A new paradigm for classifying and treating HER2‐positive breast cancer

Abstract Background Because of the phenomenal success of treatment with monoclonal antibodies and antibody‐drug conjugates targeting human epidermal growth factor receptor 2 (HER2), most patients with early‐stage HER2‐positive breast cancer (HER2+ BC) and some with limited metastatic diseases have been cured, and those who have not been cured have achieved significant improvements in overall survival, which has weakened the role of the TNM staging system in the prognosis of HER2+ BC today. Given that the disease is now highly curable, treatment conception, classification, and modalities should differ from those of cancer types with a poor prognosis. It is warranted to build a new paradigm for classifying and treating HER2+ BC. Recent findings In our personal view, we suggest that the classification system should be based not only on traditional anatomy and cancer biology but also on available treatment regimens, their exceptional outcomes, and their toxicities. In this regard, we developed a new concise classification of HER2+ BC based on the TNM staging system, a review of the literature, research results, and our clinical experience, dividing the patients into four distinct groups: curable (lymph‐node negative and small (≤3 cm) early breast cancer), do our best to cure (locally advanced or tumors >3 cm early breast cancer), hope for cure (local‐regional recurrent, limited metastases, and exceptional responders), and incurable (metastatic breast cancer with poor performance status or non‐exceptional responders). Conclusion It will assist clinicians in developing an optimal treatment regimen at the outset, curing more HER2+ BC patients and improving their quality of life.

cured have achieved considerable and long-lasting improvement in quality of life and overall survival. 2,5 Furthermore, patients with HER2+ limited metastatic (less extensive / small-volume burden of metastatic disease) or extensive loco-regional recurrent disease, or who had metastatic disease but were exceptional responders (achieving a long-lasting complete response), had a cure rate of more than 30%. 6,7 The 8th American Joint Commission of Cancer (AJCC) for breast cancer staging system added genomic assays, HER2, hormone receptors, and histologic grade to the classic TNM staging system, to define the prognostic stage grouping. 8 However, the successful development of HER2 targeted therapies has weakened the weight of tumor size and axillary lymph node involvement on the prognosis of HER2+ breast cancer in recent years. For example, integration of HER2 targeted monoclonal antibodies, antibody-drug conjugates, and cytotoxic drugs has significantly improved prognosis for patients with HER2+ breast cancer regardless of initial tumor size and lymph node involvement. 9 In selected solid tumors (e.g., colorectal cancer and non-small-cell lung cancer), current AJCC staging criteria takes into account location and extent of distant metastatic disease to provide more accurate prognostic estimates. 8 This is not the case in metastatic breast cancer, despite wide variations in progression-free survival rates and overall survival rates across metastatic cancer patients with different subgroups. 10 This is an area of increasing clinical relevance, particularly in metastatic HER2+ breast cancer where the overall survival rates have improved dramatically over the past two decades. 5 Because early-stage HER2+ breast cancer is highly curable with available therapeutic modalities, 2,5,7,11 the staging (or more accurately, classification) and treatment planning should differ from those cancer types with poor prognosis (e.g., pancreatic cancer, triple-negative breast cancer). We believe it is necessary to develop a new paradigm to define distinct prognostic subgroups, establish goals of treatment for individual patients and improve the cure rate for HER2+ breast cancer overall.

| CLASSIFICATION AND TREATMENT OF HER2+ BREAST CANCER
The classification system that we propose is based not only on traditional anatomy, clinical characteristics, and cancer biology, but also on available treatment regimens and outcomes (e.g., long-term complete response, high cure rate), toxicities, and tolerability. In this regard, we offer an update of the recommended current practices for classifying and treating HER2+ breast cancer and associated impediments ( Figure 1).
We propose a new classification of HER2+ breast cancer that takes into account clinical, pathological and therapeutic considerations. In our opinion, HER2+ breast cancer be categorized into four distinct groups: A. Early breast cancer with small (≤3 cm) tumors and no lymph node involvement (Group A). Approximately 60% of patients with breast cancer belong to this group, 2 and the cure rate is more than 95%. 11 Standard adjuvant systemic therapy includes de-escalation approaches (e.g., 12 cycles of weekly paclitaxel plus 1 year of trastuzumab) that limit the risk of late toxicities in long-term survivors. 11,12 For those with large (size >20 mm) or moderate-sized (20 mm ≥ size≥8 mm) hormone receptor-negative breast cancer in this group, neoadjuvant therapy may be an option. 13 Low-risk patients (e.g., grade I, strongly ER/PR-positive, low Ki-67, tumor size <8 mm) may be considered for chemotherapy-free targeted therapy trials, especially patients with homogeneous HER2 overexpression. 14 B. Early breast cancer that is locally advanced or has tumors >3 cm in Patients with hormone receptor-positive disease should receive at least 5 years of adjuvant endocrine therapy after completion of adjuvant chemotherapy. We therefore propose that these patients should be treated with curative intent with standard treatment and response-guided therapy.
C. Local-regional recurrent tumors, limited metastases, or exceptional responders to metastatic breast cancer (Group C). Although individuals with metastatic breast cancer would not be cured according to our oncologic dogma, appropriate treatments have resulted in some of these patients having no evidence of disease (NED) for long periods of time. 5,7,16 In this setting, the challenge of identifying the optimal potential curable population has emerged, including identifying populations in whom treatments that precisely target cancer-specific vulnerabilities would be possible or escalation strategies may be beneficial, while avoiding overtreatment in patients with incurable disease. In this proposal, it is suggested that patients in this group have: (1) local or regional recurrence, including contralateral axillary lymph node relapse or sternal metastases, which should be referred to as the treatment principle of locoregional recurrence; (2) de-novo, late, or early limited metastases, including solitary metastases (e.g., solitary metastases in the brain, bone, or liver) and oligometastases; or  AnnotaƟon: Cure was defined as iDFS or NED ( complete radiological response) lasƟng ≥ 10 years.
F I G U R E 1 Classification and management approach for HER2+ breast cancer. HER2+ breast cancer. In the future, this could mean less use of nontargeted chemotherapy. 19 Although immunotherapies inhibiting programmed cell death protein 1 or ligand 1 were not successful for HER2+ breast cancer patients, 20 antibody-dependent cell-mediated cytotoxicity from trastuzumab, pertuzumab, and antibody drug conjugates has played a key curative role by eliminating microscopic metastases, increasing immune surveillance, and preventing late recurrence. 21 The peptide vaccine GM2 combined with trastuzumab and novel immune-stimulating antibody drug conjugates may have potential as effective immunotherapies in the future. 22 Lastly, an immunologically active breast cancer microenvironment (e.g., expression of CD8 + tumor infiltrating lymphocytes) has a favorable prognosis for HER2+ breast cancer patients. 23 Late recurrence after early breast cancer (typically occurring more than 5 years after initial diagnosis and treatment) is a significant clinical issue, especially in hormone receptor-positive disease. 24  Circulating tumor DNA analysis can also test whether we can use minimal residual disease and exceptional responders to determine which patients can stop treatment for HER2+ breast cancer, whereas HER2-targeted antibody-conjugated nuclear probes could be used to guide anti-HER2 therapy for metastatic brain lesions. De-escalation of therapy and molecular imaging-adapted approaches may be able to reduce the risk of late toxicities that continue to plague many longterm survivors of early-stage breast cancer.
For HER2+ breast cancer patients with a high cure rate (Group A), comprehensive cancer treatment, cardiovascular complications, and comorbidity management are active areas of investigation and should be paramount clinically, as should nutrition and physical activity for survivors. 28 In breast cancer survivors, the risk for cardiovascular disease is heightened by cancer treatments (e.g., targeted therapy, chemotherapy, and radiation therapy) and modifiable factors, including diabetes, obesity, physical inactivity, poor diet, and tobacco use. 29 These risk factors for cardiovascular disease should be addressed promptly.
For example, patients with uncontrolled hypertension should avoid anthracycline usage, and type 2 diabetes patients with HER2+ breast cancer are advised to take metformin if not contraindicated. 30,31 Risk-adapted and response-guided therapy is the frontier for tailoring therapy for HER2+ breast cancer. 32 Among HER2+ early breast cancer patients who had residual invasive cancer after completion of neoadjuvant therapy, the risk of recurrence of invasive breast cancer or death was 50% lower with adjuvant trastuzumab-emtansine compared to trastuzumab alone. 15 Additionally, the response-adapted phase 2 PHERGain trial, in which patients received trastuzumab and pertuzumab using 18

PREVIOUS PRESENTATION
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