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Primary chemotherapy in breast cancer poses a dilemma with regard to adjuvant locoregional radiotherapy, as guidelines for locoregional radiotherapy were originally based on pathology results of primary surgery. We aimed to evaluate the oncological safety of de-escalated locoregional radiotherapy in patients with cT1–2N1 breast cancer treated with primary chemotherapy, according to a predefined, consensus-based study guideline. In this prospective registry study (RAPCHEM, BOOG 2010–03), patients referred to one of 17 participating radiation oncology centres in the Netherlands between Jan 1, 2011, and Jan 1, 2015, with cT1–2N1 breast cancer (one to three suspicious nodes on imaging before primary chemotherapy, of which at least one had been pathologically confirmed), and who were treated with primary chemotherapy and surgery of the breast and axilla were included in the study. The study guideline comprised three risk groups for locoregional recurrence, with corresponding locoregional radiotherapy recommendations: no chest wall radiotherapy and no regional radiotherapy in the low-risk group, only local radiotherapy in the intermediate-risk group, and locoregional radiotherapy in the high-risk group. Radiotherapy consisted of a biologically equivalent dose of 25 fractions of 2 Gy, with or without a boost. During the study period, the generally applied radiotherapy technique in the Netherlands was forward-planned or inverse-planned intensity modulated radiotherapy. 5-year follow-up was assessed, taking into account adherence to the study guideline, with locoregional recurrence rate as primary endpoint. We hypothesised that 5-year locoregional recurrence rate would be less than 4% (upper-limit 95% CI 7·8%). This study was registered at ClinicalTrials.gov, NCT01279304, and is completed. 838 patients were eligible for 5-year follow-up analyses: 291 in the low-risk group, 370 in the intermediate-risk group, and 177 in the high-risk group. The 5-year locoregional recurrence rate in all patients was 2·2% (95% CI 1·4–3·4). The 5-year locoregional recurrence rate was 2·1% (0·9–4·3) in the low-risk group, 2·2% (1·0–4·1) in the intermediate-risk group, and 2·3% (0·8–5·5) in the high-risk group. If the study guideline was followed, the locoregional recurrence rate was 2·3% (0·8–5·3) for the low-risk group, 1·0% (0·2–3·4) for the intermediate-risk group, and 1·4% (0·3–4·5) for the high-risk group. In this study, the 5-year locoregional recurrence rate was less than 4%, which supports our hypothesis that it is oncologically safe to de-escalate locoregional radiotherapy based on locoregional recurrence risk, in selected patients with cT1–2N1 breast cancer treated with primary chemotherapy, according to this predefined, consensus-based study guideline. Dutch Cancer Society. For the Dutch translation of the abstract see Supplementary Materials section.

BackgroundTargeted axillary dissection (TAD) involves locating and removing both clipped nodes and sentinel nodes for assessment of the axillary response to neoadjuvant chemotherapy (NAC) by clinically node-positive breast cancer patients. Initial reports described radioactive seeds used for localization, which makes the technique difficult to implement in some settings. This trial was performed to determine whether magnetic seeds can be used to locate clipped axillary lymph nodes for removal.MethodsThis prospective registry trial enrolled patients who had biopsy-proven node-positive disease with a clip placed in the node and treatment with NAC. A magnetic seed was placed under ultrasound guidance in the clipped node after NAC. All the patients underwent TAD.ResultsMagnetic seeds were placed in 50 patients by 17 breast radiologists. All the patients had successful seed placement at the first attempt (mean time for localization was 6.1 min; range 1–30 min). The final position of the magnetic seed was within the node (n = 44, 88%), in the cortex (n = 3, 6%), less than 3 mm from the node (n = 2, 4%), or by the clip when the node could not be adequately visualized (n = 1, 2%). The magnetic seed was retrieved at surgery from all the patients. In 49 (98%) of the 50 cases, the clip and magnetic seed were retrieved from the same node. Surgeons rated the transcutaneous and intraoperative localization as easy for 43 (86%) of the 50 cases. No device-related adverse events occurred.ConclusionsLocalization and selective removal of clipped nodes can be accomplished safely and effectively using magnetic seeds.

Purpose In breast cancer, neoadjuvant chemotherapy (NAC) can downstage the nodal status, and can even result in a pathological complete response, which is associated with improved prognosis. This study aimed to determine the prognostic effect of nodal status before and after NAC. Methods Women with breast cancer treated with NAC were selected from the Netherlands Cancer Registry if diagnosed between 2005 and 2019, and classified based on nodal status before NAC: node-negative (cN0), or node-positive based on fine needle aspiration cytology or core needle biopsy (cN+). Subgroups were based on nodal status after NAC: absence (ypN0) or presence (ypN+) of nodal disease. Five-year overall survival (OS) was assessed with Kaplan–Meier survival analyses, also per breast cancer molecular subtype. To adjust for potential confounders, multivariable analyses were performed. Results A total of 6,580 patients were included in the cN0 group, and 11,878 in the cN+ group. The 5-year OS of the cN0ypN0-subgroup was statistically significant better than that of the cN+ypN0-subgroup (94.4% versus 90.1%, p  < 0.0001). In cN0 as well as cN+ disease, ypN+ had a statistically significant worse 5-year OS compared to ypN0. For hormone receptor (HR)+ human epidermal growth factor receptor 2 (HER2)−, HR+ HER2+, HR-HER2+, and triple negative disease, respectively, 5-year OS in the cN0ypN+-subgroup was 89.7%, 90.4%, 73.7%, and 53.6%, and in the cN+ypN+-subgroup 84.7%, 83.2%, 61.4%, and 48.8%. In multivariable analyses, cN+ and ypN+ disease were both associated with worse OS. Conclusion This study suggests that both cN-status and ypN-status, and molecular subtype should be considered to further improve prognostication.

BackgroundThe ACOSOG-Z0011- and the AMAROS-trial obviated the need for axillary surgery in most sentinel node-positive (SLN+) breast cancer patients undergoing breast-conserving surgery (BCS). Data for patients who undergo mastectomy is scarce. The purpose of this study was to investigate patterns of axillary treatment in SLN+ patients treated by mastectomy in the years after the publication of landmark studies regarding axillary treatment in SLN+ breast cancer patients undergoing BCS.MethodsThis was a population-based study in cT1-3N0M0 breast cancer patients treated by mastectomy and staged as SLN+ between 2009 and 2018. The performance of an axillary lymph node dissection (ALND) and/or administration of postmastectomy radiotherapy (PMRT) were primary outcomes and were studied over time.ResultsThe study included 10,633 patients. The frequency of ALND performance decreased from 78% in 2009 to 10% in 2018, whereas PMRT increased from 4 to 49% (P < 0.001). In ≥N1a patients, ALND performance decreased from 93 to 20%, whereas PMRT increased to 70% (P < 0.001). In N1mi and N0itc patients, ALND was abandoned during the study period, whereas PMRT increased to 38% and 13% respectively (P < 0.001), respectively. Age, tumor subtype, N-stage, and hospital type affected the likelihood that patients underwent ALND.ConclusionsIn this study in SLN+ breast cancer patients undergoing mastectomy, use of ALND decreased drastically over time. By the end of 2018 most ≥N1a patients received PMRT as the only adjuvant axillary treatment, whereas the majority of N1mi and N0itc patients received no additional treatment.

PurposeThe extended role of breast-conserving surgery (BCS) in the neoadjuvant setting may raise concerns on the oncologic safety of BCS compared to mastectomy. This study compared long-term outcomes after neoadjuvant chemotherapy (NAC) between patients treated with BCS and mastectomy.MethodsAll breast cancer patients treated with NAC from 2008 until 2017 at the Amphia Hospital (the Netherlands) were included. Disease-free and overall survival were compared between BCS and mastectomy with survival functions. Multivariable Cox proportional hazard regression was performed to determine prognostic variables for disease-free survival.Results561 of 612 patients treated with NAC were eligible: 362 (64.5%) with BCS and 199 (35.5%) with mastectomy. Median follow-up was 6.8 years (0.9–11.9). Mastectomy patients had larger tumours and more frequently node-positive or lobular cancer. Unadjusted five-year disease-free survival was 90.9% for BCS versus 82.9% for mastectomy (p = .004). Unadjusted five-year overall survival was 95.3% and 85.9% (p < .001), respectively. In multivariable analysis, clinical T4 (cT4) (HR 3.336, 95% CI 1.214–9.165, p = .019) and triple negative disease (HR 5.946, 95% CI 2.703–13.081, p < .001) were negative predictors and pathologic complete response of the breast (HR 0.467, 95% CI 0.238–0.918, p = .027) and axilla (HR 0.332, 95% CI 0.193–0.572, p = .001) were positive predictors for disease-free survival. Mastectomy versus BCS was not a significant predictor for disease-free survival when adjusted for the former variables (unadjusted HR 2.13 (95%CI: 1.4–3.24), adjusted HR 1.31 (95%CI: 0.81–2.13)). In the BCS group, disease-free and overall survival did not differ significantly between cT1, cT2 or cT3 tumours.ConclusionBCS does not impair disease-free and overall survival in patients treated with NAC. Tumour biology and treatment response are significant prognostic indicators.

Marshall Horwitz, Charles Mullighan, Kenneth Offit and colleagues report the identification of a recurrent germline PAX5 mutation in families with pre–B cell acute lymphoblastic leukemia. They also identify sporadic cases of this leukemia with the same mutation that arose somatically. Somatic alterations of the lymphoid transcription factor gene PAX5 (also known as BSAP ) are a hallmark of B cell precursor acute lymphoblastic leukemia (B-ALL) 1 , 2 , 3 , but inherited mutations of PAX5 have not previously been described. Here we report a new heterozygous germline variant, c.547G>A (p.Gly183Ser), affecting the octapeptide domain of PAX5 that was found to segregate with disease in two unrelated kindreds with autosomal dominant B-ALL. Leukemic cells from all affected individuals in both families exhibited 9p deletion, with loss of heterozygosity and retention of the mutant PAX5 allele at 9p13. Two additional sporadic ALL cases with 9p loss harbored somatic PAX5 substitutions affecting Gly183. Functional and gene expression analysis of the PAX5 mutation demonstrated that it had significantly reduced transcriptional activity. These data extend the role of PAX5 alterations in the pathogenesis of pre-B cell ALL and implicate PAX5 in a new syndrome of susceptibility to pre-B cell neoplasia.