536 Background: International guidelines differ in their recommendation for adjuvant chemotherapy in small node negative TNBC. We evaluated associations of chemotherapy with long-term outcome in a large population-based TNBC cohort. Methods: All patients diagnosed with pT1N0M0 TNBC between 2005 and 2015 were identified from the Netherlands Cancer Registry. Patient, tumor and therapy characteristics were recorded. Date and cause of death were obtained from Statistics Netherlands. We used multivariable cox regression models to evaluate associations of chemotherapy with overall survival (OS) and breast-cancer specific survival (BCSS), adjusted for baseline characteristics. Subgroup analyses were performed by tumor size and grade. Results: We identified 4393 patients: 284 with T1a, 924 with T1b, and 3185 with T1c tumors. Chemotherapy was administered in 53% of patients: 6% with T1a, 17% with T1b and 67% with T1c. Chemotherapy use increased over time and varied by geographic region. Patients receiving chemotherapy were younger, had larger tumors, higher tumor grade, and more often isolated tumor cells (itc) in the lymph nodes. At a median follow-up of 7 years (IQR 5-10 years), 611 patients had died, of whom 287 due to breast cancer. Chemotherapy was associated with improved OS in the whole group (adjusted hazard ratio [aHR] 0.55; 95% CI 0.44–0.69), in the pT1c subgroup (aHR 0.53, 95% CI 0.41-0.67), and in grade 3 tumors (aHR 0.50, 95% CI 0.39-0.65). Associations were not significant for pT1ab or grade 1-2 tumors (table). Findings for BCSS were in line with OS results (table). To illustrate the absolute difference we estimated 10-year OS and BCSS for a 60-year old woman with a pT1cN0(itc+) grade 3 TNBC. The predicted 10-year OS was 67% with chemotherapy and 49% without; predictions for 10-year BCSS were 80% and 66%, respectively. Conclusions: Adjuvant chemotherapy is associated with higher OS and BCSS in small node negative TNBC. Benefit is most evident in grade 3 tumors and tumors > 1cm and not evident in tumors ≤1cm and grade 1-2.[Table: see text]
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1097 Background: Oligometastatic breast cancer (OMBC) is a clinical entity with favorable prognosis compared to MBC in general, but the optimal treatment for individual patients remains unclear. We compared high dose chemotherapy (HDCT) to conventional dose chemotherapy (CDCT) in patients receiving local ablative therapy (LAT) of all disease sites in HER2-negative OMBC that harbors homologous recombination deficiency (HRD). Methods: In this open-label phase 3 study, we randomly assigned patients with OMBC after 3 cycles of induction CDCT to either continue with CDCT (up to a maximum total of 8 cycles) or switch to HDCT. OMBC was defined as 1-3 distant metastatic lesions, with or without locoregional disease, all amenable to LAT. Main eligibility criteria included pathologic proof of a distant metastatic lesion, HRD (based on either germline BRCA1/2 mutation and/or a BRCA-like profile in the tumor), and a favorable response to induction CDCT. The primary endpoint was event-free survival (EFS), defined as time since randomization to recurrence or death. Overall survival (OS), safety and quality of life (QoL) were key secondary endpoints. Following the advice of the independent data monitoring committee, analyses were performed before the prespecified number of events was reached. Results: Between November 2012 and May 2022, 36 patients were allocated to HDCT and 39 to CDCT. 52 (69%) tumors were triple negative and 23 (31%) were hormone receptor positive; 39 patients (52%) had a solitary metastasis and 43 (57%) had synchronous OMBC. After a median follow-up of 52 months (interquartile range 28-97), 42 EFS-events had occurred. Median EFS in the HDCT-group was 28 months (95% CI 21 – not reached (NR)) compared to 25 months (95% CI 14 – NR) in the CDCT-group (hazard ratio (HR) 0.78 (95% CI 0.42 – 1.42, p = 0.411). Median OS was 67 months (95% CI 37 – NR) in the HDCT-group versus 36 months (95% CI 26 – NR) in the CDCT-group (HR 0.74, 95% CI 0.37 – 1.48, p = 0.398). 5-year EFS was 40% and 30%, and 5-year OS was 51% and 49% in the HDCT- and CDCT-group, respectively. 34 (94%) patients in the HDCT-group experienced grade 3 or higher adverse events, compared to 25 (64%) patients in the CDCT-group; no grade 5 adverse events occurred. QoL was comparable between groups at 12 months. Conclusions: HDCT does not improve outcome compared to CDCT in patients with OMBC harboring HRD and can therefore not be recommended. Survival in this highly selected group of patients with OMBC, all receiving LAT, compares favorably to survival in the overall MBC population. The optimal systemic therapy for patients with OMBC requires further study. Clinical trial information: NCT01646034 .
BackgroundPrevious 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.MethodsIn 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.FindingsWe 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).InterpretationRCB 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.FundingNational Cancer Institute at the US National Institutes of Health.
An inherited single nucleotide variant (SNV) in the 5'UTR of the BRCA1 gene c.-107A > T was identified to be related to BRCA1 promoter hypermethylation and a hereditary breast and ovarian cancer phenotype in two UK families. We investigated whether this BRCA1 variant was also present in a Dutch cohort of breast and ovarian cancer patients with tumor BRCA1 promoter hypermethylation. We selected all breast and ovarian cancer cases that tested positive for tumor BRCA1 promoter hypermethylation at the Netherlands Cancer Institute and Sanger sequenced the specific mutation in the tumor DNA. In total, we identified 193 tumors with BRCA1 promoter hypermethylation in 178 unique patients. The wild-type allele was identified in 100% (193/193) of sequenced tumor samples. In a large cohort of 178 patients, none had tumors harboring the previously identified c.-107A > T SNV in BRCA1. We therefore can conclude that the germline SNV is not pervasive in patients with tumor BRCA1 promoter hypermethylation.
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.
Importance The absolute benefit of chemotherapy for all patients with stage I triple-negative breast cancer (TNBC) is unclear, and biomarkers are not currently available for selecting patients with an excellent outcome for whom neoadjuvant or adjuvant chemotherapy may have negligible benefit. High levels of stromal tumor-infiltrating lymphocytes (sTILs) are associated with favorable survival in TNBC, but data solely in stage I TNBC are lacking. Objective To examine the outcomes of patients of all ages with stage I TNBC solely and who received neither neoadjuvant nor adjuvant chemotherapy, according to centrally reviewed sTIL levels at prespecified cutoffs. Design, Setting, and Participants This cohort study used the Netherlands Cancer Registry to identify patients diagnosed with stage I TNBC between January 1, 2005, and December 31, 2015, who were not treated with chemotherapy. Only patients who did not receive neoadjuvant and/or adjuvant chemotherapy were selected. The clinical data were matched with their corresponding pathology data provided by the Dutch Pathology Registry. Data analysis was performed between February and October 2023. Main Outcomes and Measures The primary end point was breast cancer–specific survival (BCSS) at 5, 10, and 15 years for the prespecified sTIL level cutoffs of 30%, 50%, and 75%. Hematoxylin and eosin–stained slides were used for central review of histologic subtype, grade, and lymphovascular invasion. The International Immuno-Oncology Biomarker Working Group guidelines were used to score the sTIL levels; these levels were determined for 1041 patients. Results Of a total of 4511 females with stage I TNBC, patients who were not treated with chemotherapy were selected and tissue blocks requested; sTILs were scored in 1041 patients (mean [SD] age at diagnosis, 64.4 [11.1] years, median follow-up 11.4 [95% CI, 10.9-11.9] years) who were included in the analyses.. Most tumors (952 [91.5%]) were invasive carcinomas of nonspecial histologic subtype. Most patients (548 [52.6%]) had pT1cN0 tumors. Median (range) sTIL level was 5% (1%-99%). A total of 775 patients (74.4%) had sTIL levels below 30%, 266 (25.6%) had 30% or greater, 203 (19.5%) had 50% or greater, and 141 (13.5%) had 75% or greater. Patients with pT1abN0 tumors had a more favorable outcome vs patients with pT1cN0 tumors, with a 10-year BCSS of 92% (95% CI, 89%-94%) vs 86% (95% CI, 82%-89%). In the overall cohort, sTIL levels of at least 30% were associated with better BCSS compared with sTIL levels less than 30% (96% and 87%, respectively; hazard ratio [HR], 0.45; 95% CI, 0.26-0.77). High sTIL levels of 50% or greater were associated with a better outcome than low sTIL levels of less than 50% (HR, 0.27; 95% CI, 0.10-0.74) in patients with pT1C tumors, with a 10-year BCSS of 95% increasing to 98% with sTIL levels of 75% or greater. Conclusions and Relevance Results of this study showed that patients with stage I TNBC and high level of sTILs who did not receive neoadjuvant or adjuvant chemotherapy had excellent 10-year BCSS. The findings further support the role of sTILs as integral biomarkers in prospective clinical trials of therapy optimization for this patient population.
Abstract Introduction International guidelines recommend chemotherapy for most patients with stage I triple negative breast cancer (TNBC), except for special histological subtypes. However, the absolute benefit of systemic treatment for all stage I TNBC patients is not well known and no tools are yet available to select patients with an excellent prognosis for whom the chemotherapy can be safely omitted. High levels of stromal tumor infiltrating lymphocytes (sTILs) are strongly associated with favorable prognosis in TNBC, however, data solely focusing on patients with stage I TNBC who did not receive chemotherapy are lacking. Methods Patients with pT1N0M0 TNBC diagnosed between 2005 and 2015 not treated with (neo)adjuvant chemotherapy were identified from the nationwide Netherlands Cancer Registry (NCR) and linked to the national pathology database (PALGA). Newly sectioned hematoxylin & eosin (H&E) slides were used for central review of the histology and sTILs scoring following the International TIL working group guidelines (www.tilsinbreastcancer.org). Cause of death was provided by Statistics Netherlands (CBS). Primary endpoint was breast-cancer specific survival (BCSS) at 5-, 10- and 15-years for prespecified sTILs cut-offs of 30%, 50% and 75% sTILs. Results sTILs were evaluated for 1,041 patients with stage I TNBC who did not receive (neo)adjuvant chemotherapy. Mean age at diagnosis was 64.4 years [range 26 – 96] and median sTILs value was 5%. Most tumors (91.5%) were invasive ductal adenocarcinomas of no special type (NST) and 6.6% were of histological special types. In 52% of the patients the tumor was >1cm (pT1cN0). Median follow-up was 9.4 years in which 335 patients had died, of whom 107 due to breast cancer. Patients with pT1abN0 tumors had a favorable prognosis compared with patients with a pT1cN0 tumor (HR 0.47, CI 0.32- 0.72). 10-year BCSS in patients with pT1ab was 91.8% and 85.8% in patients with pT1c tumors. In the overall cohort, sTILs-levels of at least 30% were associated with better BCSS compared to sTILs < 30% (HR 0.45, CI 0.26 – 0.77), with 10year-BCSS of 96% and 87%, respectively (table 1). Patients with TNBC of special histological subtype had low sTILs (median 1%). A univariate cox model showed no association between sTILs (continuous) and BCSS in TNBC of special histological subtype (p = 0.56). Next, the prognostic value of sTILs was evaluated separately for pT1ab and pT1c. High sTILs ≥50% were not associated with improved BCSS compared to low sTILs < 50% in patients with pT1ab (HR 1.35, CI 0.65 – 2.82, p = 0.42). In contrast, high sTILs ≥50% showed a strong prognostic importance over low sTILs < 50% (HR 0.27, CI 0.10 – 0.74) in patients with pT1C tumors. We found excellent 10year-BCSS of 95% for patients if sTILs ≥50%, which further increases to 98% with sTILs ≥75% contrasting 10year-BCSS of 83% for patients with sTILs < 30%. Conclusions sTILs-levels provide important prognostic information in patients with stage I TNBC who did not receive (neo)adjuvant chemotherapy. The outcome of patients with pT1c TNBC and sTILs ≥50% was excellent, with 10year-BCSS of 95%, and 98% if sTILs >75%. This large registry study provides a foundation for clinical trials in patients with stage I TNBC with high TILs to prospectively confirm their excellent survival without chemotherapy. Citation Format: Veerle Geurts, Sara Balduzzi, Hugo Horlings, Tessa G Steenbruggen, Sabine Siesling, Sylvia Adams, Gabe Sonke, Roberto Salgado, Marleen Kok. Tumor Infiltrating Lymphocytes identify patients with stage I TNBC with excellent outcome without chemotherapy [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-28-10.
Excessive hair growth is a common and distressing complaint in women. It is imperative to differentiate excessive hair growth from hirsutism with possible other signs of virilization. Hirsutism is commonly attributed to polycystic ovary syndrome (PCOS). Hirsutism with rapid onset or progression, potentially combined with other signs of virilisation or secondary amenorrhea, should prompt evaluation of other underlying causes. In this clinical lesson, we present three cases of hirsutism to illustrate red flags to consider rare diagnoses. Diagnoses include non-classical congenital adrenal hyperplasia, a testosterone-secreting Leydig-cell tumour and PCOS. Early recognition and diagnosis can improve quality of life and, in cases of malignancy, enhance survival outcomes.
