MRI-guided optimisation of neoadjuvant chemotherapy duration in stage II-III HER2-positive breast cancer (TRAIN-3): a multicentre, single-arm, phase 2 study.

BACKGROUND: Patients with stage II-III HER2-positive breast cancer have good outcomes with the combination of neoadjuvant chemotherapy and HER2-targeted agents. Although increasing the number of chemotherapy cycles improves pathological complete response rates, early complete responses are common. We investigated whether the duration of chemotherapy could be tailored on the basis of radiological response. METHODS: TRAIN-3 is a single-arm, phase 2 study in 43 hospitals in the Netherlands. Patients with stage II-III HER2-positive breast cancer aged 18 years or older and a WHO performance status of 0 or 1 were enrolled. Patients received neoadjuvant chemotherapy consisting of paclitaxel (80 mg/m2 of body surface area on day 1 and 8 of each 21 day cycle), trastuzumab (loading dose on day 1 of cycle 1 of 8 mg/kg bodyweight, and then 6 mg/kg on day 1 on all subsequent cycles), and carboplatin (area under the concentration time curve 6 mg/mL per min on day 1 of each 3 week cycle) and pertuzumab (loading dose on day 1 of cycle 1 of 840 mg, and then 420 mg on day 1 of each subsequent cycle), all given intravenously. The response was monitored by breast MRI every three cycles and lymph node biopsy. Patients underwent surgery when a complete radiological response was observed or after a maximum of nine cycles of treatment. The primary endpoint was event-free survival at 3 years; however, follow-up for the primary endpoint is ongoing. Here, we present the radiological and pathological response rates (secondary endpoints) of all patients who underwent surgery and the toxicity data for all patients who received at least one cycle of treatment. Analyses were done in hormone receptor-positive and hormone receptor-negative patients separately. This trial is registered with ClinicalTrials.gov, number NCT03820063, recruitment is closed, and the follow-up for the primary endpoint is ongoing. FINDINGS: Between April 1, 2019, and May 12, 2021, 235 patients with hormone receptor-negative cancer and 232 with hormone receptor-positive cancer were enrolled. Median follow-up was 26·4 months (IQR 22·9-32·9) for patients who were hormone receptor-negative and 31·6 months (25·6-35·7) for patients who were hormone receptor-positive. Overall, the median age was 51 years (IQR 43-59). In 233 patients with hormone receptor-negative tumours, radiological complete response was seen in 84 (36%; 95% CI 30-43) patients after one to three cycles, 140 (60%; 53-66) patients after one to six cycles, and 169 (73%; 66-78) patients after one to nine cycles. In 232 patients with hormone receptor-positive tumours, radiological complete response was seen in 68 (29%; 24-36) patients after one to three cycles, 118 (51%; 44-57) patients after one to six cycles, and 138 (59%; 53-66) patients after one to nine cycles. Among patients with a radiological complete response after one to nine cycles, a pathological complete response was seen in 147 (87%; 95% CI 81-92) of 169 patients with hormone receptor-negative tumours and was seen in 73 (53%; 44-61) of 138 patients with hormone receptor-positive tumours. The most common grade 3-4 adverse events were neutropenia (175 [37%] of 467), anaemia (75 [16%]), and diarrhoea (57 [12%]). No treatment-related deaths were reported. INTERPRETATION: In our study, a third of patients with stage II-III hormone receptor-negative and HER2-positive breast cancer had a complete pathological response after only three cycles of neoadjuvant systemic therapy. A complete response on breast MRI could help identify early complete responders in patients who had hormone receptor negative tumours. An imaging-based strategy might limit the duration of chemotherapy in these patients, reduce side-effects, and maintain quality of life if confirmed by the analysis of the 3-year event-free survival primary endpoint. Better monitoring tools are needed for patients with hormone receptor-positive and HER2-positive breast cancer. FUNDING: Roche Netherlands.

Prognostic effect of nodal status before and after neoadjuvant chemotherapy in breast cancer: a Dutch population-based study.

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.

Clinical implications of non-breast cancer related findings on FDG-PET/CT scan prior to neoadjuvant chemotherapy in patients with breast cancer.

PURPOSE: Breast cancer (BC) patients undergoing FDG-PET/CT scans for neoadjuvant chemotherapy (NAC) may have additional non-BC related findings. The aim of this study is to describe the clinical implications of these findings. METHODS: We included BC patients who underwent an FDG-PET/CT scan in our institute between 2011-2020 prior to NAC. We focused on patients with an additional non-BC related finding (i.e. BC metastases were excluded) for which diagnostic work-up was performed. Information about the diagnostic work-up and the clinical consequences was retrospectively gathered. A revision of all FDG-PET/CT scans was conducted by an independent physician to assess the suspicion level of the additional findings. RESULTS: Of the 1337 patients who underwent FDG-PET/CT, 202 patients (15%) had an non-BC related additional finding for which diagnostic work-up was conducted, resulting in 318 examinations during the first year. The non-BC related findings were mostly detected in the endocrine region (26%), gastro-intestinal region (16%), or the lungs (15%). Seventeen patients (17/202: 8%, 17/1337: 1.3%) had a second primary malignancy. Only 8 patients (8/202: 4%, 8/1337: 0.6%) had a finding that was considered more prognosis-determining than their BC disease. When revising all FDG-PET/CT scans, 57 (202/57: 28%) of the patients had an additional finding categorized as low suspicious, suggesting no indication for diagnostic work-up. CONCLUSION: FDG-PET/CT scans used for dissemination imaging in BC patients detect a high number of non-BC related additional findings, often clinically irrelevant and causing a large amount of unnecessary work-up. However, in 8% of the patients undergoing diagnostic work-up for an additional finding, a second primary malignancy was detected, warranting diagnostic attention in selected patients.

Breast surgery after neoadjuvant chemotherapy in patients with lobular carcinoma: surgical and oncologic outcome.

INTRODUCTION: Breast cancer patients with invasive lobular carcinoma (ILC) have an increased risk of positive margins after surgery and often show little response to neoadjuvant chemotherapy (NAC). We aimed to investigate surgical outcomes in patients with ILC treated with NAC. METHODS: In this retrospective cohort study, all breast cancer patients with ILC treated with NAC who underwent surgery at the Netherlands Cancer Institute from 2010 to 2019 were selected. Patients with mixed type ILC in pre-NAC biopsies were excluded if the lobular component was not confirmed in the surgical specimen. Main outcomes were tumor-positive margins and re-excision rate. Associations between baseline characteristics and tumor-positive margins were assessed, as were complications, locoregional recurrence rate (LRR), recurrence-free survival (RFS), and overall survival (OS). RESULTS: We included 191 patients. After NAC, 107 (56%) patients had breast conserving surgery (BCS) and 84 (44%) patients underwent mastectomy. Tumor-positive margins were observed in 67 (35%) patients. Fifty five (51%) had BCS and 12 (14%) underwent mastectomy (p value < 0.001). Re-excision was performed in 35 (33%) patients with BCS and in 4 (5%) patients with mastectomy. Definitive surgery was mastectomy in 107 (56%) patients and BCS in 84 (44%) patients. Tumor-positive margins were associated with cT ≥ 3 status (OR 4.62, 95% CI 1.26-16.98, p value 0.021) in the BCS group. Five-year LRR (4.7%), RFS (81%), and OS (93%) were not affected by type of surgery after NAC. CONCLUSION: Although 33% of ILC breast cancer patients undergoing BCS after NAC required re-excision for positive resection margins, it is considered safe given that five-year RFS remained excellent and LRR and OS did not differ by extent of surgery.

Systematic review of targeted axillary dissection in node-positive breast cancer treated with neoadjuvant systemic therapy: variation in type of marker and timing of placement.

BACKGROUND: In node-positive (cN+) breast cancer treated with neoadjuvant systemic therapy, combining sentinel lymph node biopsy and targeted lymph node excision, that is targeted axillary dissection, increases accuracy. Targeted axillary dissection procedures differ in terms of the targeted lymph node excision technique. This systematic review aimed to provide an overview of targeted axillary dissection procedures regarding definitive marker type and timing of placement: before neoadjuvant systemic therapy (1-step procedure) or after neoadjuvant systemic therapy adjacent to a clip placed before the neoadjuvant therapy (2-step procedure). METHODS: PubMed and Embase were searched, to 4 July 2023, for RCTs, cohort studies, and case-control studies with at least 25 patients. Studies of targeted lymph node excision only (without sentinel lymph node biopsy), or where intraoperative localization of the targeted lymph node was not attempted, were excluded. For qualitative synthesis, studies were grouped by definitive marker and timing of placement. The targeted lymph node identification rate was reported. Study quality was assessed using a National Institutes of Health quality assessment tool. RESULTS: Of 277 unique records, 51 studies with a total of 4512 patients were included. Six definitive markers were identified: wire, 125I-labelled seed, 99mTc, (electro)magnetic/radiofrequency markers, black ink, and a clip. Fifteen studies evaluated one-step procedures, with the identification rate of the targeted lymph node at surgery varying from 8 of 13 to 47 of 47. Forty-one studies evaluated two-step procedures, with the identification rate of the clipped targeted lymph node on imaging after neoadjuvant systemic therapy varying from 49 to 100%, and the identification rate of the targeted lymph node at surgery from 17 of 24 to 100%. Most studies (40 of 51) were rated as being of fair quality. CONCLUSION: Various targeted axillary dissection procedures are used in clinical practice. Owing to study heterogeneity, the optimal targeted lymph node excision technique in terms of identification rate and feasibility could not be determined. Two-step procedures are at risk of not identifying the clipped targeted lymph node on imaging after neoadjuvant systemic therapy.

Joint EANM-SNMMI guideline on the role of 2-[18F]FDG PET/CT in no special type breast cancer : (endorsed by the ACR, ESSO, ESTRO, EUSOBI/ESR, and EUSOMA).

INTRODUCTION: There is much literature about the role of 2-[18F]FDG PET/CT in patients with breast cancer (BC). However, there exists no international guideline with involvement of the nuclear medicine societies about this subject. PURPOSE: To provide an organized, international, state-of-the-art, and multidisciplinary guideline, led by experts of two nuclear medicine societies (EANM and SNMMI) and representation of important societies in the field of BC (ACR, ESSO, ESTRO, EUSOBI/ESR, and EUSOMA). METHODS: Literature review and expert discussion were performed with the aim of collecting updated information regarding the role of 2-[18F]FDG PET/CT in patients with no special type (NST) BC and summarizing its indications according to scientific evidence. Recommendations were scored according to the National Institute for Health and Care Excellence (NICE) criteria. RESULTS: Quantitative PET features (SUV, MTV, TLG) are valuable prognostic parameters. In baseline staging, 2-[18F]FDG PET/CT plays a role from stage IIB through stage IV. When assessing response to therapy, 2-[18F]FDG PET/CT should be performed on certified scanners, and reported either according to PERCIST, EORTC PET, or EANM immunotherapy response criteria, as appropriate. 2-[18F]FDG PET/CT may be useful to assess early metabolic response, particularly in non-metastatic triple-negative and HER2+ tumours. 2-[18F]FDG PET/CT is useful to detect the site and extent of recurrence when conventional imaging methods are equivocal and when there is clinical and/or laboratorial suspicion of relapse. Recent developments are promising. CONCLUSION: 2-[18F]FDG PET/CT is extremely useful in BC management, as supported by extensive evidence of its utility compared to other imaging modalities in several clinical scenarios.

Clinical impact of MRI-detected additional lesions in breast cancer patients with neoadjuvant systemic therapy at the Netherlands cancer institute.

BACKGROUND: In breast cancer patients treated with neoadjuvant systemic therapy (NST), MRI is used pre- and post-NST for response monitoring. The relevance of additional MRI-detected lesions in these patients is unclear. Therefore, we aimed to assess the impact of pre-NST MRI-detected additional lesions on surgical treatment and outcome. METHODS: We retrospectively selected all early-stage breast cancer patients with MRI pre-NST at our institute from January 2010-2015. MRI-detected lesions were defined as separated from the index tumor and occult at conventional mammography and ultrasound. Outcomes were change in surgical treatment and five-year recurrence-free and overall survival. RESULTS: Overall, MRI detected additional lesions in 206 (31%) of 656 patients: in 160 patients in the ipsilateral breast and in 78 contralateral breasts, including 32 bilateral cases. Ipsilateral lesions were mostly categorized BI-RADS 5 (54 %) and contralateral lesions BI-RADS 3 (64%). Targeted ultrasound was performed in 115 (56%) patients: in 70 ipsilateral and in 64 contralateral cases. Biopsy was obtained in 44 (28% of 160) ipsilateral and 50 (64% of 78) contralateral breasts, containing tumor foci in 20 (13% of 160) and 11 (14% of 78) cases, respectively. Surgical treatment changed in 54 (26% of 206) patients: 19 (9%) had mastectomy, 24 (12%) had wider local excision and 11 (5%) underwent contralateral surgery. Five-year recurrence-free and overall survival did not differ for patients with local excision or mastectomy. CONCLUSION: Pre-NST MRI-detected additional lesions in 31% of patients, resulting in more extensive surgery in 26% of these patients, including 5% contralateral surgeries.

Immediate or delayed oncoplastic surgery after breast conserving surgery at the Netherlands Cancer Institute: a cohort study of 251 cases.

PURPOSE: Oncoplastic surgery (OPS) after breast conserving surgery is preferably performed during the same operation. Offering delayed OPS instead of mastectomy to patients with a high risk of tumor-positive margins allows breast conservation with the option of margin re-excision during OPS, without having to dismantle the reconstruction. We aimed to evaluate surgical outcomes after immediate and delayed OPS. METHODS: We included early-stage breast cancer patients who underwent OPS at the Netherlands Cancer Institute between 2016 and 2019. Patients were selected for delayed OPS after multidisciplinary consultation if the risk of tumor-positive margins with immediate OPS was considered significant (> 30%). Groups were compared on baseline characteristics and short-term surgical outcomes. RESULTS: Of 242 patients with 251 OPS, 130 (52%) OPS had neoadjuvant chemotherapy. Immediate OPS was performed in 176 (70%) cases and delayed OPS in 76 (30%). Selection for delayed OPS was associated with tumor size (OR 1.03, 95% CI 1.01-1.04), ILC (OR 2.61, 95% CI 1.10-6.20), DCIS (OR 3.45, 95% CI 1.42-8.34) and bra size (OR 0.76, 95% CI 0.62-0.94). Delayed and immediate OPS differed in tissue weight (54 vs. 67 g, p = 0.034), tissue replacement (51% vs. 26%, p < .001) and tumor-positive margins (66% vs. 18%, p < .001). Re-excision was performed in 48 (63%) delayed OPS and in 11 (6%) immediate OPS. Groups did not differ in complications (21% vs. 18%, p = 0.333). Breast conservation after immediate and delayed OPS was 98% and 93%, respectively. CONCLUSION: Performing delayed OPS in selected cases facilitated simultaneous margin re-excision without increasing complications, and resulted in an excellent breast conservation rate.

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

PURPOSE: Neoadjuvant 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. METHODS: The 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. CONCLUSION: This 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).

Changes in breast cancer treatment during the COVID-19 pandemic: a Dutch population-based study.

PURPOSE: We aimed to compare (1) treatments and time intervals between treatments of breast cancer patients diagnosed during and before the COVID-19 pandemic, and (2) the number of treatments started during and before the pandemic. METHODS: Women were selected from the Netherlands Cancer Registry. For aim one, odds ratios (OR) and 95% confidence intervals (95%CI) were calculated to compare the treatment of women diagnosed within four periods of 2020: pre-COVID (weeks 1-8), transition (weeks 9-12), lockdown (weeks 13-17), and care restart (weeks 18-26), with data from 2018/2019 as reference. Wilcoxon rank-sums test was used to compare treatment intervals, using a two-sided p-value < 0.05. For aim two, number of treatments started per week in 2020 was compared with 2018/2019. RESULTS: We selected 34,097 women for aim one. Compared to 2018/2019, neo-adjuvant chemotherapy was less likely for stage I (OR 0.24, 95%CI 0.11-0.53), stage II (OR 0.63, 95%CI 0.47-0.86), and hormone receptor+/HER2- tumors (OR 0.55, 95%CI 0.41-0.75) diagnosed during transition. Time between diagnosis and first treatment decreased for patients diagnosed during lockdown with a stage I (p < 0.01), II (p < 0.01) or III tumor (p = 0.01). We selected 30,002 women for aim two. The number of neo-adjuvant endocrine therapies and surgeries starting in week 14, 2020, increased by 339% and 18%, respectively. The number of adjuvant chemotherapies decreased by 42% in week 15 and increased by 44% in week 22. CONCLUSION: The pandemic and subsequently altered treatment recommendations affected multiple aspects of the breast cancer treatment strategy and the number of treatments started per week.

In vivo deglycosylation of recombinant glycoproteins in tobacco BY-2 cells.

Production of recombinant pharmaceutical glycoproteins has been carried out in multiple expression systems. However, N-glycosylation, which increases heterogeneity and raises safety concerns due to the presence of non-human residues, is usually not controlled. The presence and composition of N-glycans are also susceptible to affect protein stability, function and immunogenicity. To tackle these issues, we are developing glycoengineered Nicotiana tabacum Bright Yellow-2 (BY-2) cell lines through knock out and ectopic expression of genes involved in the N-glycosylation pathway. Here, we report on the generation of BY-2 cell lines producing deglycosylated proteins. To this end, endoglycosidase T was co-expressed with an immunoglobulin G or glycoprotein B of human cytomegalovirus in BY-2 cell lines producing only high mannose N-glycans. Endoglycosidase T cleaves high mannose N-glycans to generate single, asparagine-linked, N-acetylglucosamine residues. The N-glycosylation profile of the secreted antibody was determined by mass spectrometry analysis. More than 90% of the N-glycans at the conserved Asn297 site were deglycosylated. Likewise, extensive deglycosylation of glycoprotein B, which possesses 18 N-glycosylation sites, was observed. N-glycan composition of gB glycovariants was assessed by in vitro enzymatic mobility shift assay and proven to be consistent with the expected glycoforms. Comparison of IgG glycovariants by differential scanning fluorimetry revealed a significant impact of the N-glycosylation pattern on the thermal stability. Production of deglycosylated pharmaceutical proteins in BY-2 cells expands the set of glycoengineered BY-2 cell lines.

Biopsy-Guided Pathological Response Assessment in Breast Cancer is Insufficient: Additional Pathology Findings of the MICRA Trial.

BACKGROUND: Neoadjuvant systemic treatment (NST) leads to pathologic complete response (pCR) in 10-89% of breast cancer patients depending on subtype. The added value of surgery is uncertain in patients who reach pCR; however, current imaging and biopsy techniques aiming to predict pCR are not accurate enough. This study aims to quantify the residual disease remaining after NST in patients with a favorable response on MRI and residual disease missed with biopsies. METHODS: In the MICRA trial, patients with a favorable response to NST on MRI underwent ultrasound-guided post-NST 14G biopsies followed by surgery. We analyzed pathology reports of the biopsies and the surgical specimens. Primary outcome was the extent of residual invasive disease among molecular subtypes, and secondary outcome was the extent of missed residual invasive disease. RESULTS: We included 167 patients. Surgical specimen showed residual invasive disease in 69 (41%) patients. The median size of residual invasive disease was 18 mm (interquartile range [IQR] 12-30) in hormone receptor-positive (HR+)/human epidermal growth factor receptor 2-negative (HER2-) patients, 8 mm (IQR 3-15) in HR+/HER2-positive (HER2+) patients, 4 mm (IQR 2-9) in HR-negative (HR-)/HER2+ patients, and 5 mm (IQR 2-11) in triple-negative (TN) patients. Residual invasive disease was missed in all subtypes varying from 4 to 7 mm. CONCLUSION: Although the extent of residual invasive disease is small in TN and HER2+ subtypes, substantial residual invasive disease is left behind in all subtypes with 14G biopsies. This may hamper local control and limits adjuvant systemic treatment options. Therefore, surgical excision remains obligatory until accuracy of imaging and biopsy techniques improve.

Management of Benign Phyllodes Tumors: A Dutch Population-Based Retrospective Cohort Between 1989 and 2022.

BACKGROUND: Phyllodes tumors (PTs) are rare tumors of the breast. The current National Comprehensive Cancer Network (NCCN) guidelines recommend excision of benign PTs, accepting close or positive margins. Controversy about the optimal treatment for benign PTs remains, especially regarding the preferred margin width after surgical excision and the need for follow-up evaluation. METHODS: A nationwide retrospective study analyzed the Dutch population from 1989 to 2022. All patients with a diagnosis of benign PT were identified through a search in the Dutch nationwide pathology databank (Palga). Information on age, year of diagnosis, size of the primary tumor, surgical treatment, surgical margin status, and local recurrence was collected. RESULTS: The study enrolled 1908 patients with benign PT. The median age at diagnosis was 43 years (interquartile range [IQR], 34-52 years), and the median tumor size was 30 mm (IQR, 19-40 mm). Most of the patients (95%) were treated with breast-conserving surgery (BCS). The overall local recurrence rate was 6.2%, and the median time to local recurrence was 31 months (IQR, 15-61 months). Local recurrence was associated with bilaterality of the tumor (odds ratio [OR], 4.91; 95% confidence interval [CI], 2.95-28.30) and positive margin status (OR, 2.51; 95% CI 1.36-4.63). The local recurrence rate was 8.9% for the patients with positive excision margins and 4.0% for the patients with negative excision margins. Notably, for 27 patients (22.6%) who experienced a local recurrence, histologic upgrading of the recurrent tumor was reported, 7 (5.9%) of whom had recurrence as malignant lesions. CONCLUSIONS: This nationwide series of 1908 patients showed a low local recurrence rate of 6.2% for benign PT, with higher recurrence rates following positive margins.

Three-year follow-up of de-escalated axillary treatment after neoadjuvant systemic therapy in clinically node-positive breast cancer: the MARI-protocol.

PURPOSE: In clinically node-positive (cN+) breast cancer patients, evidence supporting response-guided treatment after neoadjuvant systemic therapy (NST) instead of axillary lymph node dissection (ALND) is increasing, but follow-up results are lacking. We assessed three-year axillary recurrence-free interval (aRFI) in cN+ patients with response-adjusted axillary treatment according to the 'Marking Axillary lymph nodes with Radioactive Iodine seeds' (MARI)-protocol. METHODS: We retrospectively assessed all stage II-III cytologically proven cN+ breast cancer patients who underwent the MARI-protocol between July 2014 and November 2018. Pre-NST axillary staging with FDG-PET/CT (less- or more than four suspicious axillary nodes; cALN < 4 or cALN ≥ 4) and post-NST pathological axillary response measured in the pre-NST largest tumor-positive axillary lymph node marked with an iodine seed (MARI-node; ypMARI-neg or ypMARI-pos) determined axillary treatment: no further treatment (cALN < 4, ypMARI-neg), axillary radiotherapy (ART) (cALN < 4, ypMARI-pos and cALN ≥ 4, ypMARI-neg) or ALND plus ART (cALN ≥ 4, ypMARI-pos). RESULTS: Of 272 women included, the MARI-node was tumor-negative in 56 (32%) of 174 cALN < 4 patients and 43 (44%) of 98 cALN ≥ 4 patients. According to protocol, 56 (21%) patients received no further axillary treatment, 161 (59%) received ART and 55 (20%) received ALND plus ART. Median follow-up was 3.0 years (IQR 1.9-4.1). Five patients (one no further treatment, four ART) had axillary metastases. Three-year aRFI was 98% (95% CI 96-100). The overall recurrence risk remained highest for patients with ALND (HR 4.36; 95% CI 0.95-20.04, p = 0.059). CONCLUSIONS: De-escalation of axillary treatment according to the MARI-protocol prevented ALND in 80% of cN+ patients with an excellent three-year aRFI of 98%.

Sustainable health-based soil standards for arsenic using epidemiological data and toxicokinetic/probabilistic modelling.

This study presents an alternative method to the traditional reference dose approach for the determination of health risk-based soil standards for arsenic. The model combines multimedia equations for air, soil and dietary exposure, a toxicokinetic component, a probabilistic output, a reference distribution for urine arsenic in the general population and exposure parameters values traceable in US-EPA or EFSA reference studies. The model calculates a mean inorganic As urine concentration AsU (sum of inorganic arsenic Asi and its metabolites) from environmental data and exposure parameters, which is attributed to the central value of a lognormal distribution. Risk is assessed by comparing a high percentile of the modelled distribution to the target AsU attributed to the reference value of 10 µg/gCREA (microgram As per gram of creatinine), the upper confidence interval of the 95th percentile from the AsU distribution in the French population. A soil standard value of 40 mg/kg is determined as being the arsenic concentration in soil not giving rise to more than 5% probability of having a AsU concentration above the target value of 10 µg/gCREA. Once soil As concentrations above 40 mg/kg are measured, further environmental investigations should be carried, involving an assessment of As bioaccessibility to address health risks and decide of regulatory measures in residential setting.

Breast conservation and axillary management after primary systemic therapy in patients with early-stage breast cancer: the Lucerne toolbox.

Primary systemic therapy is increasingly used in the treatment of patients with early-stage breast cancer, but few guidelines specifically address optimal locoregional therapies. Therefore, we established an international consortium to discuss clinical evidence and to provide expert advice on technical management of patients with early-stage breast cancer. The steering committee prepared six working packages to address all major clinical questions from diagnosis to surgery. During a consensus meeting that included members from European scientific oncology societies, clinical trial groups, and patient advocates, statements were discussed and voted on. A consensus was reached in 42% of statements, a majority in 38%, and no decision in 21%. Based on these findings, the panel developed clinical guidance recommendations and a toolbox to overcome many clinical and technical requirements associated with the diagnosis, response assessment, surgical planning, and surgery of patients with early-stage breast cancer. This guidance could convince clinicians and patients of the major clinical advancements purported by primary systemic therapy, the use of less extensive and more targeted surgery to improve the lives of patients with breast cancer.

Optical tissue measurements of invasive carcinoma and ductal carcinoma in situ for surgical guidance.

BACKGROUND: Although the incidence of positive resection margins in breast-conserving surgery has decreased, both incomplete resection and unnecessary large resections still occur. This is especially the case in the surgical treatment of ductal carcinoma in situ (DCIS). Diffuse reflectance spectroscopy (DRS), an optical technology based on light tissue interactions, can potentially characterize tissue during surgery thereby guiding the surgeon intraoperatively. DRS has shown to be able to discriminate pure healthy breast tissue from pure invasive carcinoma (IC) but limited research has been done on (1) the actual optical characteristics of DCIS and (2) the ability of DRS to characterize measurements that are a mixture of tissue types. METHODS: In this study, DRS spectra were acquired from 107 breast specimens from 107 patients with proven IC and/or DCIS (1488 measurement locations). With a generalized estimating equation model, the differences between the DRS spectra of locations with DCIS and IC and only healthy tissue were compared to see if there were significant differences between these spectra. Subsequently, different classification models were developed to be able to predict if the DRS spectrum of a measurement location represented a measurement location with "healthy" or "malignant" tissue. In the development and testing of the models, different definitions for "healthy" and "malignant" were used. This allowed varying the level of homogeneity in the train and test data. RESULTS: It was found that the optical characteristics of IC and DCIS were similar. Regarding the classification of tissue with a mixture of tissue types, it was found that using mixed measurement locations in the development of the classification models did not tremendously improve the accuracy of the classification of other measurement locations with a mixture of tissue types. The evaluated classification models were able to classify measurement locations with > 5% malignant cells with a Matthews correlation coefficient of 0.41 or 0.40. Some models showed better sensitivity whereas others had better specificity. CONCLUSION: The results suggest that DRS has the potential to detect malignant tissue, including DCIS, in healthy breast tissue and could thus be helpful for surgical guidance.

Pathologic response of ductal carcinoma in situ to neoadjuvant systemic treatment in HER2-positive breast cancer.

PURPOSE: The presence of extensive ductal carcinoma in situ (DCIS) adjacent to HER2-positive invasive breast cancer (IBC) is often a contra-indication for breast-conserving surgery, even in case of excellent treatment response of the invasive component. Data on the response of DCIS to neoadjuvant systemic treatment (NST) are limited. Therefore, we estimated the response of adjacent DCIS to NST-containing HER2-blockade in HER2-positive breast cancer patients and assessed the association of clinicopathological and radiological factors with response. METHODS: Pre-NST biopsies were examined to determine presence of DCIS in all women with HER2-positive IBC treated with trastuzumab-containing NST ± pertuzumab between 2004 and 2017 in a comprehensive cancer center. When present, multiple DCIS factors, including grade, calcifications, necrosis, hormone receptor, and Ki-67 expression, were scored. Associations of clinicopathological and radiological factors with complete response were assessed using logistic regression models. RESULTS: Adjacent DCIS, observed in 138/316 patients with HER2-positive IBC, was eradicated after NST in 46% of patients. Absence of calcifications suspicious for malignancy on pre-NST mammography (odds ratio (OR) 3.75; 95% confidence interval (95% CI) 1.72-8.17), treatment with dual HER2-blockade (OR 2.36; 95% CI 1.17-4.75), a (near) complete response on MRI (OR 3.55; 95% CI 1.31-9.64), and absence of calcifications (OR 3.19; 95% CI 1.34-7.60) and Ki-67 > 20% in DCIS (OR 2.74; 95% CI 1.09-6.89) on pre-NST biopsy were significantly associated with DCIS response. CONCLUSIONS: As DCIS can respond to NST containing HER2-blockade, the presence of extensive DCIS in HER2-positive breast cancer before NST should not always indicate a mastectomy. The predictive factors we found could be helpful when considering breast-conserving surgery in these patients.

Breast-Conserving Therapy in Patients with cT3 Breast Cancer with Good Response to Neoadjuvant Systemic Therapy Results in Excellent Local Control: A Comprehensive Cancer Center Experience.

BACKGROUND: Many cT3 breast cancer patients are treated with mastectomy, regardless of response to neoadjuvant systemic therapy (NST). We evaluated local control of cT3 patients undergoing breast-conserving therapy (BCT) based on magnetic resonance imaging (MRI) evaluation post-NST. In addition, we analyzed predictive characteristics for positive margins after breast-conserving surgery (BCS). METHODS: All cT3 breast cancer patients who underwent BCS after NST between 2002 and 2015 at the Netherlands Cancer Institute were included. Local recurrence-free interval (LRFI) was estimated using the Kaplan-Meier method, and predictors for positive margins were analyzed using univariable analysis and multivariable logistic regression. RESULTS: Of 114 patients undergoing BCS post-NST, 75 had negative margins, 16 had focally positive margins, and 23 had positive margins. Of those with (focally) positive margins, 12 underwent radiotherapy, 6 underwent re-excision, and 21 underwent mastectomy. Finally, 93/114 patients were treated with BCT (82%), with an LRFI of 95.9% (95% confidence interval [CI] 91.5-100%) after a median follow-up of 7 years. Predictors for positive margins in univariable analysis were hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) subtype, lobular carcinoma, and non-mass enhancement (NME) on pre-NST MRI. MRI response was not correlated to positive margins. In multivariable regression, the odds of positive margins were decreased in patients with HER2-positive (HER2+; odds ratio [OR] 0.27, 95% CI 0.10-0.73; p = 0.01) and TN tumors (OR 0.17, 95% CI 0.03-0.82; p = 0.028). A trend toward positive margins was observed in patients with NME (OR 2.38, 95% CI 0.98-5.77; p = 0.055). CONCLUSION: BCT could be performed in 82% of cT3 patients in whom BCT appeared feasible on post-NST MRI. Local control in these patients was excellent. In those patients with HR+/HER2- tumors, NME on MRI, or invasive lobular carcinoma, the risk of positive margins should be considered preoperatively.

Minimally Invasive Complete Response Assessment of the Breast After Neoadjuvant Systemic Therapy for Early Breast Cancer (MICRA trial): Interim Analysis of a Multicenter Observational Cohort Study.

BACKGROUND: The added value of surgery in breast cancer patients with pathological complete response (pCR) after neoadjuvant systemic therapy (NST) is uncertain. The accuracy of imaging identifying pCR for omission of surgery, however, is insufficient. We investigated the accuracy of ultrasound-guided biopsies identifying breast pCR (ypT0) after NST in patients with radiological partial (rPR) or complete response (rCR) on MRI. METHODS: We performed a multicenter, prospective single-arm study in three Dutch hospitals. Patients with T1-4(N0 or N +) breast cancer with MRI rPR and enhancement ≤ 2.0 cm or MRI rCR after NST were enrolled. Eight ultrasound-guided 14-G core biopsies were obtained in the operating room before surgery close to the marker placed centrally in the tumor area at diagnosis (no attempt was made to remove the marker), and compared with the surgical specimen of the breast. Primary outcome was the false-negative rate (FNR). RESULTS: Between April 2016 and June 2019, 202 patients fulfilled eligibility criteria. Pre-surgical biopsies were obtained in 167 patients, of whom 136 had rCR and 31 had rPR on MRI. Forty-three (26%) tumors were hormone receptor (HR)-positive/HER2-negative, 64 (38%) were HER2-positive, and 60 (36%) were triple-negative. Eighty-nine patients had pCR (53%; 95% CI 45-61) and 78 had residual disease. Biopsies were false-negative in 29 (37%; 95% CI 27-49) of 78 patients. The multivariable associated with false-negative biopsies was rCR (FNR 47%; OR 9.81, 95% CI 1.72-55.89; p = 0.01); a trend was observed for HR-negative tumors (FNR 71% in HER2-positive and 55% in triple-negative tumors; OR 4.55, 95% CI 0.95-21.73; p = 0.058) and smaller pathological lesions (6 mm vs 15 mm; OR 0.93, 95% CI 0.87-1.00; p = 0.051). CONCLUSION: The MICRA trial showed that ultrasound-guided core biopsies are not accurate enough to identify breast pCR in patients with good response on MRI after NST. Therefore, breast surgery cannot safely be omitted relying on the results of core biopsies in these patients.