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Background: The nodal positivity rate after neoadjuvant chemotherapy (ypN+) in patients with clinically node-negative (cN0) breast cancer is low, especially in those with a pathological complete response of the breast. The aim of this study was to identify characteristics known before surgery that are associated with achieving ypN0 in patients with cN0 disease. These characteristics could be used to select patients in whom sentinel lymph node biopsy may be omitted after neoadjuvant chemotherapy., Methods: This cohort study included patients with cT1-3 cN0 breast cancer treated with neoadjuvant chemotherapy followed by breast surgery and sentinel node biopsy between 2013 and 2018. cN0 was defined by the absence of suspicious nodes on ultrasound imaging and PET/CT, or absence of tumour cells at fine-needle aspiration. Univariable and multivariable logistic regression analyses were performed to determine predictors of ypN0., Results: Overall, 259 of 303 patients (85.5 per cent) achieved ypN0, with high rates among those with a radiological complete response (rCR) on breast MRI (95·5 per cent). Some 82 per cent of patients with hormone receptor-positive disease, 98 per cent of those with triple-negative breast cancer (TNBC) and all patients with human epidermal growth factor receptor 2 (HER2)-positive disease who had a rCR achieved ypN0. Multivariable regression analysis showed that HER2-positive (odds ratio (OR) 5·77, 95 per cent c.i. 1·91 to 23·13) and TNBC subtype (OR 11·65, 2·86 to 106·89) were associated with ypN0 status. In addition, there was a trend toward ypN0 in patients with a breast rCR (OR 2·39, 0·95 to 6·77)., Conclusion: The probability of nodal positivity after neoadjuvant chemotherapy was less than 3 per cent in patients with TNBC or HER2-positive disease who achieved a breast rCR on MRI. These patients could be included in trials investigating the omission of sentinel node biopsy after neoadjuvant chemotherapy., (© The Author(s) 2020. Published by Oxford University Press on behalf of BJS Society Ltd. All rights reserved.For permissions, please email: journals.permissions@oup.com.)

Aim: Breast radiotherapy accounts for a significant workload in radiotherapy departments. In 2015 it became clinical practice at the Netherlands Cancer Institute for radiation therapists (RTTs) to delineate the clinical target volume of the breast tissue (CTVbreast) and in 2017 axilla level I-II (CTVln12) according to a delineation atlas. All RTTs were trained and got individual feedback. The aim of this retrospective study was to investigate the variation between the CTVbreast with or without CTVln12 delineated by a trained group of radiation therapists and the clinical adjusted delineations by the radiation oncologist/physician assistant (RO/PA), in a large group of patients treated between January 2017 and June 2020., Materials and Methods: 1012 computer tomography based delineations of CTVbreast and 146 of CTVln12 were collected from January 2017-June 2020. The RTT and RO/PA delineations were compared using the Dice coefficient and the 95th percentile Hausdorff Distance (95%HD). Statistical significance of the differences was tested using a Mann-Whitney test., Results: Differences in CTVbreast delineations were small. A median Dice score of 1.00 for all years, where 83% of the patients had a Dice score > 0.99. For CTVln12 the magnitude of edits made by RO/PAs decreased over time, with the Dice increasing from a median of 0.87 in 2017 to 0.90 in 2020 (p = 0.031). The 95%HD decreased from a median of 0.93 cm in 2017 to 0.61 cm in 2020 (p = 0.051)., Conclusions: This retrospective study shows that trained dedicated RTTs are capable in delivering the same quality delineations as RO/PAs. The low variability supports the increasing role of RTTs in the contouring process, likely making it more time efficient., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s).)

Background: Poly (ADP-ribose) Polymerase (PARP) inhibitors are promising novel radiosensitisers. Pre-clinical models have demonstrated potent and tumour-specific radiosensitisation by PARP inhibitors. Olaparib is a PARP inhibitor with a favourable safety profile in comparison to clinically used radiosensitisers including cisplatin when used as single agent. However, data on safety, tolerability and efficacy of olaparib in combination with radiotherapy are limited., Methods: Olaparib is dose escalated in combination with radical (chemo-)radiotherapy regimens for non-small cell lung cancer (NSCLC), breast cancer and head and neck squamous cell carcinoma (HNSCC) in three parallel single institution phase 1 trials. All trials investigate a combination treatment of olaparib and radiotherapy, the NSCLC trial also investigates a triple combination of olaparib, radiotherapy and concurrent low dose cisplatin. The primary objective is to identify the maximum tolerated dose of olaparib in these combination treatments, defined as the dose closest to but not exceeding a 15% probability of dose limiting toxicity. Each trial has a separate dose limiting toxicity definition, taking into account incidence, duration and severity of expected toxicities without olaparib. Dose escalation is performed using a time-to-event continual reassessment method (TITE-CRM). TITE-CRM enables the incorporation of late onset toxicity until one year after treatment in the dose limiting toxicity definition while maintaining an acceptable trial duration. Olaparib treatment starts two days before radiotherapy and continues during weekends until two days after radiotherapy. Olaparib will also be given two weeks and one week before radiotherapy in the breast cancer trial and HNSCC trial respectively to allow for translational research. Toxicity is scored using common terminology criteria for adverse events (CTCAE) version 4.03. Blood samples, and tumour biopsies in the breast cancer trial, are collected for pharmacokinetic and pharmacodynamic analyses., Discussion: We designed three parallel phase 1 trials to assess the safety and tolerability of the PARP inhibitor olaparib in combination with radical (chemo-)radiotherapy treatment regimens. PARP inhibitors have the potential to improve outcomes in patients treated with radical (chemo-)radiotherapy, by achieving higher locoregional control rates and/or less treatment associated toxicity., Trial Registration: ClinicalTrials.gov Identifiers: NCT01562210 (registered March 23, 2012), NCT02227082 (retrospectively registered August 27, 2014), NCT02229656 (registered September 1, 2014).

Background: Axillary lymph node dissection (ALND) is frequently performed for node-positive (cN+) breast cancer patients. Combining positron emission tomography/computed tomography (PET/CT) before-NST and the MARI (marking axillary lymph nodes with radioactive iodine seeds) procedure after neoadjuvant systemic therapy (NST) has the potential for avoiding unnecessary ALNDs. This report presents the results from implementation of this strategy., Methods: All breast cancer patients treated with NST at the Netherlands Cancer Institute who underwent a PET/CT and the MARI procedure from July 2014 to July 2017 were included in the study. All the patients underwent tailored axillary treatment according to a protocol based on the combined results of PET/CT before NST and the MARI procedure after NST. With this protocol, patients showing one to three FDG-avid axillary lymph nodes (ALNs) on PET/CT (cN<4) and a tumor-negative MARI node receive no further axillary treatment. All cN (<4) patients with a tumor-positive MARI node receive locoregional radiotherapy, as well as patients with four or more FDG-avid ALNs [cN(4+)] and a tumor-negative MARI node after NST. An ALND is performed only for cN(4+) patients with a tumor-positive MARI node., Results: The data of 159 patients who received a PET/CT before NST and a MARI procedure after NST were analyzed. Of these patients, 110 had one to three FDG-avid ALNs and 49 patients showed four or more FDG-avid ALNs on PET/CT before NST. For 130 patients (82%), ALND was omitted. Locoregional radiotherapy was administered to 91 patients (57%), and 39 patients (25%) received no further axillary treatment., Conclusion: Combining pre-NST axillary staging with PET/CT and post-NST staging with the MARI procedure resulted in an 82% reduction of ALNDs for cN + breast cancer patients.

Introduction: 18 F-FDG PET/CT has high positive predictive value for the detection of avid lymph node metastases in breast cancer patients. We analysed the effect of upstaging lymph nodes by PET/CT on short-term outcome in stage II/III breast cancer patients., Patients and Methods: A total of 278 stage II/III primary breast cancer patients (mean age 48.9 years, range 19-75 years) were re-staged with 18 F-FDG PET/CT before start of pre-operative systemic treatment (PST). Patients were divided in three groups based on risk for local recurrence: a low - (T2N0), intermediate - (T0-2N1 and T3N0) and a high-risk group (T0-3N2-3, T3N1 and T4). Within these groups we looked at local recurrence-free survival (LRFS), recurrence-free survival (RFS) and overall survival (OS) within the first 3 years of follow-up., Results: With a median follow-up (FU) of 50 months the RFS, LRFS and OS were 87%, 88% and 92% respectively for the whole group. PET/CT upstaged 43 patients from the low- and intermediate risk group to the high-risk group, based on detection of ≥4 avid axillary nodes or occult N2/3-disease. Patients upstaged with PET/CT had more events for all three analyses compared to the original risk groups, which resulted in a significantly worse RFS (69.8%; p = 0.03) a nearly significantly worse LRFS (p = 0.052) and no effect in OS (p = 0.433)., Discussion: Additional PET/CT staging allows breast cancer patients to be treated according to the true stage, still stage II/III breast cancer patients upstaged to N2/3 by PET/CT have worse short-term outcome, despite adjustment of treatment, than patients staged high-risk with conventional imaging., (Copyright © 2016 Elsevier Ltd, BASO ~ The Association for Cancer Surgery, and the European Society of Surgical Oncology. All rights reserved.)

Importance: Prognostic factors of ipsilateral breast tumor recurrence (IBTR) may change over time following breast-conserving therapy., Objective: The EORTC "boost no boost" trial showed that young age and high-grade invasive carcinoma were the most important risk factors for IBTR. This study reanalyses pathological prognostic factors related to IBTR using long-term follow-up., Design, Setting, and Participants: Participants included 5569 early-stage breast cancer patients, treated with breast-conserving surgery (BCS) and whole-breast irradiation (WBI), who were randomized between no boost and a 16-Gy boost in the EORTC phase III "boost no boost" trial (1989-1996). A total of 1616 patients with a microscopically complete resection (according to local pathologists), included in the central pathology review, have been analyzed in this study. Median follow-up was 18.2 years., Interventions: No further treatment or 16-Gy boost, after BCS and 50-Gy WBI., Main Outcomes and Measures: Time to ipsilateral breast tumor recurrence (IBTR) as first event., Results: The 20-year cumulative incidence of IBTR in 1616 patients (160 events observed) was 15% (95% CI, 12%-17%). Young age (P < .001) and presence of ductal carcinoma in situ (DCIS) (HR, 2.15; 95% CI, 1.36-3.38; P = .001) were associated with an increased risk of IBTR in multivariable analysis. The cumulative incidence of IBTR at 20 years was 34% (95% CI, 25%-41%), 14% (95% CI, 10%-18%), and 11% (95% CI, 8%-15%), in patients 40 years or younger, 41 to 50 years and 50 years or older, respectively (P < .001). This incidence was 18% (95% CI, 14%-22%) and 9% (95% CI, 6%-12%) for tumors with and without DCIS (P < .001). High-grade tumors relapsed more frequently early during follow-up but the relative effect of age and presence of DCIS seemed stable over time. The boost reduced the 20-year IBTR incidence from 31% (95% CI, 22%-39%) to 15% (95% CI, 8%-21%) (HR, 0.37; 95% CI, 0.22-0.62; P < .001) in high-risk patients (≤50 years with DCIS present)., Conclusions and Relevance: The association of high-grade invasive tumor with IBTR diminished during follow-up, while the effect of DCIS adjacent to invasive tumor seemed to remain stable. Therefore, patients with high-grade invasive tumors should be monitored closely, especially in the first 5 years, while additional DCIS is an indication for longer follow-up, emphasizing the importance of long-term trial follow-up to estimate absolute effects accurately., Trial Registration: clinicaltrials.gov Identifier: NCT02295033.

The purpose of this study was to study the impact of changes in clinical practice on outcome in patients treated with breast-conserving therapy (BCT) over a period of 28 years. Patients with early invasive breast cancer, who were treated with BCT at the Netherlands Cancer Institute between 1980 and 2008, were studied. Clinical characteristics, treatment and outcome were compared between groups (1980-1987; 1988-1998; 1999-2008). The main endpoint analyzed was ipsilateral breast tumor recurrence (IBTR). 8485 patients with a median follow-up of 9 years (IQR 6-14 years) were analyzed. The cumulative 5- and 10-year IBTR incidences were, respectively, 2 and 5 % for the whole cohort and 4 and 9 % in patients ≤40 years. Young age was a significant risk factor for IBTR in multivariable analysis. IBTR-free interval was better for patients who received a RT boost (HR 0.65) or systemic therapy (HR 0.52). In later years, patients less often received a boost and more often underwent adjuvant systemic treatment. 761 patients (9.0 %) underwent a re-excision; the tumor resection margins were tumor free for 85 %. In later years (1999-2008), 89 % of patients had a tumor-free margin. The margin status of invasive carcinoma did not influence IBTR, DM rate, or OS. Between 1980 and 2008, locoregional control after BCT remained stable with low IBTR rates, even in young patients. These good results were achieved under the policy of accepting close or focally positive margins, indicating this is a safe approach. The results of this study may help in lowering the re-excision rates, which are high in many centers.

Background: Since the introduction of breast-conserving treatment, various radiation doses after lumpectomy have been used. In a phase 3 randomised controlled trial, we investigated the effect of a radiation boost of 16 Gy on overall survival, local control, and fibrosis for patients with stage I and II breast cancer who underwent breast-conserving treatment compared with patients who received no boost. Here, we present the 20-year follow-up results., Methods: Patients with microscopically complete excision for invasive disease followed by whole-breast irradiation of 50 Gy in 5 weeks were centrally randomised (1:1) with a minimisation algorithm to receive 16 Gy boost or no boost, with minimisation for age, menopausal status, presence of extensive ductal carcinoma in situ, clinical tumour size, nodal status, and institution. Neither patients nor investigators were masked to treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. The trial is registered with ClinicalTrials.gov, number NCT02295033., Findings: Between May 24, 1989, and June 25, 1996, 2657 patients were randomly assigned to receive no radiation boost and 2661 patients randomly assigned to receive a radiation boost. Median follow-up was 17.2 years (IQR 13.0-19.0). 20-year overall survival was 59.7% (99% CI 56.3-63.0) in the boost group versus 61.1% (57.6-64.3) in the no boost group, hazard ratio (HR) 1.05 (99% CI 0.92-1.19, p=0.323). Ipsilateral breast tumour recurrence was the first treatment failure for 354 patients (13%) in the no boost group versus 237 patients (9%) in the boost group, HR 0.65 (99% CI 0.52-0.81, p<0.0001). The 20-year cumulative incidence of ipsilatelal breast tumour recurrence was 16.4% (99% CI 14.1-18.8) in the no boost group versus 12.0% (9.8-14.4) in the boost group. Mastectomies as first salvage treatment for ipsilateral breast tumour recurrence occurred in 279 (79%) of 354 patients in the no boost group versus 178 (75%) of 237 in the boost group. The cumulative incidence of severe fibrosis at 20 years was 1.8% (99% CI 1.1-2.5) in the no boost group versus 5.2% (99% CI 3.9-6.4) in the boost group (p<0.0001)., Interpretation: A radiation boost after whole-breast irradiation has no effect on long-term overall survival, but can improve local control, with the largest absolute benefit in young patients, although it increases the risk of moderate to severe fibrosis. The extra radiation dose can be avoided in most patients older than age 60 years., Funding: Fonds Cancer, Belgium., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

The 70-gene signature (MammaPrint) has been developed to predict the risk of distant metastases in breast cancer and select those patients who may benefit from adjuvant treatment. Given the strong association between locoregional and distant recurrence, we hypothesize that the 70-gene signature will also be able to predict the risk of locoregional recurrence (LRR). 1,053 breast cancer patients primarily treated with breast-conserving treatment or mastectomy at the Netherlands Cancer Institute between 1984 and 2006 were included. Adjuvant treatment consisted of radiotherapy, chemotherapy, and/or endocrine therapy as indicated by guidelines used at the time. All patients were included in various 70-gene signature validation studies. After a median follow-up of 8.96 years with 87 LRRs, patients with a high-risk 70-gene signature (n = 492) had an LRR risk of 12.6% (95% CI 9.7-15.8) at 10 years, compared to 6.1% (95% CI 4.1-8.5) for low-risk patients (n = 561; P < 0.001). Adjusting the 70-gene signature in a competing risk model for the clinicopathological factors such as age, tumour size, grade, hormone receptor status, LVI, axillary lymph node involvement, surgical treatment, endocrine treatment, and chemotherapy resulted in a multivariable HR of 1.73 (95% CI 1.02-2.93; P = 0.042). Adding the signature to the model based on clinicopathological factors improved the discrimination, albeit non-significantly [C-index through 10 years changed from 0.731 (95% CI 0.682-0.782) to 0.741 (95% CI 0.693-0.790)]. Calibration of the prognostic models was excellent. The 70-gene signature is an independent prognostic factor for LRR. A significantly lower local recurrence risk was seen in patients with a low-risk 70-gene signature compared to those with high-risk 70-gene signature.

In contrast to most new oncology treatments, wide clinical introduction of partial breast irradiation (PBI) is not based on level A trial evidence. Despite promising phase I/II data, new reports based upon large cohorts of patients mention more recurrences and/or complications from PBI compared with whole breast irradiation (WBI), necessitating more careful selection of patients for PBI while awaiting long term results of major clinical trials. In an attempt to improve this we give preoperative PBI within a prospective trial., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background and Purpose: The EORTC 22881-10882 trial showed that for patients treated with breast conserving therapy (BCT), a 16Gy boost dose significantly improved local control, but increased the risk of breast fibrosis. A model to estimate the risk of ipsilateral breast relapse (IBR) already exists, but now a model has been developed which takes boost treatment into account and is based on centrally reviewed pathology., Materials and Methods: A Cox model was developed based on central pathology review data and clinical data of 1603 patients from the EORTC 22881-10882 trial with a median follow-up of 11.5years. From a predefined set of variables, predictors with a maximal effect on 10-year IBR rate >4% were retained in the model. Bootstrap re-sampling was used to assess model calibration and discrimination. The results are presented in the form of a nomogram., Results: Apart from young age and no boost, presence of DCIS adjacent to the invasive tumor was associated with increased risk of IBR (HR 1.96, p=0.001). Patients with high grade invasive tumors were younger than patients with low/intermediate grade (p<0.0001). The nomogram includes histologic grade, DCIS, tumor diameter, age, tamoxifen, chemotherapy, and boost with a concordance probability estimate of 0.68., Conclusions: The nomogram for predicting IBR 10years after BCT includes seven factors, with young age, presence of DCIS and boost treatment as the most dominant factors. The nomogram estimates IBR and confirms the importance of a boost dose. Combined with a model to predict fibrosis published previously, the nomogram presented here may assist in decision making for individual patients., (Copyright © 2011 Elsevier Ireland Ltd. All rights reserved.)

The Dutch evidence-based guideline 'Treatment of breast cancer' has been revised, and integrated with the guideline 'Screening for and diagnosis of breast cancer'. The guideline can be found on www. oncoline.nl and on www.cbo.nl. The Internet programme 'Adjuvant!' (www.adjuvantonline.com) can be used to predict both the prognosis and the efficacy of systemic adjuvant therapy for each patient. The indications for adjuvant chemotherapy and endocrine therapy have been widened. The aim is to reduce the absolute probability of death by at least 4-5% within 10 years. The goal of neoadjuvant chemotherapy in operable breast cancer is to enable breast-conserving therapy for large tumours in relatively small breasts. One could consider transferring responsibility for follow-up after 5 years from the hospital to the screening organisation following mastectomy, to the family doctor following breast-conserving therapy, and to an outpatient clinic for hereditary tumours in carriers of gene mutation. Cessation of follow-up above the age of 75 could also be considered.

Purpose: To quantify the interfraction position variability of the excision cavity (EC) and to compare the rib and breast surface as surrogates for the cavity. Additionally, we sought to determine the required margin for on-line, off-line and no correction protocols in external beam radiotherapy., Methods and Materials: A total of 20 patients were studied who had been treated in the supine position for 28 daily fractions. Cone-beam computed tomography scans were regularly acquired according to a shrinking action level setup correction protocol based on bony anatomy registration of the ribs and sternum. The position of the excision area was retrospectively analyzed by gray value cone-beam computed tomography-to-computed tomography registration. Subsequently, three setup correction strategies (on-line, off-line, and no corrections) were applied, according to the rib and breast surface registrations, to estimate the residual setup errors (systematic [Sigma] and random [sigma]) of the excision area. The required margins were calculated using a margin recipe., Results: The image quality of the cone-beam computed tomography scans was sufficient for localization of the EC. The margins required for the investigated setup correction protocols and the setup errors for the left-right, craniocaudal and anteroposterior directions were 8.3 mm (Sigma = 3.0, sigma = 2.6), 10.6 mm (Sigma = 3.8, sigma = 3.2), and 7.7 mm (Sigma = 2.7, sigma = 2.9) for the no correction strategy; 5.6 mm (Sigma = 2.0, Sigma = 1.8), 6.5 mm (Sigma = 2.3, sigma = 2.3), and 4.5 mm (Sigma = 1.5, sigma = 1.9) for the on-line rib strategy; and 5.1 mm (Sigma = 1.8, sigma = 1.7), 4.8 mm (Sigma = 1.7, sigma = 1.6), and 3.3 mm (Sigma = 1.1, sigma = 1.6) for the on-line surface strategy, respectively., Conclusion: Considerable geometric uncertainties in the position of the EC relative to the bony anatomy and breast surface have been observed. By using registration of the breast surface, instead of the rib, the uncertainties in the position of the EC area were reduced.

We have studied the long-term prognosis of 266 patients considered to have isolated local recurrence in the breast following conservative surgery and radiotherapy for early breast cancer. The median follow-up of the patients still alive after diagnosis of local relapse was 11.2 years. At 10 years from the date of salvage treatment, the overall survival rate for the 226 patients with invasive local recurrence was 39% (95% CI, 32-46), the distant recurrence-free survival rate was 36% (95% CI, 29-42), and the local control rate (i.e., survival without subsequent local recurrence or local progression) was 68% (95% CI, 62-75). Among patients with a local recurrence at or near the original tumour site a better distant disease-free survival was observed for patients with recurrences measuring 1cm or less, compared to those with larger recurrences. This suggests, though does not prove, that early detection of local recurrence can improve the treatment outcome but might as well point towards a different biologic behaviour, facilitating early detection.

Objective: To assess the interobserver variability in the radiologic assessment of response to chemotherapy in patients with recurrent glioma., Methods: Five clinicians with experience in the treatment and follow-up of patients with glioma measured tumor size in 20 pairs of CT and 20 pairs of MRI scans of 35 patients who had been treated with chemotherapy for recurrent glioma. Tumor size was defined as the product of the two largest perpendicular enhancing tumor diameters on the postcontrast images. To assess the interobserver variability in the measurements of tumor size, and in the classification according to the widely used Macdonald response criteria, intraclass correlation coefficients (ICC) and weighted kappa values were calculated., Results: Substantial interobserver agreement was noted in the manual, two-dimensional measurements of tumor size on CT and MRI in patients treated with chemotherapy for recurrent glioma (overall ICC 0.64). Classification of response to chemotherapy according to the Macdonald criteria resulted in moderate interobserver agreement (overall weighted kappa 0.51). In 65% of evaluated CT and in 55% of evaluated MRI studies, no complete consensus was found for the categorical tumor response measurement., Conclusion: The radiologic assessment of response to chemotherapy in patients with recurrent glioma is susceptible to considerable interobserver variability. This underlines the difficulties that arise in scoring response to chemotherapy by conventional radiologic techniques.

Purpose: Local recurrence (LR) after breast-conserving therapy (BCT) is associated with an increased risk for the development of distant metastasis. We studied risk factors for distant metastasis risk (DMR) and poor prognosis within a group of patients with LR as first event., Patients and Methods: From a cohort of 1481 breast carcinomas treated with BCT in the period 1980-1994, a total of 68 pT1-3 N0-1 patients developed LR as first event. We have studied risk factors for the development of distant metastasis within this group of patients with LR. In addition to clinical factors (age at BCT and LR, mode of detection, location of LR, and treatment of LR), the histology slides of the primary and the recurrent tumor were reviewed. Immunohistochemical staining was performed for the following proteins: bcl-2, cyclin D1, E-cadherin, EGF receptor, ER, PR, Ki-67, c-erbB-2/neu, and p53. Statistical analyses were performed using conditional logistic regression., Results: At a median follow-up after LR of 5.6 years, the 5-year DMR was 53%. In univariate analysis, none of the factors of the primary tumor was found to be associated with DMR after LR. Of the recurrent tumor the following factors were found to be risk factors for high DMR after LR: interval between treatment of the primary tumor and LR at 2 years or less (relative risk, 2.38; 95% confidence interval, 1.22-4.76; p = 0.008) and high mitotic count (relative risk, 2.51; 95% confidence interval, 1.03-6.15; p = 0.04). All patients with noninvasive recurrent tumor were alive at the time of analysis. Patients with an interval of greater than 2 years and a recurrent tumor with high mitotic count were found to have an equally poor prognosis compared to patients with LRs detected after a short interval., Conclusion: LR after BCT is associated with higher DMR and poor prognosis. Patients with LR within 2 years after BCT are especially at high risk. Late recurrences with high mitotic count have the same poor prognosis as early recurrences. For these patients, systemic treatment at time of the detection of LR should be considered.

Purpose: Patients with invasive breast cancer may develop a local recurrence (LR) after breast-conserving therapy (BCT). Younger age has been found to be an independent risk factor for LR. Within a group of premenopausal node-negative breast cancer patients, we studied risk factors for LR and the effect of perioperative chemotherapy (PeCT) on LR., Patients and Methods: The European Organization for Research and Treatment of Cancer (EORTC) conducted a randomized trial (EORTC 10854) to compare surgery followed by one course of PeCT (fluorouracil, doxorubicin, and cyclophosphamide) with surgery alone. From patients treated on this trial, we selected premenopausal patients with node-negative breast cancer who were treated with BCT to examine whether histologic characteristics and the expression of various proteins (estrogen receptor, progesterone receptor, p53, Ki-67, bcl-2, CD31, c-erbB-2/neu) are risk factors for subsequent LR. Also, the effect of one course of PeCT on the LR risk (LRR) was studied., Results: Using multivariate analysis, age younger than 43 years (relative risk [RR], 2.75; 95% confidence interval [CI], 1.46 to 5.18; P =.002), multifocal growth (RR, 3.34; 95% CI, 1.27 to 8.77; P =.014), and elevated levels of p53 (RR, 2. 14; 95% CI, 1.13 to 4.05; P =.02) were associated with higher LRR. Also, PeCT was found to reduce LRR by more than 50% (RR, 0.47; 95% CI, 0.25 to 0.86; P =.02). Patients younger than 43 years who received PeCT achieved similar LR rates as those of patients younger than 43 years who were treated with BCT alone., Conclusion: In premenopausal node-negative patients, age younger than 43 years is the most important risk factor for LR after BCT; this risk is greatly reduced by one course of PeCT. The main reason for administering systemic adjuvant treatment is to improve overall survival. The important reduction of LR after BCT is an additional reason for considering systemic treatment in young node-negative patients with breast cancer.

The purpose of this study was to determine which histological factors are associated with an increased risk for local recurrence in the breast after breast-conserving therapy for early breast cancer (TNM stage I and II) and whether risk patterns vary according to menopausal status and type of local recurrence. Through complete follow-up of the patients of eight regional radiation oncology departments, two cancer institutes and one surgical clinic in The Netherlands, 360 patients were identified with local recurrence in the breast after having received breast-conserving therapy (local tumour excision, axillary dissection and irradiation of the whole breast and a boost to the tumour bed) during the 1980s. For each case, two controls with a follow-up of similar duration without local recurrence were randomly selected. Histological slides of the primary tumour were reviewed. Among premenopausal patients the risk of recurrence for those younger than 35 years was significantly higher than that for premenopausal patients of 45 years or older (relative risk (RR) 2.9; 95% confidence interval (95% CI) 1.3-6.6, P < 0.05). The risk of recurrence at or near the site of the primary tumour was most significantly increased for patients with high grade extensive intraductal component (EIC) adjacent to the primary tumour (RR 4.1; 95% CI 1.7-9.8, P < 0.01). Microscopic margin involvement was an important risk indicator for diffuse recurrence and recurrence in the skin of the breast, especially in the presence of vascular invasion (RR 25; 95% CI 4.0-150, P < 0.001). To prevent local recurrence at or near the site of the primary tumour, local excision with a 1-2 cm margin of healthy tissue and a 15 Gy boost seemed adequate local treatment for patients with well differentiated EIC. In contrast, a wider surgical margin, a higher boost dose or mastectomy should be considered for patients with poorly differentiated EIC. Microscopic margin involvement in the presence of vascular invasion significantly increases the risk of diffuse recurrence or recurrence in the skin.

Purpose: Many studies have focused on histological risk factors for local recurrence (LR) after breast-conserving therapy (BCT). In addition to histological factors, we studied alterations in the expression of various proteins in relation to LR using a case-control approach., Methods and Materials: Ninety-nine LR occurred in a patient cohort of 1,481 tumors treated with BCT. These patients were randomly matched, each with two controls. Matching was performed for age group (< or = 50 and > 50 years), pN stage, and follow-up time. Histology slides were reviewed. Immunohistochemical staining was performed for the following proteins: bcl-2, CD31, cyclin D1, E-cadherin, EGF receptor, ER, PR, Ki-67, c-erbB2/neu, and p53. Statistical analyses were performed using conditional logistic regression., Results: Sixty-six cases and 139 controls with invasive carcinoma remained for analysis. The following variables were significant risk factors for LR: young age (p = 0.006), high nuclear grade (p = 0.04), high mitotic count (p = 0.03), extensive DCIS around the tumor (p = 0.02) but not within the tumor, poorly differentiated type of DCIS (p = 0.03), > 20% ki-67 positive cells (p = 0.006), and PR negativity (p = 0.03). When the analysis was performed for patients < or = and > 50 years, these risk factors were found in the older patients, but not in the younger patients., Conclusion: High mitotic count and Ki-67 positivity are risk factors for LR. EDCIS surrounding the invasive tumor is a risk factor for LR, especially when of poorly differentiated type. Age is an important risk factor for LR independent of other risk factors, including alterations in oncogene expression.

Purpose: To study risk factors for local recurrence (LR) after breast-conserving therapy (BCT) for invasive breast cancer and, for patients with an LR, the mode of detection, location, treatment, influence of radiation therapy, and impact on survival., Methods and Materials: 1360 patients (median age 52 years; range 24-88) with a total of 1393 pT1-2 N0-1 tumors treated with BCT between 1980-1994 were studied (median follow-up 52 months). The adequacy of radiation treatment of the patients developing LR was studied in a quality control study. The impact of LR on overall survival and distant metastasis was studied in a Cox regression model with LR as a time-dependent covariate., Results: A total of 88 LR occurred with a 5- and 10-year LR risk of 8 and 12%. Age was the only significant risk factor. Compared to patients > 65 years old, patients < 45 years old and patients 45-65 years old had a relative risk (RR) of 4.09 and 2.41, respectively, of developing LR. Risk on LR was found to increase gradually with younger age. Radiation therapy was considered adequate and did not play a role in influencing the LR rate. Almost 65% of the LR were true or marginal recurrences. Of all LR, 80% appeared during the first 5 years and were detected with equal frequency by the patient herself, the physician, and annual mammography. LR was a major predictor for distant metastasis (RR: 4.90; 3.15-7.62) and death (RR: 4.29; 2.93-6.28)., Conclusion: Young age is a major risk factor for LR and there is a significant gradual increase in LR with decreasing age. LR is associated with a higher risk of distant metastasis and death. Whether LR is the cause of or a marker for distant metastasis remains unresolved.

Objective: To try and reduce the amount of routine postoperative radiotherapy that we prescribed without causing an unacceptable rise in locoregional recurrences., Design: Retrospective study., Setting: Teaching hospital, The Netherlands., Subjects: 836 women who were treated for breast cancer between January 1980 and December 1989., Interventions: These 836 had been treated by modified radical mastectomy (n = 534), excision of the tumour and axillary dissection (n = 279), lumpectomy (n = 15), or total mastectomy (n = 8). In December 1984 we stopped giving routine postoperative irradiation to women with T1 or T2 tumours unless there was any doubt about the operative specimen., Main Outcome Measures: The rate of locoregional recurrence 1985-9 compared with that from 1980-December 1984., Results: Only 1 patient of 836 had a clinically detectable recurrence in the internal mammary chain. There were only 2 recurrences in the 235 axillas that had not been irradiated., Conclusion: By a process of careful selection of patients for locoregional irradiation, the number of fields of irradiation given to patients with breast cancer can be reduced by up to 80% without causing a rise in the rate of locoregional recurrences.