SUMMARY: Breast cancer is the most common cancer among women in the US and about 1 in 8 women (12%) will develop invasive breast cancer during their lifetime. It is estimated that approximately 300,590 new cases of breast cancer will be diagnosed in 2023 and about 43,700 individuals will die of the disease, largely due to metastatic recurrence. The HER or erbB family of receptors consist of HER1, HER2, HER3 and HER4. Approximately 15-20% of invasive breast cancers overexpress HER2/neu oncogene, which is a negative predictor of outcomes without systemic therapy. Adjuvant and neoadjuvant chemotherapy given along with anti-HER2 targeted therapy reduces the risk of disease recurrence and death, among patients with HER2-positive, early stage, as well as advanced metastatic breast cancer.
Neoadjuvant or preoperative therapy is often a component of combined-modality treatment, and facilitates the rapid assessment of new cancer therapies. In addition to increasing the likelihood of tumor resectability and breast preservation, patients achieving a pathological Complete Response (pCR) following neoadjuvant chemotherapy have a longer Event Free Survival (EFS) and Overall Survival (OS). Those who do not achieve a pathological Complete Response tend to have a poor prognosis. In a comprehensive meta analysis by Spring L., et al. (Clin Cancer Res. 2020;26:2838-2848), in the subgroup of HER2-positive patients (N= 5,711), an association between pCR and both EFS and OS could be observed. With the availability of different post-neoadjuvant treatments in the HER2-positive treatment setting, it is important and relevant to define patients with increased risk of relapse, despite the achievement of pCR.
The rationale for this study was to characterize the prognostic role of pCR (pathological Complete Response) in patients with HER2-positive early breast cancer, and whether clinical factors, such as Tumor stage, Nodal involvement, and Hormone Receptor status, had prognostic relevance in patients with HER2-positive early breast cancer, with and without pCR, following neoadjuvant systemic treatment with chemotherapy plus anti-HER2 therapy.
The present analysis included individual data from 3710 patients randomly assigned in 11 neoadjuvant trials for HER2-positive early breast cancer. The following trials were included: CHERLOB, GeparQuattro, GeparQuinto, GeparSixto, HANNAH, LAPATAX, NEOALTTO, NEOSPHERE, NOAH, NSABP B-41, and TRYPHAENA. Each of these trials had 100 or more patients enrolled, and data was available for pCR, Event Free Survival (EFS), and Overall Survival (OS) after a follow up of 3 or more years. The definition of pCR used for the current analysis was the absence of residual invasive cancer in the resected breast specimen and all sampled ipsilateral lymph nodes, but allowing for in situ cancer (ypT0/Tis ypN0). Across trials, median age was 49 years, and 56.7% of patients were diagnosed with Tumor stage cT1-2. Nodal involvement was present at diagnosis in 64.9% of patients, and 54.9% were Hormone Receptor-positive. The median follow up across trials was 61.2 months. The objective of this study was to investigate prognostic factors for EFS and OS among patients with and without pCR after neoadjuvant systemic treatment consisting of chemotherapy and anti-HER2 therapy.
Across trials, approximately 40.4% of patients had a pCR and 59.6% had residual disease after neoadjuvant therapy. A pCR occurred more often in patients with T1-2 tumors, absence of Nodal metastases, and Hormone Receptor-negative disease. Patients experiencing a pCR were at lower risk of disease recurrence or death regarding EFS (HR=0.39; P<0.001) and had a significantly better OS (HR=0.32; P<0.001).
In patients who had a pCR, clinical T stage (cT1-2 versus cT3-4) and clinical N stage (cN0 versus cN+) status were independent prognostic factors for EFS, but only clinical T stage was significantly prognostic for OS, identifying patients at higher risk of relapse despite pCR . By contrast, in patients without pCR and with residual disease, clinical T stage, clinical N stage and Hormone Receptor status were independent prognostic factors for EFS as well as OS. For patients not having a PCR, risk factors included the presence of T3-4 tumors, clinical Node Positive disease or Hormone Receptor-negative status.
The authors concluded that patients achieving pathological Complete Response have better survival outcomes than patients who do not. Nonetheless, Tumor size and Nodal status remain important poor prognostic features even after a pathologic Complete Response and adjuvant therapy in pathological Complete Response patients should not be attenuated.
Pathologic Complete Response and Individual Patient Prognosis After Neoadjuvant Chemotherapy Plus Anti–Human Epidermal Growth Factor Receptor 2 Therapy of Human Epidermal Growth Factor Receptor 2–Positive Early Breast Cancer. van Mackelenbergh MT , Loibl S , Untch M, et al., on behalf of the CTNeoBC project. J Clin Oncol 2023; 41:2998-3008
