BRCA mutated pancreatic cancer: A change is coming

Table 1 Summary of studies of incidence of germline BRCA mutations in unselected pancreatic cancer cohorts

Ref.	Year	Population	Cohort size (Number AJ)	Germline BRCA1 pathogenic mutation incidence (%)	Germline BRCA2 pathogenic mutation incidence (%)	Combined germline BRCA mutation Incidence
Holter et al[23]	2015	North American	306 (33)	1.0%	3.6%	4.6%
Brand et al[24]	2018	North American	298 (26)	1.3%	1.3%	2.6%
Mizukami et al[25]	2020	Japanese	1005 (-)	1.7%	2.5%	4.2%
Grant et al[6]	2015	North American	290 (13)	0.3%	0.7%	1%
Lowery et al[26]	2018	North American	615 (111)	2.3%	5.7%	8%

AJ: Ashkenazi Jewish; BRCA: Breast cancer susceptibility gene.

Table 2 Retrospective studies of platinum-chemotherapies in BRCA-mutated pancreatic ductal adenocarcinoma

Ref.	Year	Study design	Patient population	Findings
Golan et al[43]	2014	Multi-institution cohort study	71 patients with germline BRCA mutations (21 BRCA1, 49 BRCA2, 1 both)	Superior mOS in stage 3/4 patients treated with platinum compared to non-platinum chemotherapy (22 vs 9 mo, P = 0.039)
Vyas et al[51]	2015	Cohort study	10 patients with BRCA2 mutation and known PDAC	Duration of response on platinum agents ranged from 8-32 wk, mean of 19.3 wk
Blair et al[44]	2018	Combined case control cohort study	22 patients with resected sporadic PDAC and germline BRCA mutations (1 BRCA1, 18 BRCA2)	Improved OS in BRCA-mutated patients treated with adjuvant PtCh compared to patients treated with alternative chemotherapies or no adjuvant therapy (31.0 vs 17.8 vs 9.3 mo, P < 0.001)
Reiss et al[52]	2018	Cohort study	29 patients with unresectable PDAC and germline mutations of BRCA1, BRCA2 or PALB2(12 BRCA1, 15 BRCA2, 2 PALB2)	Superior mOS in platinum-treated patients (undefined mOS (median follow up 21 mo) vs 15.5 mo, P = 0.02)
Kondo et al[35]	2018	Cohort study	28 patients with advanced PDAC (13 had HR-related gene mutations, 15 without mutations to HR-related genes)	Superior median PFS in HR-mutated PDAC patients treated with platinum chemotherapy compared to PDAC patients without HR mutations treated with platinum therapy (20.8 mo vs 1.7 mo, P = 0.049)
Yu et al[54]	2019	Case control study	32 resected PC patients with germline BRCA1, BRCA2, or PALB2 mutation, 64 resected PC patient controls without germline mutations	With peri-operative platinum exposure, mOS was longer in mutation-positive group that mutation negative group (mOS not yet met vs 23.1 mo, HR= 0.12)
Wattenberg et al[53]	2020	Case control study	26 platinum-treated patients with advanced stage PDAC and mutations of BRCA1, BRCA2 or PALB2, 52 platinum-treated, wildtype, age-matched controls	Improved ORR in patients with mutations compared to controls (58% vs 21%, P = 0.0022). Improved real world PFS in mutation carriers (10.1 mo vs 6.9 mo, HR = 0.43, P = 0.0068)

HR: Homologous Repair; mOS: Median overall survival; ORR: Objective response rate; PDAC: Pancreatic adenocarcinoma; PtCh: Platinum chemotherapy; BRCA: Breast cancer susceptibility gene.

Table 3 Ongoing phase II clinical trials investigating poly (ADP-ribose) polymerase inhibitor/Immune Checkpoint blockade combination therapy in pancreatic ductal adenocarcinoma

Study identifier	Patient population	Immunotherapy	PARP inhibitor	Phase and design	Estimated completion date
NCT03404960	Advanced PDAC patients who did not progress on PtCh	Nivolumab or Ipilimumab	Niraparib	Phase Ib/II trial evaluating effectiveness of olaparib with either nivolumab or ipilimumab	June 2021
NCT03851614	Advanced PDAC, leiomyosarcoma or mismatch repair-proficient colorectal cancer	Durvalumab	Olaparib	Phase II trial evaluating impact of combination therapy on genomic and immune biomarkers	March 2022
NCT04493060	Metastatic PDAC with mutations of BRCA1/2 or PALB2, previously treated with 1-2 lines of chemotherapy including a PtCh agent	Dostarlimab	Niraparib	Phase II, evaluating the disease control rate at 12 weeks (DCR12) with combination therapy	December 2022
NCT04548752	Metastatic PDAC with germline BRCA1 or BRCA2 mutation treated with first-line PtCh	Pembrolizumab	Olaparib	Phase II trial comparing combination therapy to olaparib alone as maintenance therapy	March 2025

PDAC: Pancreatic adenocarcinoma; PtCh: Platinum chemotherapy; BRCA: Breast cancer susceptibility gene.