In this study, we tested the hypothesis whether breast conserving therapy (BCT) compared with mastectomy is associated with a negative outcome in terms of distant metastases or death (DMD) and investigated the relation between locoregional recurrence (LRR) and DMD in young breast cancer (BC) patients. This study included a consecutive series of 536 patients ≤40 years of age at diagnosis with pathological T1N0-3M0 BC, treated between 1989 and 2005. A multistate survival model was used to evaluate the influences of local treatment and LRR on DMD, adjusted for potential prognostic factors. Patients were treated with mastectomy (N = 213) or BCT (N = 323). Median age at diagnosis was 36.3 years, with a median follow-up of 9.0 years. The 10-year actuarial cumulative incidence of DMD was 30.6 % after mastectomy and 26.3 % after BCT (P = 0.04). In total, 81 (15 %) LRRs were observed. After BCT, patients had a threefold higher risk of LRR than after mastectomy (HR 2.9; 95 % CI 1.6-5.3). Patients with LRR had a higher risk of DMD compared with patients without LRR (HR 5.5; 95 % CI 2.1-14.5). However, BCT was not negatively associated with DMD-after-LRR (HR 0.47; 95 % CI 0.2-1.1, BCT vs mastectomy). In conclusion, although LRR significantly affected DMD, the increased risk of LRR after BCT compared with mastectomy did not lead to a worse DMD outcome in BC patients ≤40 years of age.
BACKGROUND: Through the International Male Breast Cancer Program, a prospective registry for male BC was created with the goals of evaluating 1) the clinical and biological features of this disease and 2) assessing feasibility of a prospective therapeutic clinical trial. METHODS: All men, with any stage histologically proven invasive breast cancer, age 3 18 years, and newly presenting at the participating institutions (within 3 months prior) were eligible. Patients were enrolled for 30 months after activation of the first center, through February 2017. Per the study design, if <100 men enrolled, the study would be considered a failure and therapeutic trials would not be pursued through this network. Epidemiologic data, staging, pathologic features, and BRCA status were collected. Treatment and outcome data collection is ongoing. Optional collection of FFPE tumor samples, blood, and QOL were performed in the US, the Netherlands, and Latin America. Clinical database lock for this report was May 30, 2017. We currently report patient and disease characteristics and will update with patterns of treatment for the presentation. Outcomes and biological samples will be analyzed in the future. RESULTS: 557 patients were enrolled: 75% in Europe, 20% in United States, 5% in other countries. 6.3% of patients had missing forms. Median age was 67 years (range 26-92). 93% were diagnosed 2010-2017. Among patients with complete data, 79% presented with a breast mass. 88% were M0 and 12% M1. Among M0 patients: 47%, 39%, 2%, and 11% had T1, T2, T3, and T4 disease respectively; 52% were N0. Overall, 98% had ER+ disease and 11% had HER2+ cancer. 14% had grade 1, 56% had grade 2, and 30% had grade 3 tumors. Among 112 men who underwent BRCA1 testing, 1 was positive. Among 118 men who had BRCA2 testing, 18 (15%) were positive. 21% of men had prior or concurrent malignancies, with the following most common sites: prostate, non-melanoma skin, colorectal, and melanoma. The prevalence of previously identified possible risk factors for male breast cancer were: overweight/obesity (72%), former/current smoker (51%), current alcohol 31 drink daily (41%), family history of breast cancer (35%), gynecomastia (16%), history radiation exposure (8%), use of anti-androgens (1%), and use of estrogens (1%). CONCLUSION: Through an international collaborative effort, we were able to prospectively accrue 557 patients to a male breast cancer registry. These results demonstrate feasibility of pursuing a therapeutic clinical trial in men with breast cancer. In addition, this study shows the relatively low uptake of BRCA testing, high rates of concurrent/prior malignancy, and the rates of potentially modifiable risk factors in this patient population. Funding from Breast Cancer Research Foundation, Susan G. Komen, Dutch Pink Ribbon Foundation, Swedish Breast Cancer Association (BRO) and EBCC Council. Citation Format: Giordano SH, Schröder CP, Poncet C, van Leeuwen-Stok E, Linderholm B, Abreu MH, Rubio I, Van Poznak C, Morganstern D, Cameron D, Vleugel MM, Smilde TJ, Bozovic-Spasojevic I, Korde L, Russell NS, den Hoed IDM, Honkoop AH, van der Velden AWG, van 't Riet M, Dijkstra N, Bogler O, Goulioti T, Hilsenbeck S, Ruddy KJ, Wolff A, van Deurzen CHM, Martens J, Bartlett JMS, Aalders K, Tryfonidis K, Cardoso F. Clinical and biological characterization of male breast cancer (BC) EORTC 10085/TBCRC 029/BOOG 2013-02/BIG 2-07: Baseline results from the prospective registry [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 P5-23-01.
The administration of platinum-based chemotherapy induces serotonin release from the enterochromaffin cells, causing nausea and vomiting. This study was conducted to evaluate parameters of serotonin metabolism following platinum-based chemotherapy given in combination with the serotonin type-3 antagonist tropisetron as an antiemetic agent. In nine chemotherapy-naive patients with disseminated germ-cell tumors, parameters of serotonin metabolism in both blood and urine were evaluated during two consecutive courses of platinum-based chemotherapy. Serotonin concentrations in platelet-rich plasma and platelet-poor plasma as well as urinary 5-hydroxyindoleacetic acid (5-HIAA) and serotonin levels were measured during the full length of the courses. By means of comparison with the antiemetic agent chlorpromazine, used on day 1 of the first course only, the effect of the serotonin type-3 antagonist tropisetron, the antiemetic agent used during the rest of the courses, on these parameters was studied. Clinical effects were also recorded. No change in the parameters of serotonin metabolism could be demonstrated during either course by the serotonin type-3 antagonist tropisetron. Also in vitro, no effect of tropisetron on the active serotonin uptake by platelets was found. Serotonin levels in platelets showed no correlation with emetic response. However, the platelet serotonin content decreased significantly between the first and the second course (P < 0.01). The significant reduction in platelet serotonin content observed between the first and the second course indicates a depletion of total body serotonin. The role of a serotonin type-3 antagonist might be affected by the altered serotonin equilibrium during later courses of chemotherapy.
Palbociclib plus letrozole has improved both progression free survival and overall response rate in metastatic breast cancer (MBC) patients. For response to palbociclib, the best biomarker is ER expression. 16α-[18F]Fluoro-17β-estradiol (FES) -PET allows whole body ER level assessment, and provides insight in the heterogeneity of ER expression throughout the body. We hypothesized that lesions with low uptake on FES-PET are unlikely to respond to letrozole plus palbociclib. METHODS: Post-menopausal women with ER positive MBC were eligible for this pilot study. All patients were staged with fludeoxyglucose (FDG)-PET and CT scan, and in addition a FES-PET was performed at baseline. After 8 weeks treatment an FDG-PET/CT was used for response evaluation. The primary endpoint was the relation between standard uptake value (SUV) per lesion on FES-PET to response, as measured by RECIST 1.1 criteria in case of measurable disease. In case of non-measurable bone lesions, progression was defined as an increase in SUV on FDG-PET of more than 30% per lesion compared to baseline (based on PERCIST). RESULTS: 15 patients were included of which 14 were evaluable for primary endpoint. Mean age was 50 years (range 35-76). Median number of prior therapies was 1. A total of 280 lesions were detected on conventional imaging of which 50 showed low uptake (SUV<1.5) on FES-PET. 29/50 low uptake lesions showed progression based on diagnostic CT (n=9) or FDG PET (n=20). In contrast, 28/230 FES positive lesions showed progression. ResponseStable diseaseProgression FES uptake >1.51089428230FES uptake <1.57142950 11510857280 DISCUSSION: this pilot trial indicates negative predictive value of low FES uptake for response to letrozol plus palbociclib in ER positive MBC. The FES-PET may therefore be a biomarker for response for this combination treatment. This will have to be explored further in future clinical trials. Citation Format: Venema CM, de Vries EFJ, Glaudemans AWJM, Hospers GAP, Schröder CP. Molecular imaging for early identification of patients who benefit from palbociclib in addition to letrozole [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 PD2-12.
Introduction. Male breast cancer (male BC) is a rare disease for which disease management is extrapolated from females. IMBC, an international consortium, which previously reported on clinico-pathological aspects, now reports on molecular subgroups revealed by RNA sequencing and their relation to patient outcome. Methods. Tumor samples from the retrospective MALE BC registry diagnosed between 1990-2010 and with pathology and outcome data (relapse-free- (RFS) and overall survival (OS)) were included (n=699). To allow the discovery of prognostic features, we selected, stratified for known risk factors (TN stage, grade, age at diagnose and adjuvant endocrine treatment), from the cohort 152 cases with poor (RFS <= 4 yrs) and good outcome (RFS > 7yrs) evenly distributed. Here, we report RNA sequencing results of the first 73 cases, 38 with poor and 35 with good outcome. RNA sequencing reads were used to generate gene expression values and to report transcripts carrying driver mutations. Unsupervised clustering identified subgroups and within subgroups differentially expressed genes were identified. The reported prognostic male BC subgroups M1 and M2 (Johansson BCR 2012(14):R31) were also annotated. All identified subgroups were related to outcome using logistic regression (p-value using Wald test). Results. Unsupervised clustering revealed 2 main subgroups of which group 1 was enriched for expression of ER target genes, WNT3 and genes from amplicons known for female BC, e.g. 19p13 (CCNE1), 8q24 (MYC), and 11q13 (CCND1). The biology of the smaller group 2 was less defined but TGFβ2 expression was high as were various kallikreins (KLK) including interestingly KLK3 (prostate specific antigen). Other known amplified regions [(8p11 (FGFR1), 20q13 (ZNF217) and 12q15 (MDM2)] and mutated transcripts [PIK3CA (H1047R/L/Q; E542K, E545K, N345K; 16% of cases), TP53 and SF3B1 (K700E) (2% of cases)] were identified. Profound tumor infiltrate gene expression was present in 5% of cases and one third of cases expressed proliferation markers. Except for TP53, none of these latter characteristics were unevenly distributed among the 2 main subgroups. ER and AR were highly correlated, particularly in group 1. The two main groups could be further subdivided. Group 1 comprised 3 subgroups of which subgroup 1a expressed TFF1/3 and NAT1, well-known ER targets, while subgroups 1b and 1c expressed other ER targets,respectively BEX1 and PITX1. HOXC cluster expression differentiated subgroup 1b from 1a and 1c. None of these intrinsic subgroups were, however, related to RFS. The previously reported M2 subgroup, which largely segregated with subclusters 1a and 1b, was associated with a better RFS than the M1 subgroup (OR=2.9; 95%CI 1.1-7.5; p-value=0.03). Conclusions. 1) Intrinsic subtypes of male BC were revealed and their subgrouping is defined by ER associated subsets of genes. 2) The association of the reported M2 subgroup of male BC with longer RFS was validated; 3) Currently identified biological characteristics of male BC may improve future treatments. The full report on 152 cases including a comparison to female BC will be presented at the conference. This research was funded by Breast Cancer Research Foundation Citation Format: Martens JWM, Sieuwerts A, Ponchet C, Smid M, de Weerd V, Slaets L, Piper T, van Deurzen CHM, Schroder CP, Stangle C, Kloosterman W, van Leeuwen-Stok E, Nilsson C, Vermeij J, Peeters S, Goulioti T, Nowaczyk M, Aebi S, Rubio IT, Kelly C, Bayani J, Porter P, Murray M, Hudis C, Middleton L, Korde L, Ruddy K, Winer E, Bogler O, van den Weyngaert D, dal Lago L, Fraser J, Benstead K, van Asperen C, Linderholm B, Hedenfalk I, Tryfonidis K, Giordano S, Bartlett J, Cardoso F. Molecular subtyping of male breast cancer by the International male breast cancer program (IMBC): EORTC 10085/TBCRC 0-29/BIG 2-07/NABCG/BOOG 2009-04 [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 PD7-12.
Introduction Currently, there is no clear biomarker to predict which breast cancer patient may benefit from immunotherapy. High somatic point mutational load is thought to lead to immune activation and CD8+ T cell activation and infiltration. In addition, pre-existing CD8+ T cells distinctly located at the invasive tumor margin are associated with expression of the PD-1/PD-L1 immune inhibitory axis and may predict response to PD-1 targeted therapy. However, breast tumors are considered copy number-driven rather than mutational-driven cancers. Therefore, in order to identify which breast cancer patients may potentially benefit from immunotherapy, we investigated relations between copy number load and CD8+ T cell abundance, immune pathways and immune activation scores in a large set of publically available breast cancer expression profiles. Methods Functional genomic mRNA-profiling (Fehrmann et al., Nat Genet, 2015) was used to capture the downstream effect of somatic copy number alterations on gene expression levels. This method allowed using gene expression profiles to quantify somatic copy number load occurring in tumor samples in a univariate measurement called the copy number load index (CNL-index). Immune activation scores were calculated according to two known gene immune signatures (Teschendorff et al., Genome Biol, 2007 and Desmedt et al., Clin Cancer Res, 2008). Cibersort (Newman et al., Nat Methods, 2015) was applied to estimate CD8+ T cell abundance. Publicly available gene expression profiles of 7,270 primary breast cancer samples were used. The relation between CNL-index, immune activation scores and disease-free survival (DFS), defined as time from diagnosis until distant metastasis development, was assessed by multivariate cox-regression analysis including age, ER and HER2 status, tumor size, lymph node involvement, tumor grade and treatment regimen. Gene set enrichment analysis (GSEA) was applied to assess relations between immune pathways and CNL-index. Results In primary breast cancer, low CNL-index was found in 1,796 samples (24.7%) versus 5,474 samples with a high CNL-index (75.3%). Higher CNL-index was correlated with shorter DFS (HR 2.51, P = 1.6x10-4), whereas higher immune activation scores were associated with prolonged DFS (HR 0.199, P = 0.003 and HR 0.347, P = 0.017). CD8+ T cell abundance was negatively correlated with the CNL-index (Spearman R = -0.14, P = 8.11x10-34). GSEA showed enrichment of immune pathways amongst genes that negatively correlated with CNL-index. Subset analysis in 1,555 TNBC samples showed low CNL-index in 287 samples (18.5%) versus high CNL-index in 1,268 samples (81.5%). Similar to the entire breast cancer set, CD8+ T cell abundance and CNL-index were negatively correlated in TNBC (Spearman R = -0.11, P = 4.11x10-05). Immune pathway enrichment in genes in TNBC also negatively correlated to CNL-index. Conclusion High CNL-index (i.e. high copy number load) is inversely related to immunoactivation, immune pathways and CD8+ T cell abundance. This implies that in breast cancer, tumors with low CNL-index may be intrinsically sensitive to immune modulation, which warrants further confirmation in prospective trials. This research was supported by Dutch Cancer Society Grants RUG 2010-4739 and RUG 2013-5960. Citation Format: Bense RD, van der Vegt B, de Vries EGE, van Vugt MATM, Schröder CP, Fehrmann RSN. Inverse relationships between high somatic copy number load and immune phenotypes in breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P6-08-01.
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