC patients with classic presentation. cN2-3 disease was associated with improved survival. Using the SEER database, Chen et al. evaluated 3374 women However, no survival advantage was noted with extent of with non-metastatic IBC and found similar 5-year breast axillary surgery for patients who presented with less nodal cancer-specific survival rates in patients treated with BCS disease (cN1 or cN0) [61�� ]. These results, coupled with the compared to those treated with mastectomy . A higher increasing ability to achieve an axillary pCR in up to 35% of OS in BCS patients suggests implicit selection bias. patients [61, 62], compel the consideration of less axillary Additionally, only 4.4% of the population received BCS in surgery in a subset of IBC patients with clinically low nodal this study, and thus, without propensity score matching or disease and/or an excellent response to PST. competing risk analysis, this study is unlikely to represent a Several recent prospective trials have evaluated the feasi- valid comparison of the groups based on the type of surgery. bility and safety of SLNB alone for patients undergoing sur- gery after PST in both cN0 patients and cN1 patients who Safety of Immediate Breast Reconstruction achieve clinical axillary downstaging prior to surgery [63–65]. However, IBC patients were actively excluded from A few single-institution studies and a SEER-Medicare data- these trials, and thus, results cannot be extrapolated for use in base study have suggested that performing IBR for patients IBC patients. Curr Breast Cancer Rep (2020) 12:326–335 331 Indeed, trials evaluating use of SLNB in IBC have been once-daily radiotherapy has shown similar toxicity and local discouraging. While two prospective series have reported suc- control outcomes in the appropriate settings [71� ]. Bolus is cessful mapping in up to 75–80% of IBC patients, the staging typically used throughout the radiotherapy treatment to max- accuracy was unacceptable with false-negative rates of 18–30% imize the dose to the skin. [66, 67]. In a more recent prospective series by DeSynder et al. including 16 IBC patients undergoing dual-tracer SLN map- Preoperative Radiotherapy ping, a SLN was not identified in 75% of patients [68�� ]. Among the four patients who did successfully map, 3 patients Preoperative radiotherapy is recommended when a patient re- had achieved pCR in the axilla, perhaps suggesting a future role mains inoperable after PST. Patients may not be candidates for for SLNB in a rare subset of IBC patients. However, additional surgical resection due to the extent of their residual breast/skin studies and/or more reliable mapping techniques are necessary, disease or nodal disease that may involve sensitive areas like and until then, ALND remains standard of care for all IBC the brachial plexus. Situations like these would benefit from patients regardless of treatment response. disease reduction with radiotherapy prior to surgery to maxi- mize chances for negative margins. Radiosensitizing chemo- therapy, such as capecitabine, may also be administered con- Radiotherapy currently to improve resectability . Radiotherapy Field Selection and Design Re-Irradiation PMRT is routinely recommended in virtually all IBC settings, The recommendation for or against re-irradiation should be given the high risk for LRR even in those patients who made in the context of the clinical situation, balancing the high achieve a pCR after PST . Following an MRM, adjuvant risk for LRR in the setting of IBC with the potential morbid- PMRT fields include the chest wall and all regional lymph ities of re-irradiation. Patients with a prior radiotherapy course node basins, including the ipsilateral axillary, infraclavicular, completed over a year ago without significant toxicity from supraclavicular, and internal mammary lymph nodes. their initial treatment can be considered acceptable candidates The mastectomy flaps are included in their entirety, as is for re-irradiation. the scar, typically spanning from the mid-sternum to the mid- A similar dosing strategy is recommended, with an accept- axillary line. The scar may extend to the contralateral breast, able cumulative total dose to the chest wall up to 110 Gy . for which the radiotherapy field coverage should extend as If the regional lymph nodes had been treated previously in the well. The chest wall volume may be more extensive depend- initial radiotherapy course, then typically, they would not be ing on the amount of skin involvement, and a careful exami- re-treated, especially given the high risk for brachial nation of the skin is important for adequate radiotherapy plan- plexopathy. However, even with previous nodal-directed irra- ning and delivery. A radiotherapy boost volume is adminis- diation, isolated gross nodal disease that remains after surgery tered to the chest wall to encompass the scar and high-risk may be targeted in a more focal manner. Re-irradiation fields areas, including areas with a positive margin, or residual are typically limited to high-risk areas in the setting of breast skin/nodal involvement. cancer recurrence, but in IBC, this high-risk area remains quite large and is similar to, or even larger than, a typical post- Radiotherapy Dose and Schedule mastectomy chest wall field. Hyperthermia may be utilized concurrently with radiotherapy to improve locoregional con- Various radiotherapy regimens have been described for the trol in the setting of re-irradiation . treatment of IBC, including the use of twice-daily radiothera- py , dose-escalated radiotherapy , and the use of a tissue-equivalent bolus for increasing skin coverage . A Locoregional Management in De Novo common regimen used at our institution is once-daily radio- Metastatic Disease therapy using conventional fractionation (1.8–2 Gy per frac- tion) up to 60 Gy to the chest wall and areas with residual An area of controversy in the management of breast cancer is gross nodal disease. This dose is typically escalated to 66 Gy, the utilization of locoregional treatment in patients presenting especially for younger patients, those with close or positive with de novo distant metastatic disease, given the negative re- margins, or those with a poor response to chemotherapy . sults of a randomized trial incorporating locoregional treatment While dose escalation to 66 Gy has been typically studied in or omission in this setting [75, 76]. 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