Patients with Biallelic BRCA1/2 Inactivation respond to Olaparib treatment across Histologic tumor types

Purpose: To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with BRCA1/2 mutations, regardless of histologic tumor type. Patients and Methods: Patients with treatment-refractory BRCA1/2-mutated cancer were included for treatment with offlabel olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In Drug Rediscovery Protocol (DRUP), patients with treatment-refractory solid malignancies receive offlabel drugs based on tumor molecular profiles while whole-genome sequencing (WGS) is performed on baseline tumor biopsies. The primary endpoint was clinical benefit (CB; defined as objective response or stable disease ≥ 16 weeks according to RECIST 1.1). Per protocol patients were enrolled using a Simon-like two-stage model. Results: Twenty-four evaluable patients with nine different tumor types harboring BRCA1/2 mutations were included, 58% had CB from treatment with olaparib. CB was observed in patients with complete loss of function (LoF) of BRCA1/2, while 73% of patients with biallelic BRCA LoF had CB. In 17 patients with and seven without current labeled indication, 10 and four patients had CB, respectively. Treatment resistance in four patients with biallelic loss might be explained by an additional oncogenic driver which was discovered by WGS, including Wnt pathway activation, FGFR amplification, and CDKN2A loss, in three tumor types. Conclusions: These data indicate that using PARPis is a promising treatment strategy for patients with non-BRCA-associated histologies harboring biallelic BRCA LoF. WGS allows to accurately detect complete LoF of BRCA and homologous repair deficiency (HRD) signature as well as oncogenic drivers that may contribute to resistance, using a single assay

Fluorescent imaging using indocyanine green during esophagectomy to prevent surgical morbidity: A systematic review and meta-analysis

Background: Fluorescent imaging using indocyanine green (ICG) is an emerging technique that aids the surgeon with intraoperative decision making during upper gastrointestinal cancer surgery. In this systematic review we aim to provide an overview of current practice of fluorescence imaging using ICG during esophagectomy, and to show how this technology can prevent surgical morbidity, such as anastomotic leakage, graft necrosis and chylothorax. Methods: The PRISMA standard for systematic reviews was used. The PubMed and Embase database were searched to identify articles matching our systematic literature search. Two authors screened all included articles for eligibility. Risk of bias was assessed for all included articles. Results: A total of 25 articles were included in this review: 22 articles on perfusion assessment, and three on the detection of chyle fistula. Five out of 22 articles concerning perfusion assessment evaluated fluorescence signals in quantitative values. In 20 articles the pooled incidence of anastomotic leakage and graft necrosis in the ICG group was 11.10% (95% CI: 8.06–15.09%) and in eight studies the pooled change in management rate was 24.55% (95% CI: 19.16–30.88%). After change in management, the pooled incidence of anastomotic leakage and graft necrosis was 14.08% (95% CI: 6.55–27.70%). A meta-analysis showed that less anastomotic leakages and graft necrosis occur in the ICG group (OR 0.30, 95% CI: 0.14–0.63). Three case-reports (N=3) were identified regarding chyle fistula detection, and ICG lymphography detected the thoracic duct in all cases and the chyle fistula in one case. Conclusions: Fluorescence imaging using ICG is a promising and safe technology to reduce surgical morbidity after esophagectomy with continuity restoration. ICG fluorescence angiography showed a reduction in anastomotic leakage and graft necrosis. Future studies are needed to demonstrate the feasibility of ICG lymphography for chyle fistula detection

Early postoperative decrease of albumin is an independent predictor of major complications after oncological esophagectomy: A multicenter study

Background and Objectives: Serum albumin perioperative decrease (∆Alb) may reflect the magnitude of the physiological stress induced by surgery. Studies highlighted its value to predict adverse postoperative outcomes, but data in esophageal surgery are scant. This study aimed to investigate the role of ∆Alb to predict major complications after esophagectomy for cancer. Methods: Multicenter retrospective study conducted in five high-volume centers, including consecutive patients undergoing an esophagectomy for cancer between 2006 and 2017. Patients were randomly assigned to a training (n = 696) and a validation (n = 350) cohort. Albumin decrease was calculated on postoperative day 1 and defined as ΔAlb. The primary endpoint was major complications according to Clavien classification. Results: In the training cohort, esophagectomy induced a rapid drop of albumin. Cut-off of ΔAlb was established at 11 g/L and allowed to distinguish patients with adverse outcomes. On multivariable analysis, ΔAlb was identified as an independent predictor of major complications (OR, 1.06; 95% CI, 1.01–1.11; p =.014). Higher BMI and laparoscopy were associated with lower ΔAlb. Analysis of the validation cohort provided consistent findings. Conclusions: ΔAlb appeared as a promising biomarker after oncological esophagectomy, allowing prediction of potential adverse outcomes

Patients with Biallelic BRCA1/2 Inactivation Respond to Olaparib Treatment Across Histologic Tumor Types

PURPOSE: To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with BRCA1/2 mutations, regardless of histologic tumor type. PATIENTS AND METHODS: Patients with treatment-refractory BRCA1/2-mutated cancer were included for treatment with off-label olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In Drug Rediscovery Protocol (DRUP), patients with treatment-refractory solid malignancies receive off-label drugs based on tumor molecular profiles while whole-genome sequencing (WGS) is performed on baseline tumor biopsies. The primary endpoint was clinical benefit (CB; defined as objective response or stable disease ≥ 16 weeks according to RECIST 1.1). Per protocol patients were enrolled using a Simon-like two-stage model. RESULTS: Twenty-four evaluable patients with nine different tumor types harboring BRCA1/2 mutations were included, 58% had CB from treatment with olaparib. CB was observed in patients with complete loss of function (LoF) of BRCA1/2, while 73% of patients with biallelic BRCA LoF had CB. In 17 patients with and seven without current labeled indication, 10 and four patients had CB, respectively. Treatment resistance in four patients with biallelic loss might be explained by an additional oncogenic driver which was discovered by WGS, including Wnt pathway activation, FGFR amplification, and CDKN2A loss, in three tumor types. CONCLUSIONS: These data indicate that using PARPis is a promising treatment strategy for patients with non-BRCA-associated histologies harboring biallelic BRCA LoF. WGS allows to accurately detect complete LoF of BRCA and homologous repair deficiency (HRD) signature as well as oncogenic drivers that may contribute to resistance, using a single assay

Patients with Biallelic BRCA1/2 Inactivation respond to Olaparib treatment across Histologic tumor types

Purpose: To assess the efficacy of olaparib, a PARP inhibitor (PARPi) in patients with tumors with BRCA1/2 mutations, regardless of histologic tumor type. Patients and Methods: Patients with treatment-refractory BRCA1/2-mutated cancer were included for treatment with offlabel olaparib 300 mg twice daily until disease progression or unacceptable toxicity. In Drug Rediscovery Protocol (DRUP), patients with treatment-refractory solid malignancies receive offlabel drugs based on tumor molecular profiles while whole-genome sequencing (WGS) is performed on baseline tumor biopsies. The primary endpoint was clinical benefit (CB; defined as objective response or stable disease ≥ 16 weeks according to RECIST 1.1). Per protocol patients were enrolled using a Simon-like two-stage model. Results: Twenty-four evaluable patients with nine different tumor types harboring BRCA1/2 mutations were included, 58% had CB from treatment with olaparib. CB was observed in patients with complete loss of function (LoF) of BRCA1/2, while 73% of patients with biallelic BRCA LoF had CB. In 17 patients with and seven without current labeled indication, 10 and four patients had CB, respectively. Treatment resistance in four patients with biallelic loss might be explained by an additional oncogenic driver which was discovered by WGS, including Wnt pathway activation, FGFR amplification, and CDKN2A loss, in three tumor types. Conclusions: These data indicate that using PARPis is a promising treatment strategy for patients with non-BRCA-associated histologies harboring biallelic BRCA LoF. WGS allows to accurately detect complete LoF of BRCA and homologous repair deficiency (HRD) signature as well as oncogenic drivers that may contribute to resistance, using a single assay

Limited clinical activity of palbociclib and ribociclib monotherapy in advanced cancers with cyclin D-CDK4/6 pathway alterations in the Dutch DRUP and Australian MoST trials

The Dutch Drug Rediscovery Protocol (DRUP) and the Australian Cancer Molecular Screening and Therapeutic (MoST) Program are similar nonrandomized, multidrug, pan-cancer trial platforms that aim to identify signals of clinical activity of molecularly matched targeted therapies or immunotherapies outside their approved indications. Here, we report results for advanced or metastatic cancer patients with tumors harboring cyclin D-CDK4/6 pathway alterations treated with CDK4/6 inhibitors palbociclib or ribociclib. We included adult patients that had therapy-refractory solid malignancies with the following alterations: amplifications of CDK4, CDK6, CCND1, CCND2 or CCND3, or complete loss of CDKN2A or SMARCA4. Within MoST, all patients were treated with palbociclib, whereas in DRUP, palbociclib and ribociclib were assigned to different cohorts (defined by tumor type and alteration). The primary endpoint for this combined analysis was clinical benefit, defined as confirmed objective response or stable disease ≥16 weeks. We treated 139 patients with a broad variety of tumor types; 116 with palbociclib and 23 with ribociclib. In 112 evaluable patients, the objective response rate was 0% and clinical benefit rate at 16 weeks was 15%. Median progression-free survival was 4 months (95% CI: 3-5 months), and median overall survival 5 months (95% CI: 4-6 months). In conclusion, only limited clinical activity of palbociclib and ribociclib monotherapy in patients with pretreated cancers harboring cyclin D-CDK4/6 pathway alterations was observed. Our findings indicate that monotherapy use of palbociclib or ribociclib is not recommended and that merging data of two similar precision oncology trials is feasible.</p

Efficacy, safety and biomarker analysis of durvalumab in patients with mismatch-repair deficient or microsatellite instability-high solid tumours

Background: In this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication, based on their tumour molecular profile. Patients and methods: Patients with dMMR/MSI-H solid tumours who had exhausted all standard of care options were eligible. Patients were treated with durvalumab. The primary endpoints were clinical benefit ((CB): objective response (OR) or stable disease ≥16 weeks) and safety. Patients were enrolled using a Simon like 2-stage model, with 8 patients in stage 1, up to 24 patients in stage 2 if at least 1/8 patients had CB in stage 1. At baseline, fresh frozen biopsies were obtained for biomarker analyses. Results: Twenty-six patients with 10 different cancer types were included. Two patients (2/26, 8%) were considered as non-evaluable for the primary endpoint. CB was observed in 13 patients (13/26, 50%) with an OR in 7 patients (7/26, 27%). The remaining 11 patients (11/26, 42%) had progressive disease. Median progression-free survival and median overall survival were 5 months (95% CI, 2-not reached) and 14 months (95% CI, 5-not reached), respectively. No unexpected toxicity was observed. We found a significantly higher structural variant (SV) burden in patients without CB. Additionally, we observed a significant enrichment of JAK1 frameshift mutations and a significantly lower IFN-γ expression in patients without CB. Conclusion: Durvalumab was generally well-tolerated and provided durable responses in pre-treated patients with dMMR/MSI-H solid tumours. High SV burden, JAK1 frameshift mutations and low IFN-γ expression were associated with a lack of CB; this provides a rationale for larger studies to validate these findings. Trial registration: Clinical trial registration: NCT02925234. First registration date: 05/10/2016

Efficacy, safety and biomarker analysis of durvalumab in patients with mismatch-repair deficient or microsatellite instability-high solid tumours

Background: In this study we aimed to evaluate the efficacy and safety of the PD-L1 inhibitor durvalumab across various mismatch repair deficient (dMMR) or microsatellite instability-high (MSI-H) tumours in the Drug Rediscovery Protocol (DRUP). This is a clinical study in which patients are treated with drugs outside their labeled indication, based on their tumour molecular profile. Patients and methods: Patients with dMMR/MSI-H solid tumours who had exhausted all standard of care options were eligible. Patients were treated with durvalumab. The primary endpoints were clinical benefit ((CB): objective response (OR) or stable disease ≥16 weeks) and safety. Patients were enrolled using a Simon like 2-stage model, with 8 patients in stage 1, up to 24 patients in stage 2 if at least 1/8 patients had CB in stage 1. At baseline, fresh frozen biopsies were obtained for biomarker analyses. Results: Twenty-six patients with 10 different cancer types were included. Two patients (2/26, 8%) were considered as non-evaluable for the primary endpoint. CB was observed in 13 patients (13/26, 50%) with an OR in 7 patients (7/26, 27%). The remaining 11 patients (11/26, 42%) had progressive disease. Median progression-free survival and median overall survival were 5 months (95% CI, 2-not reached) and 14 months (95% CI, 5-not reached), respectively. No unexpected toxicity was observed. We found a significantly higher structural variant (SV) burden in patients without CB. Additionally, we observed a significant enrichment of JAK1 frameshift mutations and a significantly lower IFN-γ expression in patients without CB. Conclusion: Durvalumab was generally well-tolerated and provided durable responses in pre-treated patients with dMMR/MSI-H solid tumours. High SV burden, JAK1 frameshift mutations and low IFN-γ expression were associated with a lack of CB; this provides a rationale for larger studies to validate these findings. Trial registration: Clinical trial registration: NCT02925234. First registration date: 05/10/2016