Introduction
Pancreatic cancer (PC) is currently the seventh leading cause of cancer death worldwide,
but is predicted to become the second leading cause of worldwide cancer death by 2030.
1
More than 80% of patients present with locally advanced or metastatic disease,
2
and the mainstay of treatment in this setting is systemic chemotherapy.
3
Despite incremental advances in recent years, prognosis remains poor with a median
5-year survival rate of just 10%.
4
Barriers to the implementation of precision medicine in PC include a heterogeneous
molecular landscape with most actionable changes occurring at low individual frequencies
across the population,
5,6
difficulties in accessing and sequencing high-quality biopsy material in a timely
fashion,
7
and patient factors including a propensity for rapid clinical decline.
7
Here, we present a case of metastatic pancreatic adenocarcinoma harboring a germline
BRCA1 mutation and a high tumor mutation burden (TMB), demonstrating an excellent
response to initial platinum-based chemotherapy, followed by a complete radiologic
response to maintenance immunotherapy and poly (ADP-ribose) polymerase (PARP) inhibition.
Case Report
A 76-year-old man was diagnosed with metastatic PC after presenting with fatigue and
weight loss, on a background history of an acute myocardial infarction 6 weeks before.
The Eastern Oncology Cooperative Group (ECOG) performance status (PS) at presentation
was 2. His family history was significant for PC, diagnosed in his father in his early
70s. There was no family history of breast, ovarian, or prostate cancer.
Baseline imaging revealed a 3 cm head of pancreas mass and diffuse extensive hepatic
metastases (at least 20 lesions, with the largest measuring 48 mm; Figs 1A and 1B).
Percutaneous biopsy of the liver was felt to be at high risk because of dual antiplatelet
therapy, and he proceeded to endoscopic ultrasound, which confirmed a vascular head
of pancreas mass and multiple liver metastases. An endoscopic ultrasound fine needle
biopsy of a liver mass confirmed a diagnosis of metastatic poorly differentiated carcinoma.
Immunohistochemical staining for cytokeratin 7 was positive, and mismatch repair (MMR)
staining revealed a normal pattern of expression. Programmed death ligand-1 (PD-L1)
status was not assessed.
FIG 1.
PET scan at baseline and after six cycles of carboplatin and nab-paclitaxel chemotherapy
reveals excellent partial response to initial systemic therapy. Baseline PET scan
including (A) MIP and (B) computed tomography fused axial views demonstrates pancreatic
primary and extensive liver metastases. Follow-up (C) MIP and (D) fused axial views
after six cycles of platinum-based chemotherapy with the addition of pembrolizumab
from C4 demonstrate near-complete resolution of disease, with only a solitary remaining
fluorodeoxyglucose-avid liver metastasis (arrow). MIP, maximum intensity projection;
PET, positron emission tomography.
Palliative chemotherapy was commenced with gemcitabine and nab-paclitaxel. The first
cycle was complicated by a hospital admission for management of biliary sepsis, requiring
a prolonged course of intravenous antibiotics, and severe recurrent upper gastrointestinal
tract bleeding, requiring a total of eight units of packed red cells, four units of
fresh frozen plasma, and two pools of platelets to stabilize. Ultimately, he also
underwent angioembolization of the gastroduodenal artery and proximal branch of the
superior mesenteric artery followed by palliative radiotherapy (20 Gy in five fractions)
to control upper gastrointestinal bleeding. Subsequent clinical recovery was slow,
with persistent fevers, fatigue, and a decline in PS. Because of these medical complications,
there was a delay of 7 weeks between his first and second cycles of systemic therapy.
During this time, molecular analysis of his endoscopic ultrasound fine needle biopsy
of liver was performed using the TruSight Oncology 500 (TSO-500) panel as part of
the Endoscopic Ultrasound Molecular Evaluation of Pancreatic Cancer (EU-ME-PC) Trial
(ACTRN12620000762954),
8
and germline testing was arranged through a Familial Cancer Clinic using a targeted
assay of 14 cancer predisposition genes. Both somatic and germline testing detected
a pathogenic BRCA1 mutation in exon 20 (c.5266dupC). The TSO-500 panel also detected
pathogenic KRAS and TP53 mutations (Table 1) and an extremely high TMB of 223.9 mutations
per megabase (mut/Mb). There was no evidence of microsatellite instability.
TABLE 1.
Somatic Variants Detected in the 500-Gene Next-Generation Sequencing Panel
These findings were reviewed in a local molecular tumor board, and on the basis of
consensus recommendation, platinum-based chemotherapy was commenced (carboplatin and
nab-paclitaxel). He completed six cycles of this regimen. In light of the extremely
high TMB, he also elected to self-fund pembrolizumab, which was added from cycle four.
He had an excellent clinical and radiologic response to platinum-based chemotherapy
and immunotherapy (Figs 1C and 1D) and subsequently continued on maintenance pembrolizumab.
His PS improved to ECOG 0. Because of persistent chemotherapy-induced anemia and in
light of an excellent ongoing response to immunotherapy, maintenance PARP inhibition
was considered but not commenced after completing chemotherapy.
Five months after commencing maintenance pembrolizumab (10 months after his initial
diagnosis), imaging revealed an excellent ongoing response with near-complete resolution
of the pancreatic and liver tumors. However, oligometastatic progression was evident
in a solitary liver metastasis (Figs 2A and 2B), possibly representing a resistant
clonal population. Because of the known BRCA1 mutation, olaparib was added to the
ongoing pembrolizumab therapy.
FIG 2.
Response to olaparib after oligometastatic progression in liver. (A) PET scan and
(B) MRI of liver after 5 months of maintenance pembrolizumab reveal progression in
the sole remaining metastatic liver lesion. Olaparib was added, and 5 months later,
a repeat (C) PET scan and (D) MRI demonstrate complete radiologic and metabolic response
to therapy. MRI, magnetic resonance imaging PET, positron emission tomography.
Ongoing therapy with olaparib and pembrolizumab has been well tolerated, and he remains
clinically well with an excellent PS. Imaging 6 months after the addition of olaparib
(16 months after his initial diagnosis) has revealed a complete radiologic response
to therapy, with no evidence of residual active malignancy on positron emission tomography
or computed tomography or magnetic resonance imaging (Figs 2C and 2D).
Clinical and molecular data for this patient were obtained from the Victorian Pancreatic
Cancer Biobank and EU-ME-PC study databases after appropriate local institutional
ethics board review (HREC/15/MonH/117 and HREC/61006/MonH-2020-200407). The patient
described in this report provided informed written consent for the collection and
publication of his clinical and molecular data and deidentified images.
Discussion
Pancreatic ductal adenocarcinoma is typically diagnosed at an advanced stage, and
systemic therapy remains the mainstay of treatment for this recalcitrant malignancy.
Current ASCO and National Comprehensive Cancer Network guidelines recommend different
regimens on the basis of PS. Patients with good PS (ECOG 0 or 1) are usually offered
palliative chemotherapy with folinic acid, fluorouracil, irinotecan, and oxaliplatin
or gemcitabine plus nab-paclitaxel, whereas those with poor PS (ECOG ≥ 2) are usually
offered single-agent gemcitabine or best supportive care.
3,9
Somatic driver mutations are common in pancreatic ductal adenocarcinoma and are dominated
by KRAS, P53, SMAD4, and CDKN2A. Activating mutations in KRAS are detected in > 90%
of patients with PC, with codon 12 mutations being most frequent. Until recently,
attempts to target these pathways alone or in combination with other therapies have
not yielded positive trials.
10
However, the recent development of effective therapeutic targeting of KRAS G12C in
advanced solid tumors
11
raises hope for further therapeutic development targeting KRAS.
Targeted therapy approaches either alone (except for a few genomically defined subsets)
or in combination with standard cytotoxic therapy thus far has overall proven to be
disappointing in PC,
12
with contributing factors likely including significant genomic heterogeneity, a complex
tumor microenvironment, and a rapidly progressive disease phenotype. Despite these
challenges, several recent studies have revealed that targeted molecular screening
is feasible in PC
12-14
and that patients who receive targeted molecular therapy may derive a survival benefit.
15
Pathogenic germline mutations in BRCA1 (as seen in this patient) or BRCA2 and other
related genes are seen in approximately 5%-9% of PCs.
16
The recent demonstration of a survival benefit in patients harboring germline BRCA
mutations treated with maintenance olaparib after platinum-based chemotherapy demonstrates
the importance of identifying targetable molecular phenotypes in PC.
17
However, further studies are required to determine the benefit of PARP inhibitors
outside of the maintenance setting.
Microsatellite instability-high or mismatch repair–deficient (dMMR) tumors are rare
in the PC population with a frequency of only approximately 1%-2% and are often associated
with Lynch syndrome.
18
Immune checkpoint inhibitors targeting programmed cell death protein 1 and PD-L1 are
associated with improved survival in dMMR tumors.
19,20
A recent systematic review identified that high TMB occurs in approximately 1% of
PC and is commonly associated with dMMR status.
21
High TMB is associated with immunotherapy response in other tumor types,
22,23
but limited evidence to date does not reveal a clear correlation between high TMB
and response to checkpoint inhibition in PC.
24-26
Table 2 summarizes PC studies that include data on high-TMB patients.
TABLE 2.
Summary of Cohorts Including Data on High-TMB Tumors in Pancreatic Cancer
This patient had an extremely high TMB and elected to self-fund pembrolizumab in addition
to platinum-based chemotherapy, suggesting an immune-responsive tumor despite microsatellite
stability. He demonstrated near-complete resolution of the pancreatic and liver tumors.
An updated understanding of PC pathobiology has prompted an exploration of potential
therapeutic targets and heightened interest in implementing molecular sequencing into
routine patient care. In addition to homologous repair deficiency genes, other molecular
targets in PC may include BRAF V600E and KRAS G12C mutations, HER2 amplification,
ALK and ROS1 translocations, and NTRK fusions.
12,13,36
Novel immunotherapy has revolutionized the treatment of many cancers in recent years,
37
but thus far has yielded relatively disappointing results in unselected patients with
PC.
38,39
Increasing evidence suggests that radiotherapy may enhance antitumor effects of immunotherapy
through multiple mechanisms, and in our case, it is possible that radiotherapy acted
as an immune primer.
40,41
Further research is required to clarify the predictive utility of biomarkers such
as microsatellite instability, PD-L1 expression, and TMB in PC.
In conclusion, this case report describes a profound clinical response to sequential
platinum-based chemotherapy, pembrolizumab, and olaparib in a patient with advanced
PC harboring a germline BRCA1 mutation and high TMB. Although further studies are
required to determine the role of TMB as a predictive biomarker for immunotherapy
response in microsatellite-stable PC, this case suggests that remarkable responses
can occur. In addition, although olaparib has been demonstrated to be an effective
maintenance therapy in PCs with germline BRCA mutations, this case also alludes to
a possible role for salvage therapy with olaparib in patients who progress on other
therapies. To our knowledge, this is the first report of a complete response to combination
therapy with pembrolizumab and olaparib after first-line platinum-based chemotherapy
in PC. This patient's experience clearly demonstrates the immense potential benefits
to be gained by implementing precision medicine in PC.