Wallwiener, Markus

Abstract Purpose: The aim of PREDICT was to confirm clinical validity and the potential for clinical utility of serial circulating tumor cell (CTC) enumeration in patients with metastatic breast cancer, focusing on its prognostic value in different breast cancer subtypes and clinical settings. Experimental Design: In total, 4,436 individual patient-level data with CTC results from both baseline and one follow-up (CellSearch; Menarini Silicon Biosystems) were analyzed to evaluate the association between CTC detection and overall survival (OS) in the full patient cohort and separately for tumor and treatment types. Results: Using the cutoff ≥1 CTC for CTC positivity, 913 (20.6%) patients had 0 CTCs at both time points (neg/neg) and 325 (7.3%) and 1,189 (26.8%) patients converted from CTC negative to CTC positive (neg/pos) or vice versa (pos/neg), whereas 2,009 (45.3%) patients had at least one CTC at both time points (pos/pos). The median OS for the neg/neg, neg/pos, pos/neg, and pos/pos group was 45.6, 26.1, 32.3, and 17.3 months, respectively (P < 0.0001, global log-rank test). CTC responders (pos/neg) showed a lower risk of death compared with CTC nonresponders (pos/pos; HR, 0.48; 95% confidence interval, 0.44–0.53). Similar results were obtained in subgroup analyses according to hormone receptor and HER2 subtype, treatment type, and with a ≥5 CTC cutoff for CTC positivity. Conclusions: Follow-up CTC assessments strongly predict OS independently from tumor subtype and treatment. New randomized trials to define the clinical utility of CTC monitoring for risk stratification and as an early response marker in metastatic breast cancer are urgently needed.

PURPOSE Among patients with metastatic breast cancer (mBC), the frequency of germline mutations in cancer susceptibility genes and the clinical relevance of these mutations are unclear. In this study, a prospective cohort of patients with mBC was used to determine mutation rates for breast cancer (BC) predisposition genes, to evaluate the clinical characteristics of patients with mutations, and to assess the influence of mutations on patient outcome. PATIENTS AND METHODS Germline DNA from 2,595 patients with mBC enrolled in the prospective PRAEGNANT registry was evaluated for mutations in cancer predisposition genes. The frequencies of mutations in known BC predisposition genes were compared with results from a prospective registry of patients with nonmetastatic BC sequenced using the same QIAseq method and with public reference controls. Associations between mutation status and tumor characteristics, progression-free survival, and overall survival were assessed. RESULTS Germline mutations in 12 established BC predisposition genes (including BRCA1 and BRCA2) were detected in 271 (10.4%) patients. A mutation in BRCA1 or BRCA2 was seen in 129 patients (5.0%). BRCA1 mutation carriers had a higher proportion of brain metastasis (27.1%) compared with nonmutation carriers (12.8%). Mutations were significantly enriched in PRAEGNANT patients with mBC compared with patients with nonmetastatic BC (10.4% v 6.6%, P < .01). Mutations did not significantly modify progression-free survival or overall survival for patients with mBC. CONCLUSION Multigene panel testing may be considered in all patients with mBC because of the high frequency of germline mutations in BRCA1/2 and other BC predisposition genes. Although the prognosis of mutation carriers and nonmutation carriers with mBC was similar, differences observed in tumor characteristics have implications for treatment and for future studies of targeted therapies.

1048 Background: Germline BRCA1/2 ( gBRCA) mutations (mt) are some of the few actionable alterations in mBC patients. The PARP inhibitors olaparib/talazoparib are more effective than chemotherapy (ctx) in patients with a gBRCAmt and HER2 negative(-) mBC. In mBC patients the TNT-study suggested a better progression-free survival (PFS) for g BRCA-mt compared to patients with a gBRCA1/2 wildtype (wt) when treated with platinum and not with a taxane. Otherwise little is known about the prognostic effect of g BRCA1/2mt in mBC patients. Methods: PRAEGNANT (NCT02338167) is a prospective mBC registry with a focus on molecular biomarkers. Patients were eligible for this analysis if their mBC was HER2- and treated with ctx for the first time (referred to as first-line ctx). Hormone receptor (HR) positive patients had to have all hormone therapies exhausted. Mutation frequencies and their association with patient and tumor characteristics were analyzed. Multivariable Cox regression models were built with commonly established prognostic factors and g BRCA mutation status as predictors of PFS and overall survival (OS) from first-line ctx. Results: Out of 2932 PRAEGNANT patients, 576 were HER2- and received first-line ctx. Of those 529 patients with g BRCA genotype results and follow up information could be analyzed. 24 patients (4.5%) had a g BRCAmt (11 BRCA1, 13 BRCA2). Mutation rate in HR positive patients was 3.9% (17/432) and 7.2% (7/97) in HR negative patients. Most patients received ctx either as the first treatment in the metastatic setting or after one line of hormone therapy (n=382; 72.2%). Multivariable Cox regression models showed an adjusted hazard ratio for gBRCAmt vs. gBRCAwt patients of 0.70 (95% CI: 0.43-1.15) for PFS and of 0.41 (95% CI: 0.18-0.93) for OS. Most frequent ctx treatments were taxane (52%) or capecitabine based (21%). Additionally, the prevalence of somatic BRCA1/2 mutations in this population will be presented. Conclusions: In this HER2- mBC population under ctx g BRCA mutation rates were within the expected range of about 5%. Within the analyzed population patients with a g BRCA mutation seemed to have a better OS than patients without a mutation. PFS results pointed in the same direction without statistical significance. However, with only 24 mutations replication of these results in additional cohorts is warranted. Clinical trial information: NCT02338167.

Abstract Background New treatment strategies for metastatic breast cancer (mBC) are mainly driven by therapies against specific targets. BRCA mutations are one of the few established actionable targets, with PARP-Inhibitors and Platinum showing high efficacy in mBC. Hereditary cancer testing panels are now broadly used for identification of individuals with BRCA1/2 mutations who may benefit from these therapies. Many of these panels also contain other predisposition genes involved in BRCA-related DNA repair pathways, but the clinical relevance of mutations in these genes remain unclear. The aim of this study was to describe the mutation rates of BRCA1/2 and panel-based predisposition genes, and the associated clinical characteristics of individuals with these mutations, in a prospective cohort of mBC patients. Methods The PRAEGNANT mBC registry (NCT02338167) is a prospective registry for metastatic breast cancer patients with a focus on molecular biomarkers. Patients receiving any therapeutic regimen are eligible for this registry. Germline DNA was collected at study entry and genotyped for 37 cancer predisposition genes including BRCA1 and BRCA2. The frequency of mutations in each gene was determined, and associations between mutations and patient and tumor characteristics, metastatic pattern, and overall survival were assessed. Results Mutations in established high (odds ratio (OR)&gt;5.0) and moderate risk (OR&gt;2.0) breast cancer genes (BRCA1/2, PALB2, CHEK2, ATM, RAD51D, BARD1, and MSH6) were seen in 123 of 1462 tested patients with mBC (8.4%). BRCA1 and BRCA2 mutations were seen in 1.4% and 2.9% of patients respectively. Most frequently mutated non-BRCA panel genes were CHEK2, PALB2 and ATM with 2.8%, 0.8% and 0.6% of patients. Mutation frequency varied with regard to patients who developed brain metastases, visceral metastases or bone only metastases. BRCA1 or BRCA2 mutations were seen frequently in patients with brain (5.3%) or visceral metastases (5.2%), but were present in only 2.5% patients with bone only metastases and 1.5% of patients with lesions in other locations. Panel genes were equally distributed among all metastatic patients. PALB2 mutations (n=11) were only seen in patients with brain (1.9%) and visceral metastases (0.9%), but not in patients with bone metastases or other locations. 36.4% (N=4) of all patients with PALB2 mutations developing a brain metastasis. When adjusted for other mBC prognostic factors, a mutation (all genes) was associated with an unfavorable prognosis (HR: 1.50; 95%CI: 1.04 to 2.30, p=0.03). Mutation frequencies were similar according to therapy lines. All other associations with molecular subtypes and risk factors were similar to primary breast cancer cases. Conclusion Mutations in high and moderate risk breast cancer genes were frequent in metastatic breast cancer patients. The frequency was substantially higher than the 4 to 5% mutation frequency observed among unselected primary breast cancer patients, but is consistent with recent results from studies of metastatic prostate cancer patients. Patients with brain and visceral metastases had the highest BRCA mutation rates. Results suggested that PALB2 mutations may be more frequent in patients with brain metastases. Citation Format: Fasching PA, Hu C, Hart SN, Polley EC, Lee KY, Gnanolivu RD, Lilyquist J, Hartkopf AD, Taran FA, Janni W, Hadji P, Tesch H, Haeberle L, Ettl J, Lux MP, Lueftner D, Wallwiener M, Mueller V, Beckmann MW, Belleville E, Wimberger P, Untch M, Kolberg H-C, Fehm TN, Overkamp F, Wallwiener D, Brucker SY, Schneeweiss A, Couch F. Cancer predisposition genes in metastatic breast cancer – Association with metastatic pattern, prognosis, patient and tumor characteristics [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 PD1-02.