Post-Neoadjuvant Treatment Strategies for Patients with Early Breast Cancer

Abstract

Pre-surgical treatments in patients with early breast cancer allows a direct estimation of treatment efficacy, by comparing the tumor and the treatment. Patients who achieve a pathological complete response at surgery have a better prognosis, with lower risk of disease recurrence and death. Hence, clinical research efforts have been focusing on high-risk patients with residual disease at surgery, who may be "salvaged" through additional treatments administered in the post-neoadjuvant setting. In the present review, we aim to illustrate the development and advantages of the post-neoadjuvant setting, and to discuss the available strategies for patients with early breast cancer, either approved or under investigation. This review was written after literature search on main scientific databases (e.g., PubMed) and conference proceedings from major oncology conferences up to 1 August 2022. T-DM1 and capecitabine are currently approved as post-neoadjuvant treatments for patients with HER2-positive and triple-negative breast cancer, respectively, with residual disease at surgery. More recently, other treatment strategies have been approved for patients with high-risk early breast cancer, including the immune checkpoint inhibitor pembrolizumab, the PARP inhibitor olaparib and the CDK 4/6 inhibitor abemaciclib. Novel agents and treatment combinations are currently under investigation as promising post-neoadjuvant treatment strategies.

Keywords: breast cancer; pathological complete response; post-neoadjuvant treatment; residual disease.

Figure 1

Simplified representation of post-neoadjuvant treatment strategy for breast cancer patients. Patients eligible for preoperative treatment receive neoadjuvant chemotherapy. If at the time of surgery the tumor is no longer detectable in the specimen (i.e., a pathological complete response (pCR) is achieved), these patients could be potentially candidate to de-escalation treatment strategies, as pCR is associated with lower risk of disease recurrence. The potential de-escalation strategy can apply to surgery, radiotherapy, or systemic adjuvant therapy. Of note, the management of a patient with a pCR is multifactorial, and requires multidisciplinary discussion. Indeed, caution should be paid to avoid the removal of too many treatment components. In case of invasive residual disease, patients may be considered for additional post-neoadjuvant treatments, for instance with chemotherapy (i.e., capecitabine in triple-negative breast cancer) or antibody drug conjugates (i.e., T-DM1 in HER2-positive breast cancer). The evaluation of residual disease can be done using various biomarkers for risk assessment (e.g., Ki67, TILs, RCB, gene expression, and genetic alterations). Residual disease can be classified according to the Residual Cancer Burden index, that combines pathologic measurements of primary tumor (size and cellularity) and nodal metastases (number and size), and classifies the specimen in one of four classes (RCB 0, i.e., pCR, RCB I, RCB II, RCB III). A higher RCB index (i.e., RCB III) indicates a larger amount of residual disease, and it is associated with a higher risk of recurrence.Abbreviations: CDKi 4/6: cyclin-dependent kinase inhibitor; ctDNA: circulating tumor DNA; HER2, human epidermal growth factor receptor 2; HR+, hormone receptor-positive breast cancer; LVI: lymphovascular invasion; NAC: neoadjuvant chemotherapy; NGS: next-generation sequencing; PARPi: poly ADP-ribose polymerase inhibitor; pCR: pathologic complete response; RCB: residual cancer burden; RD: residual disease; TDM1: trastuzumab-emtansine; TILS: tumors-infiltrating lymphocytes.

Figure 2

Proportion of pathological complete response (pCR) after neoadjuvant therapy according to breast cancer subtypes. HR-positive/HER2-negative (HR+/HER2−) is the most prevalent subtype in breast cancer, occurring in approximately 70% of patients, followed by HER2−positive (HER2+) and TNBC subtypes (approximately 20% and 10%, respectively). Subtype-specific pCR rate are 8.3% in HR+/HER2−, 18.7% in HER2+/HR+, 38.9% in HER2+/HR− and 31.1% in TNBC (original figure based on literature data, i.e., Houssami et al., Meta-analysis of the association of breast cancer subtype and pathologic complete response to neoadjuvant chemotherapy, Eur J Cancer 2012. doi: 10.1016/j.ejca.2012.05.023) [9]. Abbreviations: HR: hormonal receptors; TNBC: triple-negative breast cancer; pCR: pathological complete response.