High-dose alkylating chemotherapy in BRCA-altered triple-negative breast cancer:the randomized phase III NeoTN trial

Exploratory analyses of high-dose alkylating chemotherapy trials have suggested that BRCA1 or BRCA2-pathway altered (BRCA-altered) breast cancer might be particularly sensitive to this type of treatment. In this study, patients with BRCA-altered tumors who had received three initial courses of dose-dense doxorubicin and cyclophosphamide (ddAC), were randomized between a fourth ddAC course followed by high-dose carboplatin-thiotepa-cyclophosphamide or conventional chemotherapy (initially ddAC only or ddAC-capecitabine/decetaxel [CD] depending on MRI response, after amendment ddAC-carboplatin/paclitaxel [CP] for everyone). The primary endpoint was the neoadjuvant response index (NRI). Secondary endpoints included recurrence-free survival (RFS) and overall survival (OS). In total, 122 patients were randomized. No difference in NRI-score distribution (p = 0.41) was found. A statistically non-significant RFS difference was found (HR 0.54; 95% CI 0.23–1.25; p = 0.15). Exploratory RFS analyses showed benefit in stage III (n = 35; HR 0.16; 95% CI 0.03–0.75), but not stage II (n = 86; HR 1.00; 95% CI 0.30–3.30) patients. For stage III, 4-year RFS was 46% (95% CI 24–87%), 71% (95% CI 48–100%) and 88% (95% CI 74–100%), for ddAC/ddAC-CD, ddAC-CP and high-dose chemotherapy, respectively. No significant differences were found between high-dose and conventional chemotherapy in stage II-III, triple-negative, BRCA-altered breast cancer patients. Further research is needed to establish if there are patients with stage III, triple negative BRCA-altered breast cancer for whom outcomes can be improved with high-dose alkylating chemotherapy or whether the current standard neoadjuvant therapy including carboplatin and an immune checkpoint inhibitor is sufficient. Trial Registration: NCT01057069

De-Escalating Axillary Surgery in Node-Positive Breast Cancer Treated with Neoadjuvant Systemic Therapy

Background: There is a trend towards de-escalating axillary staging and treatment in breast cancer patients. On account of neoadjuvant systemic therapy, node-positive breast cancer patients can achieve a pathological complete response of the axilla. It is hypothesized that these patients do not benefit from an axillary lymph node dissection (ALND), and thus may be spared the risk of severe post-surgical morbidity. In an effort to omit standard ALND, less invasive axillary staging procedures are being implemented to establish response-guided treatment. However, it is unclear which less invasive staging procedure is most accurate, and long-term data are missing with regard to their oncologic safety. Summary: This article provides an overview of the literature on currently used less invasive axillary staging procedures, the accuracy and feasibility of these procedures in clinical practice, important issues concerning axillary treatment, and issues to be addressed in ongoing or future studies. Key messages: More evidence is needed regarding the safety of replacing standard ALND by less invasive axillary staging procedures in terms of long-term prognosis. These less invasive staging procedures not only serve to select patients who may benefit from treatment de-escalation, but also to select patients who may benefit from treatment escalation

MINImal vs. MAXimal Invasive Axillary Staging and Treatment After Neoadjuvant Systemic Therapy in Node Positive Breast Cancer: Protocol of a Dutch Multicenter Registry Study (MINIMAX)

In node positive breast cancer patients who are treated with neoadjuvant systemic therapy, axillary staging and treatment is still a topic of debate. This multicenter study will contribute to evidence-based guidelines with regard to the oncologic safety and impact on quality of life of less vs. more invasive axillary staging and treatment strategies.Background: Node positive breast cancer (cN+) patients with an axillary pathologic complete response after neoadjuvant systemic therapy (NST) are not expected to benefit from axillary lymph node dissection (ALND). Therefore, less invasive axillary staging procedures have been introduced to establish response-guided treatment. However, evidence is lacking with regard to their oncologic safety and impact on quality of life (QoL). We hypothesize that if response-guided treatment is given, less invasive staging procedures are non-inferior to standard ALND in terms of oncologic safety, and superior to standard ALND in terms of QoL. Patients and Methods: MINIMAX is a Dutch multicenter registry study that includes patients with cN1-3M0 unilateral invasive breast cancer, who receive NST, followed by axillary staging and treatment according to local protocols. In a retrospective registry of +/- 4000 patients, the primar y endpoint is oncologic safety at 5 and 10 years (disease-free, breast-cancer-specific and overall survival, and axillary recurrence rate). In a prospective multicenter registry, the primar y endpoints are QoL at 1 and 5 years, and we aim to verify the 5-year oncologic safety. With an estimated 5-year disease-free survival of 72.5% and anticipated loss to follow-up of 10%, a sample size of 549 is needed to have 80% power to detect non-infer iority (with a 10% margin) of less invasive staging procedures. Conclusion: In cN+ patients treated with NST, less invasive axillary staging procedures are already implemented globally. Evidence is needed to support the assumed oncologic safety and superior QoL of such procedures. This study will contribute to evidence-based guidelines. (C) 2021 The Authors. Published by Elsevier Inc

De-ESCAlating RadioTherapy in breast cancer patients with pathologic complete response to neoadjuvant systemic therapy: DESCARTES study

PurposeNeoadjuvant systemic therapy (NST) is increasingly used in breast cancer patients and depending on subtype, 10-89% of patients will attain pathologic complete response (pCR). In patients with pCR, risk of local recurrence (LR) after breast conserving therapy is low. Although adjuvant radiotherapy after breast conserving surgery (BCS) reduces LR further in these patients, it may not contribute to overall survival. However, radiotherapy may cause early and late toxicity. The aim of this study is to show that omission of adjuvant radiotherapy in patients with a pCR after NST will result in acceptable low LR rates and good quality of life.MethodsThe DESCARTES study is a prospective, multicenter, single arm study. Radiotherapy will be omitted in cT1-2N0 patients (all subtypes) who achieve a pCR of the breast and lymph nodes after NST followed by BCS plus sentinel node procedure. A pCR is defined as ypT0N0 (i.e. no residual tumor cells detected). Primary endpoint is the 5-year LR rate, which is expected to be 4% and deemed acceptable if less than 6%. In total, 595 patients are needed to achieve a power of 80% (one-side alpha of 0.05). Secondary outcomes include quality of life, Cancer Worry Scale, disease specific and overall survival. Projected accrual is five years.ConclusionThis study bridges the knowledge gap regarding LR rates when adjuvant radiotherapy is omitted in cT1-2N0 patients achieving pCR after NST. If the results are positive, radiotherapy may be safely omitted in selected breast cancer patients with a pCR after NST.Trial registration: This study is registered at ClinicalTrials.gov on June 13th 2022 (NCT05416164). Protocol version 5.1 (15-03-2022)