Locally Advanced and Inflammatory Breast Cancer

Defining LABC

The definition of LABC broadly includes the following stages of the disease: tumor size (T)3 or T4 with any nodal status or any T with the nodal stage (N)2 or N3 without distant metastasis. However, T3N0 (stage IIB) is not always uniform in clinical trials and the literature. The most recent National Comprehensive Cancer Network (NCCN) guideline (version 5.2021) categorizes LABC into operable versus inoperable and mainly refers to a clinical stage III disease. As such, patients with LABC may encompass patients with a large in-breast–only disease without lymph node (LN) involvement, as well as extensive disease invading into the chest wall or metastasis to supraclavicular LNs. In addition, patients with IBC are often considered as a unique subset of LABC, although the presenting features are different in each case, and research studies have been conducted exclusively in this disease subset.

Prognosis

While the widespread use of screening mammography has shifted the stage at diagnosis to an earlier stage over the past three decades, patients with LABC may present to oncology practice due to a delay in diagnosis (described sometimes as “neglected” breast cancer in the literature) or because of the aggressive, rapidly growing nature of the disease. According to the Surveillance, Epidemiology, and End Results Program (SEER), the 5-year age-adjusted incidence rates based on staging are localized at 63%, regional 29%, distant 6%, and unknown 2%.

Patients with LABC have a worse outcome compared to patients with noninflammatory non-LABC. In the current SEER database, the staging for survival statistics is separated as localized, regional, and distant. In this case, most patients with LABC likely fall in the regional stage. According to the SEER 5-year relative survival rates from 2011 to 2017, 5-year survival rates were 99.0%, 85.8%, and 29% for localized, regional, and distant, respectively. The survival differed depending on ER/PR/HER2 status categorized based on hormone responsive (HR)-positive (ER and PR positive) and HER2-negative status. Based on the most recent SEER18 data, the 5-year relative survival rates for the regional stage were 89.9%, 65.4%, 89.4%, and 82% for HR+HER2−, HR−HER2−, HR+HER2+, and HR−HER2+, respectively.

With an improvement in therapeutic options and the use of multimodality therapy, the prognosis is improving. Historically, the incorporation of systemic chemotherapy in addition to locoregional therapy has been associated with an improved outcome. One of the key improvements in contemporary practice is the use of targeted therapies (endocrine therapy and anti-HER2 biologicals). These gains have also been strengthened by the importance of ER/PR/HER2 biomarker status in prognostication, in addition to therapy selection. The most recent AJCC 8th staging offers a prognostic staging such biomarkers. For example, a subset of the non-IBC, LABC is classified as prognostically stage I and downstaged (e.g., T3N0 HR+HER2− grade 1), while others are upstaged (e.g., triple-negative breast cancer [TNBC] T2N1 G3 as stage III), as shown in the examples in Table 57.1 .

Wang and colleagues evaluated the relevance of the new prognostic staging of LABC using the SEER 18 database. The study included 10,053 patients with LABC diagnosed as anatomic stage III (A–C) between 2010 and 2013, during a period of modern therapy implementation. Based on the new prognostic stage based on the AJCC 8th edition, 33% of stage IIIC and 44% of stage IIIA patients were prognostically “downstaged”; thus the study reported that the specific extent of disease within stage III contributed independently to prognosis for LABC.

The prognostic importance of ER status and grade has been demonstrated in the study that proposed a composite pretreatment clinical and posttreatment final pathologic stage plus ER status and grade, termed CPS + EG scoring system, for patients who underwent neoadjuvant chemotherapy (NAC). This study analyzed a database of 932 patients treated with NAC from 1997 to 2003. The study reported a 5-year disease-specific survival (DSS) for clinical and pathologic stages I to III. In this study, patients with clinical stage III had 5-year DSS of 83% (IIIA), 76% (IIIB), and 67% (IIIC). This scoring system was evaluated in a study of 8949 patients treated with anthracycline-based NAC within eight prospective clinical trials. In the unselected cohort, stage III patients had a 5-year overall survival (OS) ranging from 53% to 73% with 73% (IIIA), 70% (IIIB), and 53% (IIIC). The use of CPS-EG was thus able to identify a wider range of patients with very good and poor outcomes (scores of 0 and 6, 95% and 6% 5-year OS, respectively).

Diagnostic Workup

The radiologic workup includes the standard breast imaging with mammogram and ultrasound. The imaging assessment should include the axillary assessment with ultrasound and a biopsy of suspicious nodes. The current NCCN guideline notes that the use of breast magnetic resonance imaging (MRI) can be considered, but is not required. However, MRI may be helpful in certain cases, such as preoperative evaluation or young patients with dense breasts, even though the guidelines may differ in their recommendations.

In general, additional radiologic studies to evaluate for the presence of distant metastatic disease are often guided by the presence of symptoms. The extent of disease whole-body staging is frequently considered for LABC (especially in patients with stage III disease), even in the absence of symptoms, due to a higher likelihood of distant spread (compared to patients with stage I or II disease). Moreover, should metastatic disease be identified, the locoregional management would change drastically, so computed tomography (CT) scans of thorax, abdomen, and pelvis, bone scan, and head MRI are advised for LABC. The common radiology modalities include nuclear medicine bone scan and diagnostic CT or MRI for distant disease evaluation. PET/CT may be considered but is often listed as optional. PET/CT may be useful in providing additional information when the results from initial diagnostic imaging are equivocal or to follow disease evolution during primary systemic therapy. Some studies have suggested that PET/CT may be helpful in evaluating the extent of LN involvement, which may lead to upstaging or inform local therapy planning.

As with non-LABC, the determination of ER/PR/HER2 biomarkers is critical for treatment recommendations and prognosis. Since most patients undergo neoadjuvant systemic therapy, the timely manner in which ER/PR/HER2 biomarker testing is completed is essential in planning the initiation of therapy. Laboratory tests (such as complete blood count and comprehensive metabolic panel that includes liver function tests) are conducted in anticipation of neoadjuvant systemic therapy and also may be informative for distant metastasis staging.