Abstract SP058: Exceptional responders to neoadjuvant chemotherapy - Pro
Authors: Heil J 
Published: February 2021

Abstract
Increasing use of neoadjuvant systemic treatment (NST) and improved efficacy of treatment regimens have led to increasing numbers of patients without any detectable residual cancer upon surgery (pathologic complete response, pCR, ypT0, ypN0). For these exceptional responders to NST, invasive surgery may cause more harm than benefit and thus should be tailored to this response.
For nodal disease, axillary lymph node dissection (ALND) used to be the standard of care for all patients but ALND causes relevant morbidity (i.g. lymphedema, pain, restricted mobility). Sentinel lymph node biopsy (SLNB) causes less morbidity but its use for patients receiving NST has been controversial. Based on rates of missed cancer (false-negative rate, FNR) compared to ALND, several current national guidelines recommend use of SLNB for patients undergoing NST with initial nodal negative disease (FNR about 7%; Shirzadi et al 2019, J Res Med Sci) and use of targeted axillary dissection (TAD; removal of clipped nodes plus SLNB) for patients with initial nodal positive disease converting to nodal negative disease after NST (FNR about 2%; Caudle et al 2016, J Clin Onc). However, while already implemented in clinical practice recurrence and survival data are still lacking for SLNB/TAD after NST.
For the primary tumor in the breast, breast conserving surgery (BCS) is the current standard of care. The use of NST instead of adjuvant treatment has allowed for more patients to be treated with BCS instead of mastectomy with equal survival (EBCTCG 2018, Lancet Onc). Although BCS is a low morbidity procedure compared to other oncologic surgeries, also BCS causes morbidity relevant to patients: (1) About 30% of patients undergoing BCS and SLNB report moderate, persistent pain two years after surgery (Gärtner et al 2009, JAMA); (2) the reduction in patient-reported quality of life up to 8 years after surgery is comparable between patients undergoing BCS or mastectomy (Flanagan et al 2019, Ann Surg Onc). In the light of increasing ypT0 rates, current research evaluates alternative diagnostic procedures than BCS to identify these exceptional responders to NST who achieve ypT0. Imaging (ultrasound, mammography, MRI, PET-CT) is insufficiently accurate to reliably exclude residual disease (FNR about 20% for US and mammography) and/ or specificity is suboptimal (MRI, PET-CT) (Fowler et al 2017, Radiology). Vacuum-assisted biopsies (VAB) showed promising results in some pilot trials (FNR about 5%; Heil et al 2016, Eur J Cancer and Kuerer et al 2018, Ann Surg) which could however not be confirmed in larger multicenter trials (FNR about 18%; Heil, Pfob et al 2020, Ann Surg). Recent exploratory analyses using machine learning algorithms to combine VAB with patient and tumor data could decrease the FNR to ~3% while maintaining good specificity (Pfob et al 2020, ASCO meeting). However, we do not know yet to which extend these FNR would influence local recurrence or survival rates when omitting breast surgery for these exceptional responders to NST.
In summary, several less invasive and therefore less morbidity causing procedures are currently evaluated to identify exceptional responders to NST to spare them surgery-associated morbidity in the axilla and breast. TAD to identify ypN0 patients showed an FNR &lt;2% in prospective trials and survival outcome analyses in these cohorts are underway. VAB combined with patient and tumor data to identify ypT0 patients showed promising results (FNR around 3%) in exploratory analyses but needs further prospective validation before trials with oncological endpoints should be considered. The topic is worth to be studied further to decrease potentially unnecessary treatment burden for patients, providers, and health care systems.
Citation Format: J Heil. Exceptional responders to neoadjuvant chemotherapy - Pro [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr SP058.