Residual Cancer Burden (RCB) after neoadjuvant chemotherapy (NAC) is validated to predict event-free survival (EFS) in breast cancer but has not been studied for invasive lobular carcinoma (ILC). We studied patient-level data from a pooled cohort across 12 institutions. Associations between RCB index, class, and EFS were assessed in ILC and non-ILC with mixed effect Cox models and multivariable analyses. Recursive partitioning was used in an exploratory model to stratify prognosis by RCB components. Of 5106 patients, the diagnosis was ILC in 216 and non-ILC in 4890. Increased RCB index was associated with worse EFS in both ILC and non-ILC ( p = 0.002 and p < 0.001, respectively) and remained prognostic when stratified by receptor subtype and adjusted for age, grade, T category, and nodal status. Recursive partitioning demonstrated residual invasive cancer cellularity as most prognostic in ILC. These results underscore the utility of RCB for evaluating NAC response in those with ILC.

Background The NRG/RTOG 9804 and ECOG-ACRIN E5194 studies sub-classified duct carcinoma in situ (DCIS) into different risk groups after breast conservation surgery (BCS) based on size, DCIS grade, and margin width. NRG/RTOG 9804 randomized patients with “good risk” DCIS (size ≤2.5 cm, grade 1-2, margin ≥3mm) to whole breast radiation (RT) or none, and ECOG-ACRIN E5194 had 2 cohorts, one observing patients with the same “good risk” characteristics after BCS without RT. In both trials, the use of tamoxifen) was optional but tracked. This ancillary analysis of both trials was undertaken to assess the role of tamoxifen alone on ipsilateral breast recurrence (IBR) in this “good risk” group not receiving RT. Methods A combined database from the non-RT arm of NRG/RTOG 9804 and the “good risk” cohort from ECOG-ACRIN E5194 was created and distributions of patient and DCIS characteristics by tamoxifen use (yes vs. no) were compared using the Chi-square test. IBR, invasive IBR, DCIS IBR and contralateral breast event (CBE) were estimated by the cumulative incidence method and distributions between tamoxifen use were compared using Gray’s test. A 2-sided significance level of 0.05 was used. Univariate and multivariable Fine-Gray regression was used to analyze the effects of factors, in addition to tamoxifen use, that may be associated with endpoints. Results 878 patients were analyzed, 317 patients from NRG/RTOG 9804, and 561 from ECOG-ACRIN E5194. Median age was 59, margin width was ≥3mm or negative by re-excision in 97.8%, size was ≤5mm in 48.1%, and grade was 1-2 in 87.5%. The use of tamoxifen in the combined no-RT group was 43.1% (65.6% in NRG/RTOG 9804 and 30.3% in ECOG-ACRIN E5194). Median follow up of all patients was 14.85 years. There were 117 IBR, 65 invasive and 52 DCIS. There was a statistically significant association for reduced IBR with tamoxifen use (p=0.001); estimated 15-year IBR (95% CI) with tamoxifen is 11.4% (7.9%, 15.5%) and without is 19.0% (15.3%, 22.9%). Further analysis showed the reduction to be significantly associated with tamoxifen use for invasive IBR (p=0.0048) but not for DCIS IBR (p=0.089). No associations were seen for CBE. On univariable analysis, pathologic size (≤ 5 mm vs. > 10 mm) was significantly associated with IBR (p=0.0001) as was DCIS grade (1 vs 2, p=0.042). On multivariable analysis for IBR, DCIS grade fell out of the model and after adjusting for pathologic size, tamoxifen use remained statistically significantly associated with reduced IBR. On multivariable analysis for invasive IBR, size fell out of the model and adjusting for grade, tamoxifen use remained statistically significantly associated with reduced invasive IBR. Patients who received tamoxifen were 44% less likely to have any IBR (HR = 0.56, 95% CI: 0.38, 0.84; p=0.0044), and 51% less likely to have invasive IBR (HR=0.49, 95% CI: 0.28, 0.84; p=0.0092), as compared to patients with no tamoxifen. Conclusions For women with “good risk” DCIS who opt for BCS without RT, the use of tamoxifen is significantly associated with a reduction in IBR overall and specifically invasive IBR, not DCIS IBR. Citation Format: Ian Kunkler, Nicola Russell, Niall Anderson, Fidelis Muturi, Geertjan van Tienhoven, David Cameron, John Bartlett, Karen Taylor, Tammy Piper, Mike Dixon, Galina Velikova, Edwin Aird, Boon Chua, Coen Hurkmans, Karen Venables, Linda Williams, Jeremy Thomas, Marjory Maclennan, Richard Sainsbury, Susan Cleator, Eldo Verghese, Yexiong Li, Shulian Wang, Peter Canney. Does postmastectomy radiotherapy in 'intermediate-risk' breast cancer impact overall survival? 10 year results of the BIG 2-04 MRC SUPREMO randomised trial: on behalf of the SUPREMO trial investigators [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2024; 2024 Dec 10-13; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(12 Suppl):Abstract nr GS2-03.

Microsoft Excel workbook containing the following gene lists and information; A) 500 most variable genes from Figure 1D, B) differentially expressed genes between ILC and IDC at baseline and 3 months of treatment using Rank Products with a cut-off of 0.05 PFP figure 2, C) differentially expressed genes after 3 months of letrozole in ILC and IDCILC tumors using pairwise Rank Products with a cut-off of 0.05 PFP (percent false positive) from figure 3, D) genes from Sikora et al. 2014 [5] that were represented in the combined Affymetrix/Illumina dataset, E) Additional sample information including the NCBI GEO Accession numbers of the Affymetrix data.

Breast cancers are complex ecosystems of malignant cells and the tumour microenvironment(1). The composition of these tumour ecosystems and interactions within them contribute to responses to cytotoxic therapy(2). Efforts to build response predictors have not incorporated this knowledge. We collected clinical, digital pathology, genomic and transcriptomic profiles of pre-treatment biopsies of breast tumours from 168 patients treated with chemotherapy with or without HER2 (encoded by ERBB2)-targeted therapy before surgery. Pathology end points (complete response or residual disease) at surgery(3) were then correlated with multi-omic features in these diagnostic biopsies. Here we showthat response to treatment is modulated by the pre-treated tumour ecosystem, and its multi-omics landscape can be integrated in predictive models using machine learning. The degree of residual disease following therapy is monotonically associated with pre-therapy features, including tumour mutational and copy number landscapes, tumour proliferation, immune infiltration and T cell dysfunction and exclusion. Combining these features into a multi-omic machine learning model predicted a pathological complete response in an external validation cohort (75 patients) with an area under the curve of 0.87. In conclusion, response to therapy is determined by the baseline characteristics of the totality of the tumour ecosystem captured through data integration and machine learning. This approach could be used to develop predictors for other cancers.

Abstract The prognostic value of cytonuclear grade in ductal carcinoma in situ (DCIS) is debated, partly due to high interobserver variability and the use of multiple guidelines. The aim of this study was to evaluate interobserver agreement in grading DCIS between Dutch, British, and American pathologists. Haematoxylin and eosin‐stained slides of 425 women with primary DCIS were independently reviewed by nine breast pathologists based in the Netherlands, the UK, and the USA. Chance‐corrected kappa (κma) for association between pathologists was calculated based on a generalised linear mixed model using the ordinal package in R. Overall κma for grade of DCIS (low, intermediate, or high) was estimated to be 0.50 (95% confidence interval [CI] 0.44–0.56), indicating a moderate association between pathologists. When the model was adjusted for national guidelines, the association for grade did not change (κma = 0.53; 95% CI 0.48–0.57); subgroup analysis for pathologists using the UK pathology guidelines only had significantly higher association (κma = 0.58; 95% CI 0.56–0.61). To assess if concordance of grading relates to the expression of the oestrogen receptor (ER) and HER2, archived immunohistochemistry was analysed on a subgroup (n = 106). This showed that non‐high grade according to the majority opinion was associated with ER positivity and HER2 negativity (100 and 89% of non‐high grade cases, respectively). In conclusion, DCIS grade showed only moderate association using whole slide images scored by nine breast pathologists. As therapeutic decisions and inclusion in ongoing clinical trials are guided by DCIS grade, there is a pressing need to reduce interobserver variability in grading. ER and HER2 might be supportive to prevent the accidental and unwanted inclusion of high‐grade DCIS in such trials.

Abstract Background: Achieving a pathologic complete response (pCR) has been shown on the patient level to predict excellent long-term event-free survival outcomes. Residual cancer burden (RCB) quantifies the extent of residual disease for patients who did not achieve pCR. We have previously observed in the I-SPY 2 TRIAL that while metastatic events outside the central nervous system (CNS) were dramatically reduced in the setting of pCR, the incidence of CNS metastasis remained similar across RCB classes, raising the possibility that these CNS events may be independent of response in the breast. In this study, we evaluate the type and sites of recurrences by RCB in a large pooled dataset, which allows for analysis within subtype, to validate these findings. Methods: 5161 patients pooled across 12 institutions/trials with available RCB and event-free survival (EFS) data were included in this analysis. EFS was calculated as the interval between treatment initiation, and locoregional recurrence, distant recurrence or death from any cause; patients without event are censored at time of last follow-up. The median follow-up is 4.6 years. We summarized the EFS event type, further sub-dividing the distant recurrence events (DR) by their site of relapse (CNS-only, CNS and other sites, Non-CNS). We used a competing risk (Fine-Gray) model to assess which of these site-specific relapses differ between RCB classes and estimated the cumulative incidence of CNS-only and non-CNS events at 5 years. Analyses were performed across the entire study population and within HR/HER2 defined subtypes. Results: Among the 5161 subjects, there were 1164 EFS events, including 92 (7.9%) local recurrences (without distant recurrence and/or death) and 1072 distant recurrence-free survival (DRFS) events. Among the DRFS events, 158 patients died without a distant recurrence. 914 experienced distant recurrences, including 90 (9.8%) with CNS-only, 145 (15.9%) with CNS and other sites, 664 (72.6%) with non-CNS distant recurrence; 15 (1.6%) patients had missing recurrence site information. Table 1 summarizes the cumulative incidence of CNS-only and non-CNS recurrence at 5 years and the proportion of CNS-only recurrences among DR events by RCB class overall and within each HR/HER2 subtypes. The incidence of CNS-only recurrences was low and similar across RCB classes. In contrast, the incidence of non-CNS recurrences increases with increasing RCB. As a result, CNS-only recurrences are proportionally higher within the RCB-0 and RCB-I than in the RCB-II and RCB-III groups, largely because of the low DR event rate and relative low frequency of non-CNS recurrence events within the RCB-0 and RCB-I classes. Overall, 27% of the recurrences in the setting of pCR (RCB-0) are due to CNS-only recurrences.Conclusions: Consistent with previous studies, our large pooled analysis confirmed that CNS-only recurrences are uncommon but appear similar across RCB groups, independent of response, suggesting that the CNS is a treatment sanctuary site. In contrast, non-CNS recurrence rates increase as RCB increases. These findings suggest that inclusion of CNS-only recurrences as an outcome event may impact the association between neoadjuvant therapy response and long-term outcomes in the context of current therapies. Novel therapies that cross the blood brain barrier will be needed to impact CNS recurrence rates. Table 1: Cumulative Incidence of CNS Only and non-CNS Distant Recurrences at 5 years and proportion of CNS-only events among DR eventsRCB Class0IIIIIIpOverall (5161)N16766622017806Cum. Inc. CNS Only2%2%2%1%0.627Cum. Inc. Non-CNS3%6%16%27%<0.001# CNS-Only / # DR events (%)26/96 (27%)14/74 (19%)39/443 (9%)11/301 (4%)HR-HER2- (1774)N770212590202Cum. Inc. CNS Only2%3%2%4%0.298Cum. Inc. Non-CNS4%11%19%42%<0.001# CNS-Only / # DR events (%)13/50 (26%)6/32 (19%)13/148 (9%)8/111 (7%)HR-HER2+ (572)N3766710029Cum. Inc. CNS Only1%5%5%0%0.022Cum. Inc. Non-CNS2%5%18%38%<0.001# CNS-Only / # DR events (%)4/17 (24%)3/10 (30%)6/31 (19%)0/13 (0%)HR+HER2+ (858)N31317229182Cum. Inc. CNS Only1%1%2%0%0.37Cum. Inc. Non-CNS2%3%15%26%<0.001# CNS-Only / # DR events (%)3/10 (30%)2/16 (12%)7/68 (10%)0/29 (0%)HR+HER2- (1957)N2172111036493Cum. Inc. CNS Only3%2%1%0.2%0.087Cum. Inc. Non-CNS5%4%13%20%<0.001# CNS-Only / # DR events (%)6/19 (32%)3/16 (19%)13/196 (7%)3/148 (2%) Citation Format: Sonal Shad, Marieke van der Noordaa, Marie Osdoit, Diane de Croze, Anne-Sophie Hamy, Marick Lae, Fabien Reyal, Miguel Martin, María Del Monte-Millán, Sara López-Tarruella, I-SPY 2 TRIAL Consortium, Judy C Boughey, Matthew P Goetz, Tanya Hoskin, Rebekah Gould, Vicente Valero, Gabe Sonke, Tessa G Steenbruggen, Maartje van Seijen, Jelle Wesseling, John Bartlett, Stephen Edge, Mi-Ok Kim, Jean Abraham, Carlos Caldas, Helena Earl, Elena Provenzano, Stephen-John Sammut, David Cameron, Ashley Graham, Peter Hall, Lorna Mackintosh, Fan Fang, Andrew K Godwin, Kelsey Schwensen, Priyanka Sharma, Angela DeMichele, Janet Dunn, Louise Hiller, Larry Hayward, Jeremy Thomas, Kimberly Cole, Lajos Pusztai, Laura Van't Veer, Fraser Symmans, Laura Esserman, Christina Yau. Site of recurrence after neoadjuvant therapy: A multi-center pooled analysis [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PD13-02.

BACKGROUND:Previous studies have independently validated the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. We used results from several independent cohorts in a pooled patient-level analysis to evaluate the relationship of RCB with long-term prognosis across different phenotypic subtypes of breast cancer, to assess generalisability in a broad range of practice settings. METHODS:In this pooled analysis, 12 institutes and trials in Europe and the USA were identified by personal communications with site investigators. We obtained participant-level RCB results, and data on clinical and pathological stage, tumour subtype and grade, and treatment and follow-up in November, 2019, from patients (aged ≥18 years) with primary stage I-III breast cancer treated with neoadjuvant chemotherapy followed by surgery. We assessed the association between the continuous RCB score and the primary study outcome, event-free survival, using mixed-effects Cox models with the incorporation of random RCB and cohort effects to account for between-study heterogeneity, and stratification to account for differences in baseline hazard across cancer subtypes defined by hormone receptor status and HER2 status. The association was further evaluated within each breast cancer subtype in multivariable analyses incorporating random RCB and cohort effects and adjustments for age and pretreatment clinical T category, nodal status, and tumour grade. Kaplan-Meier estimates of event-free survival at 3, 5, and 10 years were computed for each RCB class within each subtype. FINDINGS:We analysed participant-level data from 5161 patients treated with neoadjuvant chemotherapy between Sept 12, 1994, and Feb 11, 2019. Median age was 49 years (IQR 20-80). 1164 event-free survival events occurred during follow-up (median follow-up 56 months [IQR 0-186]). RCB score was prognostic within each breast cancer subtype, with higher RCB score significantly associated with worse event-free survival. The univariable hazard ratio (HR) associated with one unit increase in RCB ranged from 1·55 (95% CI 1·41-1·71) for hormone receptor-positive, HER2-negative patients to 2·16 (1·79-2·61) for the hormone receptor-negative, HER2-positive group (with or without HER2-targeted therapy; p<0·0001 for all subtypes). RCB score remained prognostic for event-free survival in multivariable models adjusted for age, grade, T category, and nodal status at baseline: the adjusted HR ranged from 1·52 (1·36-1·69) in the hormone receptor-positive, HER2-negative group to 2·09 (1·73-2·53) in the hormone receptor-negative, HER2-positive group (p<0·0001 for all subtypes). INTERPRETATION:RCB score and class were independently prognostic in all subtypes of breast cancer, and generalisable to multiple practice settings. Although variability in hormone receptor subtype definitions and treatment across patients are likely to affect prognostic performance, the association we observed between RCB and a patient's residual risk suggests that prospective evaluation of RCB could be considered to become part of standard pathology reporting after neoadjuvant therapy. FUNDING:National Cancer Institute at the US National Institutes of Health.

Abstract Background: Pathologic complete response (pCR) after neoadjuvant chemotherapy (NAC) in patients with breast cancer is associated with improved survival. Further assessment of the extent of residual disease, using the pathological anatomic American Joint Committee on Cancer staging method (ypStage) or the Residual Cancer Burden (RCB) method, have been shown to add prognostic information for patients with residual disease. Neo-Bioscore, an alternate system to classify response to NAC, includes clinical stage at diagnosis and biology and defines eight prognostic groups. The goal of this study was to compared three scoring systems (anatomic ypStage (7th ed), RCB Class and Neo-Bioscore) and assess whether RCB Class and Neo-Bioscore provide additional prognostic value in the context above anatomic ypStage, the most commonly used method for post-neoadjuvant residual disease assessment. Methods: Data from 5161 patients treated with NAC was pooled from 12 sites. Patients without clinical and pathological staging were excluded, as were patients with HER2+ breast cancer who did not receive neoadjuvant HER2-targeted therapy, leaving 3730 for analysis. PCR was defined as no residual invasive tumor in breast and nodes, i.e. RCB-0 or ypT0/Tis and ypN0. Patients with discordant pCR status by RCB Class vs ypStage (n=9) were excluded. Associations between each scoring system and event-free survival (EFS) were evaluated using the log rank test. EFS at 5 years was estimated using the Kaplan Meier method. Associations between Neo-Bioscore and EFS were assessed in the pCR group. For patients with residual disease, we assessed RCB and Neo-Bioscore within each ypStage. Analysis was performed overall and within subtype. Subgroups with <5 patients were excluded from the survival analyses. Results: ypAJCC staging, RCB class and Neo-Bioscore were all associated with EFS in the overall population and within each subtype (log rank p<0.0001). Of note, 13 patients with a Neo-Bioscore of 7 all recurred or died within 19 months of follow-up. Overall, 34% (1264/3721) of patients achieved a pCR. Their Neo-Bioscore ranges from 0-5, where 3% (37/1264) has a Neo-Bioscore of 5 despite achieving pCR. The Neo-Bioscore was not associated with EFS in case of a pCR, with EFS estimates at 5 years of 95%, 94%, 92%, 93%, 90% and 92% for Neo-Bioscores 0-5 respectively. As HR and HER2 status are components of the score, the range of Neo-Bioscore in the pCR group differs by subtype. However, similar to the overall analysis, the Neo-Bioscore was not prognostic within subtypes in case of pCR. Overall, among the patients who did not achieve pCR, both RCB class and Neo-Bioscore were associated with EFS within ypStages I, II and III. However, the ypStage within which RCB and Neo-Bioscore are prognostic is different for each subtype. RCB class was prognostic in ypStage I in both HR+ subtypes: patients with ypStage-I/RCB-I had significantly improved survival compared to patients with ypStage-I/RCB-II (5-year EFS: 100% vs 83% in HR+HER2- and 95% vs 77% in HR+HER2+). In contrast, for patients with triple negative breast cancer, RCB class was prognostic within ypStage II and III. Analysis by clinical stage and the components of the three systems that contribute most to prognosis will be presented. Conclusions: The degree of response to NAC adds important information to pCR versus residual disease. The Neo-Bioscore was not prognostic among patients with pCR, suggesting that clinical stage (including subtype and grade) adds little information in the setting of a pCR. In contrast, both RCB and Neo-Bioscore provide additional prognostic information to the conventional ypAJCC staging among non-pCR patients, suggesting that clinical stage, tumor biology as well as extent of residual disease all contribute to prognosis in the setting of residual disease after NAC. Citation Format: Marieke EM van der Noordaa, Christina Yau, Sonal Shad, Marie Osdoit, Tessa G Steenbruggen, Diane de Croze, Anne-Sophie Hamy, Marick Lae, Fabien Reyal, Maria Del Monte-Millán, Miguel Martin, Sara Lopez Tarruella, I-SPY 2 TRIAL Consortium, Judy C Boughey, Matthew Goetz, Tanya Hoskin, Rebecca Gould, Vincent Valero, Gabe Sonke, Maartje van Seijen, Jelle Wesseling, John Bartlett, Stephan Edge, Mi-Ok Kim, Jean Abraham, Carlos Caldas, Helena Earl, Elena Provenzano, Stephen-John Sammut, David Cameron, Ashley Graham, Peter Hall, Lorna MacKintosh, Fang Fan, Andrew K Godwin, Kelsey Schwensen, Priyanka Sharma, Angela DeMichele, Janet Dunn, Louise Hiller, Larry Hayward, Jeremy Thomas, Kimberley Cole, Lajos Pusztai, Laura van 't Veer, Fraser Symmans, Laura Esserman. Assessing prognosis after neoadjuvant therapy: A comparison between anatomic ypAJCC staging, residual cancer burden class and neo-bioscore [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr GS4-07.

We explored, within the EORTC10994 study, the outcomes for patients with molecular apocrine (MA) breast cancer, and defined immunohistochemistry (IHC) as androgen-receptor (AR) positive, oestrogen (ER) and progesterone (PR) negative. We also assessed the concordance between IHC and gene expression arrays (GEA) in the identification of MA cancers. Centrally assessed biopsies for AR, ER, PR, HER2 and Ki67 by IHC were classified into six subtypes: MA, triple-negative (TN) basal-like, luminal A, luminal B HER2 negative, luminal B HER2 positive and "other". The two main objectives were the pCR rates and survival outcomes in the overall MA subtype (and further divided by HER2 status) and the remaining five subtypes. IHC subtyping was obtained in 846 eligible patients. Ninety-three (11%) tumours were classified as the MA subtype. Both IHC and GEA data were available for 64 patients. In this subset, IHC concordance was 88.3% in identifying MA tumours compared with GEA. Within the MA subtype, pCR was observed in 33.3% of the patients (95% CI: 29.4–43.9) and the 5-year recurrence-free interval was 59.2% (95% CI: 48.2–68.6). Patients with MA and TN basal-like tumours have lower survival outcomes. Irrespective of their HER2 status, the prognosis for MA tumours remains poor and adjuvant trials evaluating anti-androgens should be considered.

Antecedentes: Las guías de práctica clínica recomiendan tratar a los pacientes con oclusión casi completa de la arteria carótida interna (internal carotid artery near occlusion, ICANO) con el mejor tratamiento médico (best medical therapy, BMT) basado en una evidencia débil.En consecuencia, pacientes con ICANO han sido excluidos de ensayos aleatorizados.El objetivo de este metaanálisis de datos de pacientes individuales (individual patient data, IPD) fue determinar el planteamiento terapéutico óptimo.Métodos: Se realizó una búsqueda sistemática en las bases de datos de MEDLINE, EMBASE y Cochrane en enero de 2018.El resultado primario fue la aparición de cualquier accidente cerebrovascular o muerte dentro de los primeros 30 días de tratamiento, analizado mediante una regresión logística multivariada de efectos mixtos.El resultado secundario fue la aparición de cualquier accidente cerebrovascular o muerte más allá de los 30 días hasta 1 año del tratamiento, analizado mediante una curva de supervivencia de Kaplan-Meyer.Resultados: La búsqueda proporcionó 15.267 artículos, de los cuales 613 fueron recuperados para la revisión del texto completo.En 32 estudios se cumplían los criterios de inclusión y en 11 se disponía de los datos de pacientes individuales agrupados, incluyendo 703 pacientes con ICANO.Dentro de los 30 días, se describió cualquier accidente cerebrovascular o muerte en 8 pacientes (2,4%) del grupo de endarterectomía carotidea (carotid endarterectomy, CEA), en 5 pacientes (2,2%) del grupo con colocación de stent en la carótida (carotid artery stenting, CAS), y en 7 pacientes (4,9%) del grupo BMT.Esto dio lugar a una tasa más elevada de accidente cerebrovascular/muerte a los 30 días después de BMT que tras CEA (razón de oportunidades, odds ratio, OR 5,63, i.c.del 95% 1,3-24,45, P = 0,021).No se hallaron diferencias entre CEA y CAS.La tasa de supervivencia libre de accidente cerebrovascular/muerte a 1 año fue del 96,1% para CEA, 94,4% para CAS y 81,2% para BMT.Conclusión: Estos datos sugieren que BMT por si solo no es superior a CEA o CAS con respecto a la prevención de accidente cerebrovascular/muerte a los 30 días o a 1 año en pacientes ICANO.Estos pacientes no parecen constituir un subgrupo de alto riesgo para la cirugía y convendría tener en cuenta incluirlos en futuros ensayos clínicos aleatorizados de intervenciones para la arteria carótida interna. Meta-analysis of completion lymph node dissection in sentinel lymph node-positive melanomaMetaanálisis sobre completar la exéresis ganglionar en el melanoma con ganglio centinela positivo

Abstract Background: The risk of recurrence for oestrogen receptor positive (ER+) breast cancer patients treated with 5 years of adjuvant endocrine therapy persists for many years or even decades following surgery and apparently successful adjuvant therapy. This period of dormancy and acquired resistance is inherently difficult to investigate. Therefore, previous efforts have been limited to in vitro or in vivo approaches. In this study sequential tumour samples from patients receiving extended neoadjuvant endocrine treatment were characterised as a novel clinical model of ER+ breast cancer dormancy and acquired resistance. Methods: Consecutive tumour samples from 62 patients undergoing extended (4-45 months) neoadjuvant letrozole therapy were subjected to transcriptomic and proteomic analysis, representing pre- (before treatment), early-on (13-120 days) and long-term (>120 days) neoadjuvant letrozole treatment. Patients with at least a 40% initial reduction in tumour size by 4 months of treatment were included. Of these, 42 patients with no subsequent progression were classified as “dormant”, and the remaining 20 patients as “acquired resistant”. Expression analysis was performed by using Illumina BeadChips. R and BioConductor packages were used for analysis. Differentially expressed genes were determined by using paired Rank Products (FDR, 5%). Results: Multidimensional scaling using most variant 500 genes demonstrated that long-term treated dormant samples clustered separately from their matched pre- and early-on samples whereas long-term treated resistant samples were indistinguishable from their pre-treatment counterparts. Therapy-induced changes in resistant tumours were common features of treatment, rather than being specific to resistant phenotype. Comparative analysis of long-term treated dormant and resistant tumours highlighted changes in epigenetics pathways including DNA methylation and histone acetylation. DNA methylation marks 5-methylcytosine and 5-hydroxymethylcytosine were significantly reduced in resistant tumours compared to dormant tissues after extended letrozole treatment. Decrease in 5-hydroxymethylcytosine were significant early-on. Conclusions: This is the first patient-matched gene expression study investigating long-term aromatase inhibitor-induced dormancy and acquired resistance in breast cancer. Dormant tumors exhibit distinct molecular changes under extended treatment whereas acquired resistant tumors are more similar to matched diagnostic samples supporting the molecular concordance between primary tumors and metastases. Global loss of DNA methylation was observed in resistant tumours under extended treatment which can be predicted within first 4 months of therapy. Epigenetic alterations may lead to escape from dormancy and drive acquired resistance in a subset of patients supporting a potential role for therapy targeted at these epigenetic alterations in the management of endocrine resistant breast cancer. Funding: This work was supported by Marie Skłodowska-Curie Individual Fellowship [H2020-MSCA-IF, 658170] and Welcome Trust Institutional Fund (ISSF3) to CS and AHS, Breast Cancer Now to AHS. Citation Format: Selli C, Turnbull AK, Pearce D, Fernando A, Renshaw L, Thomas JS, Dixon MJ, Sims AH. Molecular characterisation of ER+ breast cancer dormancy and acquired resistance using a clinical model: Potential involvement of epigenetic regulation [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-04-03.

Abstract Background: Ductal carcinoma in situ (DCIS) is a heterogeneous precursor, non-invasive breast lesion. There is a lack of specific DCIS molecular predictors of in breast tumour recurrence (IBTR) or progression to invasive breast cancer (IBC) after breast conserving surgery (BCS) +/- radiotherapy (RT). The aim of this was to identify novel biomarkers and combine these with clinical parameters to develop a new model to predict IBTR in patients treated by BCS for DCIS. Methods: A single institution DCIS biomarker discovery study included a case-control matched series of 180 patients (median age 61, range 35-94) treated at the Edinburgh Breast Unit between 2000 and 2010: · 88 patients with low/intermediate grade DCIS treated with BCS alone; 18 recurred within 10 years. · 92 patients with high grade DCIS treated by BCS and RT; 22 recurred within 10 years. Median follow-up was 7.4 years. RNA was extracted from DCIS lesions and whole-genome transcriptomics analysis was performed using Lexogen QuantSeq. Predictive models were generated based upon the most informative genes. Independent validation cohorts are also available and are currently being used for validation. Results: The models developed predict risk of IBTR in patients with low or intermediate grade DCIS treated with BCS alone and high grade DCIS treated with DCIS plus RT. The models were found to be independent of grade and stratify patients into binary groups of high and low risk of recurrence. A promising model was developed based on the expression of 5 genes combined with tumour diameter ≤15mm or >15mm. • In low/intermediate grade DCIS expression levels of a solute carrier family gene, kinetochore associated gene and an immunomodulatory gene are predictive of recurrence. • In high grade DCIS an additional solute carrier and a glutathione S-transferase related gene are predictive of recurrence. • In the training sets the models have 96% (high-grade) and 92% (low/intermediate grade) accuracy of prediction of subsequent recurrence and estimates of IBTR-free survival were highly significant in both groups (<0.0001). Validation of the model by RT-PCR and immunohistochemistry is underway in both the training cohort and an independent validation cohort. Conclusions: · Promising models to predict risk of IBTR in patients treated for DCIS have been developed. · Novel biomarkers that predict recurrence have been identified using new technologies that may have clinical potential. · Independent validation is currently underway. Citation Format: Martinez-Perez C, Turnbull AK, Fernando A, Ekatah GE, Arthur LM, Cartlidge CW, Johns N, Sims AH, Thomas JS, Dixon JM. A predictive model for local recurrence in patients treated for ductal carcinoma in situ of the breast (DCIS) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P5-18-03.

Accurate assessment of estrogen receptor (ER) expression is crucial to ensure that patients with early breast cancer are accurately identified for appropriate treatment with endocrine therapy. Reverse transcriptase polymerase chain reaction (RT-PCR), compared with immunohistochemistry (IHC), may provide a more precise indication of ER status. Data were pooled and analyzed from two independent, but similarly designed, studies that examined ER status by IHC and the 21-gene Recurrence Score that employs RT-PCR-based methodology.

The risk of recurrence for endocrine-treated breast cancer patients persists for many years or even decades following surgery and apparently successful adjuvant therapy. This period of dormancy and acquired resistance is inherently difficult to investigate; previous efforts have been limited to in-vitro or in-vivo approaches. In this study, sequential tumour samples from patients receiving extended neoadjuvant aromatase inhibitor therapy were characterised as a novel clinical model. Consecutive tumour samples from 62 patients undergoing extended (4–45 months) neoadjuvant aromatase inhibitor therapy with letrozole were subjected to transcriptomic and proteomic analysis, representing before (≤ 0), early (13–120 days), and long-term (> 120 days) neoadjuvant aromatase inhibitor therapy with letrozole. Patients with at least a 40% initial reduction in tumour size by 4 months of treatment were included. Of these, 42 patients with no subsequent progression were classified as “dormant”, and the remaining 20 patients as “acquired resistant”. Changes in gene expression in dormant tumours begin early and become more pronounced at later time points. Therapy-induced changes in resistant tumours were common features of treatment, rather than being specific to the resistant phenotype. Comparative analysis of long-term treated dormant and resistant tumours highlighted changes in epigenetics pathways including DNA methylation and histone acetylation. The DNA methylation marks 5-methylcytosine and 5-hydroxymethylcytosine were significantly reduced in resistant tumours compared with dormant tissues after extended letrozole treatment. This is the first patient-matched gene expression study investigating long-term aromatase inhibitor-induced dormancy and acquired resistance in breast cancer. Dormant tumours continue to change during treatment whereas acquired resistant tumours more closely resemble their diagnostic samples. Global loss of DNA methylation was observed in resistant tumours under extended treatment. Epigenetic alterations may lead to escape from dormancy and drive acquired resistance in a subset of patients, supporting a potential role for therapy targeted at these epigenetic alterations in the management of resistance to oestrogen deprivation therapy.

Background: Management of screen-detected ductal carcinoma in situ (DCIS) remains controversial. Methods: A prospective cohort of patients with DCIS diagnosed through the UK National Health Service Breast Screening Programme (1st April 2003 to 31st March 2012) was linked to national databases and case note review to analyse patterns of care, recurrence and mortality. Results: Screen-detected DCIS in 9938 women, with mean age of 60 years (range 46-87), was treated by mastectomy (2931) or breast conserving surgery (BCS) (7007; 70%). At 64 months median follow-up, 697 (6.8%) had further DCIS or invasive breast cancer after BCS (7.8%) or mastectomy (4.5%) (p < 0.001). Breast radiotherapy (RT) after BCS (4363/7007; 62.3%) was associated with a 3.1% absolute reduction in ipsilateral recurrent DCIS or invasive breast cancer (no RT: 7.2% versus RT: 4.1% [p < 0.001]) and a 1.9% absolute reduction for ipsilateral invasive breast recurrence (no RT: 3.8% versus RT: 1.9% [p< 0.001]), independent of the excision margin width or size of DCIS. Women without RT after BCS had more ipsilateral breast recurrences (p < 0.001) when the radial excision margin was < 2 mm. Adjuvant endocrine therapy (1208/9938; 12%) was associated with a reduction in any ipsilateral recurrence, whether RT was received (hazard ratio [HR] 0.57; 95% confidence interval [CI] 0.41-0.80) or not (HR 0.68; 95% CI 0.51-0.91) after BCS. Women who developed invasive breast recurrence had a worse survival than those with recurrent DCIS (p< 0.001). Among 321 (3.2%) who died, only 46 deaths were attributed to invasive breast cancer. Conclusion: Recurrent DCIS or invasive cancer is uncommon after screen-detected DCIS. Both RT and endocrine therapy were associated with a reduction in further events but not with breast cancer mortality within 5 years of diagnosis. Further research to identify biomarkers of recurrence risk, particularly as invasive disease, is indicated. (C) 2018 Published by Elsevier Ltd.

Abstract Background: Approximately 40% of ER+ breast cancer present with nodal metastasis. To date, there has been no comparison of the molecular response of primary cancers and metastases to ET. Recent evidence suggests that nodal metastases have different clones and subclones compared to the primary tumour. The aim of this study is to characterise the molecular response of primaries and nodal metastases to ET. Methods: A unique set of 7 post-menopausal women with ER-positive breast cancer had biopsies taken from the primary tumour and a positive lymph node at diagnosis and at surgery following 3-12 months of neoadjuvant letrozole. 14-day and 3-6 month on-treatment biopsies from the primary tumour and involved nodes were also taken from the same patients, giving a total of 75 samples. Lymph node FFPE blocks were stained for cytokeratin and macro-dissected to enrich for tumour tissue. RNA and DNA were extracted and Ribo0-RNAseq, DNA exome sequencing and somatic mutation detection using UNCeqR performed. Whole-transcriptome AmpliSeq targeted-sequencing has been analysed for 4 patients. Results: Multi-dimensional scaling and hierarchical clustering analysis based on all transcripts and the 500 most variably expressed genes revealed that primaries and nodal metastases are strongly associated at diagnosis but some nodes diverge during ET treatment. Analysis of estrogen-responsive proliferation-associated genes (n=60) in nodal metastasis revealed a reduction in expression of the majority of genes with ET. However, the expression levels of some remained high in the on-treatment node samples in all 4 patients analysed compared with the matched primary tumour on treatment. In particular, expression of genes involved in DNA replication and regulation of cell cycle including MCM6 and RRM2 (DNA replication), ASPM and CEP55 (mitosis) and CDKN3 (regulation of cell cycle) persisted at high levels in nodal metastases, but reduced in the primary cancers. Similarly, primary tumours had increased levels of ECM remodeling genes (n=60) as treatment continued, while levels in the nodal metastasis were heterogeneous on-treatment. Full genome sequencing results will be available by December 2017. Discussion · This is the first study to investigate genomic and transcriptomic changes with ET in both primary cancers and nodal metastases. · On-treatment changes in nodal disease are heterogeneous between patients and within the same patient. · Nodal metastases do respond to ET with reduced levels of proliferation-associated genes. · Some proliferation-associated genes appear to maintain higher expression in nodal disease. · Patterns of gene expression observed in some nodal metastases are consistent with profiles previously described by us for ET resistance and recurrent disease. · Nodal metastases may accumulate mutations during treatment with ET and on-going analysis will clarify this. Citation Format: Dixon JM, Turnbull AK, Tanioka M, Parker J, He X, Fernando A, Renshaw L, Keys J, Thomas JS, Sims AH, Carey LA, Perou CM. Characterising the effects of neoadjuvant endocrine therapy on primary cancers and nodal metastasis [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P4-04-02.

Aim Fibroepithelial lesions (FELs) of the breast span a morphological continuum including lesions where distinction between cellular fibroadenoma (FA) and benign phyllodes tumour (PT) is difficult. The distinction is clinically important with FAs managed conservatively while equivocal lesions and PTs are managed with surgery. We sought to audit core biopsy diagnoses of equivocal FELs by digital pathology and to investigate whether digital point counting is useful in clarifying FEL diagnoses. Method Scanned slide images from cores and subsequent excisions of 69 equivocal FELs were examined in a multicentre audit by eight pathologists to determine the agreement and accuracy of core needle biopsy (CNB) diagnoses and by digital point counting of stromal cellularity and expansion to determine if classification could be improved. Results Interobserver variation was high on CNB with a unanimous diagnosis from all pathologists in only eight cases of FA, diagnoses of both FA and PT on the same CNB in 15 and a ‘weak’ mean kappa agreement between pathologists (k=0.36). ‘Moderate’ agreement was observed on CNBs among breast specialists (k=0.44) and on excision samples (k=0.49). Up to 23% of lesions confidently diagnosed as FA on CNB were PT on excision and up to 30% of lesions confidently diagnosed as PT on CNB were FA on excision. Digital point counting did not aid in the classification of FELs. Conclusion Accurate and reproducible diagnosis of equivocal FELs is difficult, particularly on CNB, resulting in poor interobserver agreement and suboptimal accuracy. Given the diagnostic difficulty, and surgical implications, equivocal FELs should be reported in consultation with experienced breast pathologists as a small number of benign FAs can be selected out from equivocal lesions.