Association of Axillary Dissection With Systemic Therapy in Patients With Clinically Node-Positive Breast Cancer.

Importance: The role of axillary lymph node dissection (ALND) to determine nodal burden to inform systemic therapy recommendations in patients with clinically node (cN)-positive breast cancer (BC) is currently unknown. Objective: To address the association of ALND with systemic therapy in cN-positive BC in the upfront surgery setting and after neoadjuvant chemotherapy (NACT). Design, Setting, and Participants: This was a prospective, observational, cohort study conducted from August 2018 to June 2022. This was a preplanned study within the phase 3 randomized clinical OPBC-03/TAXIS trial. Included were patients with confirmed cN-positive BC from 44 private, public, and academic breast centers in 6 European countries. After NACT, residual nodal disease was mandatory, and a minimum follow-up of 2 months was required. Exposures: All patients underwent tailored axillary surgery (TAS) followed by ALND or axillary radiotherapy (ART) according to TAXIS randomization. TAS removed suspicious palpable and sentinel nodes, whereas imaging-guidance was optional. Systemic therapy recommendations were at the discretion of the local investigators. Results: A total of 500 patients (median [IQR] age, 57 [48-69] years; 487 female [97.4%]) were included in the study. In the upfront surgery setting, 296 of 335 patients (88.4%) had hormone receptor (HR)-positive and Erb-B2 receptor tyrosine kinase 2 (ERBB2; formerly HER2 or HER2/neu)-negative disease: 145 (49.0%) underwent ART, and 151 (51.0%) underwent ALND. The median (IQR) number of removed positive lymph nodes without ALND was 3 (1-4) nodes compared with 4 (2-9) nodes with ALND. There was no association of ALND with the proportion of patients undergoing adjuvant chemotherapy (81 of 145 [55.9%] vs 91 of 151 [60.3%]; adjusted odds ratio [aOR], 0.72; 95% CI, 0.19-2.67) and type of systemic therapy. Of 151 patients with NACT, 74 (51.0%) underwent ART, and 77 (49.0%) underwent ALND. The ratio of removed to positive nodes was a median (IQR) of 4 (3-7) nodes to 2 (1-3) nodes and 15 (12-19) nodes to 2 (1-5) nodes in the ART and ALND groups, respectively. There was no observed association of ALND with the proportion of patients undergoing postneoadjuvant systemic therapy (57 of 74 [77.0%] vs 55 of 77 [71.4%]; aOR, 0.86; 95% CI, 0.43-1.70), type of postneoadjuvant chemotherapy (eg, capecitabine: 10 of 74 [13.5%] vs 10 of 77 [13.0%]; trastuzumab emtansine-DM1: 9 of 74 [12.2%] vs 11 of 77 [14.3%]), or endocrine therapy (eg, aromatase inhibitors: 41 of 74 [55.4%] vs 36 of 77 [46.8%]; tamoxifen: 8 of 74 [10.8%] vs 6 of 77 [7.8%]). Conclusion: Results of this cohort study suggest that patients without ALND were significantly understaged. However, ALND did not inform systemic therapy recommendations.

Trends in use of neoadjuvant systemic therapy in patients with clinically node-positive breast cancer in Europe: prospective TAXIS study (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101).

PURPOSE: The aim of this study was to evaluate clinical practice heterogeneity in use of neoadjuvant systemic therapy (NST) for patients with clinically node-positive breast cancer in Europe. METHODS: The study was preplanned in the international multicenter phase-III OPBC-03/TAXIS trial (ClinicalTrials.gov Identifier: NCT03513614) to include the first 500 randomized patients with confirmed nodal disease at the time of surgery. The TAXIS study's pragmatic design allowed both the neoadjuvant and adjuvant setting according to the preferences of the local investigators who were encouraged to register eligible patients consecutively. RESULTS: A total of 500 patients were included at 44 breast centers in six European countries from August 2018 to June 2022, 165 (33%) of whom underwent NST. Median age was 57 years (interquartile range [IQR], 48-69). Most patients were postmenopausal (68.4%) with grade 2 and 3 hormonal receptor-positive and human epidermal growth factor receptor 2-negative breast cancer with a median tumor size of 28 mm (IQR 20-40). The use of NST varied significantly across the countries (p < 0.001). Austria (55.2%) and Switzerland (35.8%) had the highest percentage of patients undergoing NST and Hungary (18.2%) the lowest. The administration of NST increased significantly over the years (OR 1.42; p < 0.001) and more than doubled from 20 to 46.7% between 2018 and 2022. CONCLUSION: Substantial heterogeneity in the use of NST with HR+/HER2-breast cancer exists in Europe. While stringent guidelines are available for its use in triple-negative and HER2+ breast cancer, there is a need for the development of and adherence to well-defined recommendations for HR+/HER2-breast cancer.

European Society of Breast Cancer Specialists/Advanced Breast Cancer Global Alliance quality indicators for metastatic breast cancer care.

AIMS: Improvement in the care of patients with metastatic breast cancer (MBC) can only occur if the adequate quality of care is implemented and verified, including access to multidisciplinary, specialised care given in accordance with high-quality guidelines. To this purpose, European Society of Breast Cancer Specialists and the Advanced Breast Cancer Global Alliance joined efforts to develop the first set of quality indicators (QI) specifically for MBC that should be routinely measured and evaluated to ensure that breast cancer centres meet the required standards. METHODS: A working group of multidisciplinary European experts in breast cancer met to discuss each identified QI, reporting the definition, the minimum and target standard for breast cancer centres to achieve, and the motivation for selection. The level of evidence was determined according to the short version of the United States Agency for Healthcare Research and Quality classification. RESULTS: QI to measure access to and involvement in multidisciplinary and supportive care, appropriate pathological characterisation of disease, systemic therapies and radiotherapy were developed with the consensus of the working group. CONCLUSIONS: This is the first effort of a multistep project that aims to have QI for MBC routinely measured and evaluated to ensure that breast cancer centres achieve mandated standards in the care of patients with metastatic disease.

Tailored axillary surgery in patients with clinically node-positive breast cancer: Pre-planned feasibility substudy of TAXIS (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101).

AIM: We developed tailored axillary surgery (TAS) to reduce the axillary tumor volume in patients with clinically node-positive breast cancer to the point where radiotherapy can control it. The aim of this study was to quantify the extent of tumor load reduction achieved by TAS. METHODS: International multicenter prospective study embedded in a randomized trial. TAS is a novel pragmatic concept for axillary surgery de-escalation that combines palpation-guided removal of suspicious nodes with the sentinel procedure and, optionally, imaging-guided localization. Pre-specified study endpoints quantified surgical extent and reduction of tumor load. RESULTS: A total of 296 patients were included at 28 sites in four European countries, 125 (42.2%) of whom underwent neoadjuvant chemotherapy (NACT) and 71 (24.0%) achieved nodal pathologic complete response. Axillary metastases were detectable only by imaging in 145 (49.0%) patients. They were palpable in 151 (51.0%) patients, of whom 63 underwent NACT and 21 had residual palpable disease after NACT. TAS removed the biopsied and clipped node in 279 (94.3%) patients. In 225 patients with nodal disease at the time of surgery, TAS removed a median of five (IQR 3-7) nodes, two (IQR 1-4) of which were positive. Of these 225 patients, 100 underwent ALND after TAS, which removed a median of 14 (IQR 10-17) additional nodes and revealed additional positive nodes in 70/100 (70%) of patients. False-negative rate of TAS in patients who underwent subsequent ALND was 2.6%. CONCLUSIONS: TAS selectively reduced the tumor load in the axilla and remained much less radical than ALND.

The impact of isolated local recurrence on long-term outcome in early-breast cancer patients after breast-conserving therapy.

PURPOSE: To analyse the prognostic impact of isolated local recurrence (ILR) on long-term outcome for early-breast cancer patients treated with breast-conserving therapy. MATERIAL AND METHODS: The data of the EORTC 22881-10882 'boost-no boost' and 22922-10925 'IM-MS' trials were used to analyse the prevalence and outcome following ILR. A multistate model described the impact of intermediate events on long-term outcomes, taking into account various prognostic factors. This model was used to predict long-term outcomes after ILR. RESULTS: Of the 8367 patients included, 726 experienced an ILR, 11.6% of them within the first 2 years and 30.0% after 10 years. Ten-year cumulative breast cancer mortality rates after ILR were 58.2% in patients with an ILR within 2 years, 31.0% for ILR between 2 and 4 years, 17.6% in patients with an ILR between 4 and 10 years, and 29.7% for ILR after year 10 (p < 0.001). The multistate model showed that when tumour-free, younger breast cancer patients had a higher probability of developing ILR compared to older patients. Shorter time to ILR was associated with a higher chance to develop distant metastases (DM), and a shorter time to development of DM were associated with an increased hazard of breast cancer-related death. The multistate model enabled prediction of long-term outcome based on individual patient covariates, length of follow-up without recurrence and timing of ILR since randomisation. CONCLUSIONS: Outcome of early-breast cancer changed not only according to baseline risk factors but also according to the presence of intermediate events, time to these events, and subsequent follow-up without any further events.

The value of 3D images in the aesthetic evaluation of breast cancer conservative treatment. Results from a prospective multicentric clinical trial.

PURPOSE: BCCT.core (Breast Cancer Conservative Treatment. cosmetic results) is a software created for the objective evaluation of aesthetic result of breast cancer conservative treatment using a single patient frontal photography. The lack of volume information has been one criticism, as the use of 3D information might improve accuracy in aesthetic evaluation. In this study, we have evaluated the added value of 3D information to two methods of aesthetic evaluation: a panel of experts; and an augmented version of the computational model - BCCT.core3d. MATERIAL AND METHODS: Within the scope of EU Seventh Framework Programme Project PICTURE, 2D and 3D images from 106 patients from three clinical centres were evaluated by a panel of 17 experts and the BCCT.core. Agreement between all methods was calculated using the kappa (K) and weighted kappa (wK) statistics. RESULTS: Subjective agreement between 2D and 3D individual evaluation was fair to moderate. The agreement between the expert classification and the BCCT.core software with both 2D and 3D features was also fair to moderate. CONCLUSIONS: The inclusion of 3D images did not add significant information to the aesthetic evaluation either by the panel or the software. Evaluation of aesthetic outcome can be performed using of the BCCT.core software, with a single frontal image.

Prognostic Factors for Local Control in Breast Cancer After Long-term Follow-up in the EORTC Boost vs No Boost Trial: A Randomized Clinical Trial.

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.

Cardiovascular disease after cancer therapy.

Improvements in treatment and earlier diagnosis have both contributed to increased survival for many cancer patients. Unfortunately, many treatments carry a risk of late effects including cardiovascular diseases (CVDs), possibly leading to significant morbidity and mortality. In this paper we describe current knowledge of the cardiotoxicity arising from cancer treatments, outline gaps in knowledge, and indicate directions for future research and guideline development, as discussed during the 2014 Cancer Survivorship Summit organised by the European Organisation for Research and Treatment of Cancer (EORTC). Better knowledge is needed of the late effects of modern systemic treatments and of radiotherapy to critical structures of the heart, including the effect of both radiation dose and volume of the heart exposed. Research elucidating the extent to which treatments interact in causing CVD, and the mechanisms involved, as well as the extent to which treatments may increase CVD indirectly by increasing cardiovascular risk factors is also important. Systematic collection of data relating treatment details to late effects is needed, and great care is needed to obtain valid and generalisable results. Better knowledge of these cardiac effects will contribute to both primary and secondary prevention of late complications where exposure to cardiotoxic treatment is unavoidable. Also surrogate markers would help to identify patients at increased risk of cardiotoxicity. Evidence-based screening guidelines for CVD following cancer are also needed. Finally, risk prediction models should be developed to guide primary treatment choice and appropriate follow up after cancer treatment.

Accelerated partial breast irradiation: the need for well-defined patient selection criteria, improved volume definitions, close follow-up and discussion of salvage treatment.

Breast-conserving therapy, including whole breast irradiation, has become a well-established alternative to mastectomy in early-stage breast cancer patients, with similar survival rates and better cosmetic outcome. However, many women are still treated with mastectomy, due to logistical issues related to the long course of radiotherapy (RT). To reduce mastectomy rates and/or omission of RT after breast-conserving surgery, shorter, hypofractionated RT treatments have been introduced. More recently, the necessity of routinely treating the entire breast in all patients has been questioned, leading to the development of partial breast radiotherapy. With accelerated partial breast irradiation (APBI) these two approaches have been combined: the tumor bed with a 1-2 cm margin is irradiated either intra-operatively (single fraction) or postoperatively over 5-15 days. Different techniques have been developed, including interstitial brachytherapy, intra-cavity brachytherapy, intra-operative radiotherapy and external beam radiotherapy. These techniques are being evaluated in several ongoing phase III studies. Since its introduction, APBI has been the subject of continuous debate. ASTRO and GEC-ESTRO have published guidelines for patient selection for APBI, and strongly recommend that APBI be carried out within ongoing clinical trials. Recently, the patient selection criteria for APBI have also been up for debate, following the publication of results from different groups that do/do not confirm a difference in recurrence risk among the ASTRO defined risk groups. This paper reviews the different APBI techniques, current recommendations for patient selection, available clinical data and ongoing clinical trials. A case report is included to illustrate the need for careful follow-up of patients treated with APBI.

Recommendations for the aesthetic evaluation of breast cancer conservative treatment.

During the Turning Subjective Into Objective seminar held in Lisbon in May 2011, experts in the topic gathered to discuss the unsolved problems of aesthetic evaluation of breast-conserving treatment (BCT). The purpose of this study is to review the main methodological issues related to the aesthetic evaluation of BCT, to discuss currently used methods of evaluation and the lack of a gold standard, and to write a set of recommendations that can be used as guidance for the aesthetic evaluation of BCT.

Docetaxel in the management of patients with head and neck squamous cell carcinoma.

The taxanes play a significant role in the treatment of various solid tumors of epithelial origin. Docetaxel is the most extensively studied taxane in prospective head and neck cancer trials and has been investigated as induction chemotherapy or in combination with radiotherapy in locally advanced squamous cell carcinomas of the head and neck (HNSCC) and as palliation in recurrent or metastatic disease. The data in locally advanced disease are particularly compelling. Three recently reported randomized trials, carried out in patients with locally advanced disease who were receiving induction chemotherapy followed by radiotherapy or chemoradiotherapy, demonstrated that adding docetaxel to the standard induction regimen of cisplatin/5-fluorouracil (PF) significantly improved survival compared with PF alone, without significantly increasing toxicity. On the basis of these trials, docetaxel/PF (TPF) has become the current standard induction regimen and TPF-based sequential therapy can be considered a standard treatment alternative to chemoradiotherapy alone in patients with locally advanced HNSCC. This review article discusses the current developments of docetaxel-based chemotherapy and the optimal use of this agent in patients with HNSCC.

Long-term results of stomach-conserving therapy in gastric MALT lymphoma.

PURPOSE: To evaluate long-term results of stomach-conserving therapy and to assess the value of histological probable minimal residual disease (pMRD) in predicting outcome in patients with gastric MALT lymphoma. MATERIALS AND METHODS: We studied 115 patients with stage I-II(2) gastric MALT lymphoma treated between 1975 and 2002. Initially, first-line treatment consisted of radiotherapy only. Since 1994 most patients were primarily treated with Helicobacter pylori eradication; radiotherapy was used in case of eradication failure. To assess the value of pMRD, first follow-up biopsy samples classified as compete remission (CR) according to classical clinico-pathological criteria and biopsy samples 1 year after assessment of histological CR were reviewed; results were related to outcome. RESULTS: Following radiotherapy only (n=56) 96% achieved a clinical CR; 10-year cancer-specific survival rate was 94%. Following H. pylori eradication only (n=35) CR-rate was 43% and after additional treatment 89%; 5-year cause-specific survival was 93%. There was no difference in relapse rate following initial histological CR or pMRD. CONCLUSIONS: Patients with early stage gastric MALT lymphoma have a favorable long-term outcome following conservative treatment. Outcome after H. pylori eradication followed by delayed radiotherapy on indication was excellent. In our series pMRD was not associated with increased risk of recurrence.

Is face-only photographic view enough for the aesthetic evaluation of breast cancer conservative treatment?

The breast cancer conservative treatment. cosmetic results (BCCT.core) is a new software tool created for the automatic and objective evaluation of the aesthetic result of BCCT. It makes use of a face-only photographic view of each patient and might thus have been considered insufficient for an accurate evaluation, as others have used multiple views of each patient. The purpose of this work is to compare the performance of the BCCT.core (using face-only views) with a subjective expert analysis using both the face-only and four-view assessment. Photographs in four-views of 150 patients, were evaluated by a panel of experts and a consensus classification was obtained. The agreement between the consensus and the BCCT.core (face-only view) was calculated using the kappa (k) and weighted kappa (wk) statistics. Face-only views, of the same 150 patients, were subsequently sorted out in a different order and sent for individual evaluation by three specialists from the previous panel of experts. The individual agreement between the face-only view and the four-view evaluation by each of the three experts and the consensus was calculated using the same methods. Obtained results were compared to the BCCT.core performance. The software obtained a moderate agreement with the consensus (k = 0.57; wk = 0.68). The highest value of agreement, from the three experts, between the four-view evaluation and the consensus was identical to the software agreement (k = 0.55; wk = 0.67). In the face-only view experiment, the highest value of agreement between the experts and the consensus was only fair (k = 0.37; wk = 0.54). Performance of the software was thus considered equal to that obtained by experts using a four-view evaluation.

Turning subjective into objective: the BCCT.core software for evaluation of cosmetic results in breast cancer conservative treatment.

Twelve expert observers from nine different countries convened in a workshop to evaluate the validity of the Breast Cancer Conservative Treatment. Cosmetic results (BCCT.core) software, an objective method for the aesthetic evaluation of breast cancer conservative treatment. Experts were initially asked to subjectively classify the aesthetic results of 30 photographed cases submitted to breast cancer conservative treatment according to the four-point Harris scale. It was pre-established that if at least two-thirds [Cardoso MJ, Cardoso J, Santos AC, Barros H, Oliveira MC. Interobserver agreement and consensus over the esthetic evaluation of conservative treatment for breast cancer. Breast 2005] of participants provided the same classification this would be considered a consensual evaluation for that case. For cases where such agreement was not reached, consensus was obtained using a nominal group technique. Experts then individually performed objective evaluation of the same set of photographs using the BCCT.core software. This provides an automatic rating of aesthetic results, once scale and reference points in the photograph have been chosen. Agreement between observers, between each observer and the consensus, for computer evaluation obtained by the different participants and between software and consensus was calculated using multiple kappa (k) and weighted kappa (wk) statistics. In the subjective assessment, first-round consensus was achieved in 17 (57%) cases. Overall interobserver agreement was fair to moderate (k=0.40, wk=0.57). In the objective assessment there was a higher level of concordance between participants (k=0.86, wk=0.90). Agreement between software and consensus classification was fair (k=0.34, wk=0.53), but was higher in the 17 cases that reached first-round consensus (k=0.60, wk=0.73). Merging the two middle classes of the Harris scale, to form a three-point scale, led to an improvement of all non-weighted measures of agreement. These results show that the BCCT.core software provides consistent evaluation of cosmesis. It has the potential to become a gold standard method for assessment of breast cosmesis in clinical trials, as it can be used simultaneously by a panel of observers from different parts of the world to provide more reliable assessments than has been possible previously.

Factors determining esthetic outcome after breast cancer conservative treatment.

The aim of this study was to evaluate the factors that determine esthetic outcome after breast cancer conservative treatment, based on a consensual classification obtained with an international consensus panel. Photographs were taken from 120 women submitted to conservative unilateral breast cancer surgery (with or without axillary surgery) and radiotherapy. The images were sent to a panel of observers from 13 different countries and consensus on the classification of esthetic result (recorded as excellent, good, fair or poor) was obtained in 113 cases by means of a Delphi method. For each patient, data were collected retrospectively regarding patient characteristics, tumor, and treatment factors. Univariate and multivariate analysis were used to evaluate the correlation between these factors and overall cosmetic results. On univariate analysis, younger and thinner patients as well as patients with lower body mass index (BMI) and premenopausal status obtained better cosmetic results. In the group of tumor- and treatment-related factors, larger removed specimens, clearly visible scars, the use of chemotherapy and longer follow-up period were associated with less satisfactory results. On multivariate analysis, only BMI and scar visibility maintained a significant association with cosmesis. BMI and scar visibility are the only factors significantly associated with cosmetic results of breast cancer conservative treatment, as evaluated by an international consensus panel.