Wimberger, Pauline

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.

TPS5602 Background: Primary cytoreductive surgery (PDS) followed by chemotherapy has been considered as standard management for advanced ovarian cancer patients (pts) over decades. An alternative approach of interval debulking surgery (IDS) following neoadjuvant chemotherapy (NACT) was subsequently reported by two randomized phase III trials (EORTC‐GCG, CHORUS). Owing to important limitations of these studies, especially regarding surgical quality, optimal timing of surgical therapy in advanced ovarian cancer is still unclear. Methods: TRUST is an international open, randomized, controlled multicenter trial investigating overall survival (OS; primary endpoint) after PDS vs NACT and subsequent IDS in pts with FIGO stage IIIB‐IVB ovarian, tubal, and peritoneal carcinoma. Secondary objectives are safety of complete tumor resection, progression‐free survival and quality of life (QoL) as well as surgical morbidity. In order to guarantee adequate surgical quality, participating centers need to fulfill specific quality assurance criteria (e.g. ≥50% complete resection rate in upfront surgery for FIGO IIIB-IV pts, ≥36 debulking-surgeries/year) and agree to independent audits by TRUST Quality committee delegates. A 1:1 randomization to PDS or NACT followed by IDS stratified by center and age‐ECOG combination (ECOG 0 and age ≤65 years vs ECOG > 0 or age > 65 years) is performed. Pts in the PDS arm will undergo surgery followed by 6 cycles of platinum-based chemotherapy, whereas pts in the IDS arm will be treated with 3 cycles of NACT after histologic confirmation of the disease, followed by IDS and subsequently 3 cycles of platinum-based chemotherapy. Intention of surgery for both groups will be complete tumor resection as per guideline recommendations. Health related QoL will be assessed using the EORTC QLQ‐C30, QLQ‐OV28, and EQ‐5D‐3L questionnaires. For sample size planning, we considered a prolongation of median OS from 45 months in the IDS arm to 60 months in the PDS arm (HR 0.75) as clinically relevant. 380 events are needed to obtain a power of 80% in two‐sided log-rank test with significance level of 0.05. The primary analysis will be done in the ITT‐population of 686 randomized pts. By Feb 3 2017, 46 pts were randomized. Clinical trial information: NCT02828618.

1088 Background: Standard first-line treatment for mTNBC is chemotherapy. However, outcomes are poor, and new treatment options are needed. Cohort B of KEYNOTE-086 (NCT02447003) assessed the safety and antitumor activity of pembrolizumab as first-line therapy for patients (pts) with PD-L1–positive mTNBC. Methods: Men and women with centrally confirmed mTNBC, no prior systemic anticancer therapy for metastatic disease, ECOG PS 0-1, and a tumor PD-L1 combined positive score (CPS) ≥1% received pembrolizumab 200 mg Q3W for 24 mo or until disease progression, intolerable toxicity, or investigator or pt decision. Tumor imaging was performed Q9W for 12 mo and Q12W thereafter. Clinically stable pts with PD could remain on pembrolizumab until PD was confirmed on subsequent assessment. Primary end point was safety. Secondary end points included ORR, DOR, and PFS (RECIST v1.1, central review). Planned enrollment was 80 pts. This analysis included all pts who had ≥18 wk of follow-up as of Nov 10, 2016. Results: 79 of the first 137 pts with PD-L1–evaluable tumors (58%) had PD-L1 CPS ≥1%. Of the first 52 pts enrolled, 100% were women, median age was 53 y, 40% had elevated LDH, 69% had visceral metastases, and 87% received prior (neo)adjuvant therapy. After a median follow-up of 7.0 mo (range 4.4-12.5), 15 (29%) pts remained on pembrolizumab. Treatment-related AEs occurred in 37 (71%) pts, most commonly fatigue (31%), nausea (15%), and diarrhea (13%). 4 (8%) pts experienced 5 grade 3-4 treatment-related AEs: back pain, fatigue, hyponatremia, hypotension, and migraine (n = 1 each). No pts died or discontinued pembrolizumab due to an AE. ORR was 23% (95% CI 14%-36%). Best overall response was CR in 4%, PR in 19%, SD in 17%, PD in 58%, and not assessed in 2%. Median time to response was 8.7 wk (range 8.1-17.7). Median DOR was 8.4 mo (range, 2.1+ to 8.4), with 8 (67%) responses ongoing at cutoff. Median PFS was 2.1 mo (95% CI, 2.0-3.9); estimated 6-mo PFS rate was 29%. Conclusions: Data from the first 52 pts enrolled in KEYNOTE-086 cohort B suggest that pembrolizumab monotherapy has a manageable safety profile and promising antitumor activity as first-line therapy for PD-L1–positive mTNBC. Clinical trial information: NCT02447003.

Abstract Background: Patients with previously untreated mTNBC typically receive cytotoxic chemotherapy as first-line therapy for metastatic disease. However, efficacy and safety are suboptimal. KEYNOTE-086 (NCT02447003) is a multicohort, single-arm, phase 2 study of pembrolizumab monotherapy for mTNBC. In cohort B, we assessed the safety and antitumor activity of pembrolizumab as first-line therapy for patients with PD-L1-positive mTNBC. Methods: Key eligibility criteria for cohort B were age ≥18 y, centrally confirmed TNBC, no prior systemic anticancer therapy for metastatic disease, ECOG performance status 0-1, measurable disease per RECIST v1.1 by central review, no radiographic evidence of brain metastases, and a tumor PD-L1 combined positive score (CPS) ≥1. Pembrolizumab 200 mg was given once every 3 wk for 24 mo or until disease progression, intolerable toxicity, or investigator or patient decision. Tumor imaging was performed every 9 wk for 12 mo and every 12 wk thereafter. Clinically stable patients with radiologic progression could remain on pembrolizumab until progression was confirmed on subsequent assessment. Primary end point was safety. Secondary end points included ORR, duration of response, and PFS (all RECIST v1.1 by central review) and OS. Results: Of the 206 patients with tumors evaluable for PD-L1 expression, 128 (62%) had PD-L1 CPS ≥1. Of these, 84 met all eligibility criteria and enrolled. All patients were women, median age was 52.5 y, 29 (35%) had ECOG PS 1, 40 (48%) had elevated LDH, 55 (65%) had visceral ± nonvisceral metastases, and 73 (87%) received prior (neo)adjuvant therapy. All patients received ≥1 pembrolizumab dose, and after median follow-up of 10.6 mo, 18 (21%) remained on pembrolizumab. Treatment-related AEs occurred in 53 (63%) patients and were of grade 3-4 severity in 7 (8%); no patients died or discontinued pembrolizumab because of treatment-related AEs. The most common treatment-related AEs were fatigue (26%), nausea (13%), and diarrhea (12%). No grade 3-4 treatment-related AE occurred in &gt;1 patient. The most common immune-mediated AE was hypothyroidism (10%). Three patients had complete response and 16 had partial response for an ORR of 23% (95% CI 15-33). Of the 11 patients with a best response of stable disease, 1 had stable disease for ≥24 wk, leading to a disease control rate of 24% (95% CI 16-34). 12 of 19 (63%) responses were ongoing at data cutoff, and median duration of response was 8.4 mo (range 2.1+ to 13.9+). Median PFS was 2.1 mo (95% CI 2.0-2.2), with an estimated 6-mo PFS rate of 26%. Median OS was 16.1 mo (95% CI 11.3-NR), with an estimated 6-mo OS rate of 83%. Conclusions: Pembrolizumab monotherapy continues to demonstrate a favorable safety profile and robust, durable antitumor activity in patients with PD-L1-positive, previously untreated mTNBC. Citation Format: Adams S, Loi S, Toppmeyer DL, Cescon DW, De Laurentiis M, Nanda R, Winer EP, Mukai H, Tamura K, Armstrong AC, Liu MC, Iwata H, Ryvo L, Wimberger P, Rugo HS, Tan A, D'Aquanno C, Ding Y, Karantza V, Schmid P. KEYNOTE-086 cohort B: Pembrolizumab monotherapy for PD-L1–positive, previously untreated, metastatic triple-negative breast cancer (mTNBC) [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 PD6-10.

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.