This educational lecture was part of teaching courses given by the multidisciplinary oncology group in Buenos Aires - Argentina in August 2019

1. Management of pancreatic
adenocarcinoma
Prof. Eric Raymond, MD, PhD
Head of Medical Oncology - Paris Saint-Joseph Hospital Group
France - eraymond@hpsj.fr
XI CURSO DE ENTRENAMIENTO INTENSIVO
PARA EL MANEJO INTERDISCIPLINARIO DE LOS TUMORES DIGESTIVOS
Organizado por el Intergrupo Argentino para el Tratamiento
de los Tumores Gastro-Intestinales

2. Increased incidence with still a high
mortality rate
Incidence (blue) and
mortality (red) by age
Worldwide prevalence
Source: GLOBOCAN

3. Most oncogenic events occur before
clinical evidences
At primary diagnosis most tumor will have already
gain very aggressive capacities

4. Immune stromal progression in pancreatic carcinogenesis induces local
immunosuppression and desmoplastic reactions in pancreatic ductal
adenocarcinoma
• High genomic instability may be use for neoantigene expression and vaccination
• Inhibition of checkpoint inhibitors of immune stromal cell has been regarded as an
opportunity for therapy with limited effects

5. Normal EC
Tumor EC
Tumor cell
Adapted
Tumor cell
Tumor stress
Spontaneous tumor growth Treatments
Tumor adaptation
Dedifferentiation
or
transdifferentiation
Changes in stroma & tumor cells as a result of tumor growth and
treatment-induced tumor insults
EMT
Adapted from Hida K. et al, Pathology International 2011; 61: 630–637

6. Tumor stromal architecture can define tumor response to
VEGF-targeted therapy
Tumor vessel phenotype (TV)
Stromal vessel phenotype (SV)
TV are sensitive to VEGF/VEGFR therapies
SV are non- sensitive to VEGF/VEGFR therapies
Pancreatic ductal adenocarcinoma
that may display mesenchymal
reactions and stromal vessels are
often poorly sensitive to VEGF
inhibitors

7. TGF-beta activation yield multiple
consequences at early stages of progression in
pancreatic ductal adenocarcinoma

8. TGF-beta activation also facilitates the
development of liver metastases

9. Various componants of pancreatic ductal
adenocarcinomas and tumorogenic consequences
Cancer cells
Angiogenesis
(endothelial cells, pericytes)
Desmoplastic reaction
(stellate cells, fbroblasts)
Immune cell infiltration
Stroma components
-
-
+
Increased invasive and
metastatic potential
Changes in cellular
metabolism (anaerobic
metabolism)
Inhibition of local
immunity
Hypoxia
+

10. Summary of pitfalls and opportunities
in pancreatic ductal addenocarcinoma
Few genome unstable cancer cells with
very invasive and metastatic potential
Predominant stromal vessel angiogenesis
Anaerobic metabolism
Local immunodepression
Limited effects of TKI
TGF-beta receptor inhibitors
Drugs that target metabolism
Drugs that restore
immunogenicity and
vaccination
Lack of effects of VEGF
inhibition

11. Cytotoxic stress
Oncogenic control
Stromal normalization
Therapeutic approaches in
pancreatic ductal adenocarcinomas

12. INDUCING CYTOTOXIC STRESS
Antiproliferative strategies
XI CURSO DE ENTRENAMIENTO INTENSIVO
PARA EL MANEJO INTERDISCIPLINARIO DE LOS TUMORES DIGESTIVOS
Organizado por el Intergrupo Argentino para el Tratamiento
de los Tumores Gastro-Intestinales

13. Therapeutic options for
inhibition of cellular proliferation
• Radiotherapy
– Controversial for improving survival but useful for
local tumor control and reducing symptoms
• Chemotherapy
– 5FU (capecitabine)
– Gemcitabine (+/- EGFR inhibitor)
– Oxaliplatin
– Irinotecan (and liposomal irinotecan)
– Nab-paclitaxel

14. Standards & Options
• Neo-adjuvant: Folfirinox (eventually gemcitabine)
• Adjuvant : Folfirinox (eventually gemcitabine +/-
capecitabine)
• Metastatic first line
– Folfirinox
– Nab-paclitaxel + gemcitabine
– Gemcitabine alone or 5FU for disable patients
• Metastatic second line
– Liposomal irinotecan

15. Strategic management of pancreatic
adenocarcinoma
Baseline
evaluation
Operable
borderline
operable
Non operable
Jaunice
Poor performance status
pain
Etc…

16. Metastases Survival 8-12 months
Locally advanced Survival 12-15 months
Operable upfront Survival 15-20 months
60%
30%
10%
Global presentation and outcome of patients with
pancreatic adenocarcinoma at diagnosis
(including 10% ‘bordeline’)

17. Management of localized pancreatic
adenocarcinoma
Surgery feasible
Surgery not feasible
Upfront
Surgery
Neodjuvant chemotherapy is
more and more considered
neo-adjuvant
chemohterapy
Is radiotherapy capable of
improving the local control?
Adenocarcinoma
With no lymph
nodes and
distant
metastases
Adjuvant Chemotherapy
Surgery if the there is a good local control
and no occurrence of distant metastases
Operable
‘Borderline’

18. Pancreatic adenocarcinoma that will
never be amenable to surgery
Metastases upfront
Locally advanced
chemotherapy
Chemotherapy
+/- radiotherapy
non operable patients
1st intent
- FOLFIRINOX
- GEMCITABINE
- GEMOX
- (Nab-paclitaxel +
Gemcitabine)
2nd intent
- (Irinotecan liposomale)
- Other drugs not already
used in frist line therapy
- Biliary & duodenal obstruction
- Pain
- Weigth loss
- Vascular complications
Symptomatic
therapy

19. Therapeutic limitations of attempts to control
genetic alterations
• Cytotoxic drugs yield limited effects on pancreatic cancer cells
– Inhibition of proliferation/cell cycle entry (Ras/p16)
– Limited effects on cell survival (Ras) and apoptosis induction (p53)
– No effect on invasion and migration (Ras and TGF-β)
• Genomic instability (that comes as a consequence of lack of
quality controlled DNA replication)
– facilitates the acquisition of clones resistant to targeted agents
– Enhances tumor heterogeneity
• Most drugs that targets directly cancer cells are nowadays only
slightly delaying tumor progression (cytostatic effects) with
limited impact on survival

20. TARGETING ONCOGENIC ACTIVATION
Oncogenic normalization
XI CURSO DE ENTRENAMIENTO INTENSIVO
PARA EL MANEJO INTERDISCIPLINARIO DE LOS TUMORES DIGESTIVOS
Organizado por el Intergrupo Argentino para el Tratamiento
de los Tumores Gastro-Intestinales

21. Molecular underpinning consequences in pancreatic adenocarcinomas
INK4a
(p16)
>50%
Gene suppressor
inactivation
Cells loose
Gate keeper
for DNA QC
- Cell cycle
Progression
- Loss of Rb
Function
Smad4
DPC4
Deleted in
Pancreatic
Cancer locus 4
>40%
Gene suppressor
inactivation
Cells loose control of TGF-β-signaling
- Invasion, migration
- Epithelial to mesenchymal transition (EMT)
- Metastasis progression
TP53
>50%
Gene suppressor
inactivation
Cells loose control on
DNA integrity
- Genetic instability
- Lost of apoptosis
i.e. Drug resistance
BRCA2
5-7%
Oncogenic
activation
Lost of tumor
supressor genes
K-Ras
>90%
oncogenic
activation
cell loose control of
Proliferation,
Survival, and
invasion
RTK
Over
expression
30-50%
COSMIC database

22. Oncogenic
activation
Lost of tumor
supressor genes
Drugable
Drugable
Molecular underpinning consequences in pancreatic adenocarcinomas
5-7%
Drugable

23. Bypassing K-Ras activation in pancreatic
adenocarcinomas

24. Gemcitabine with targeted agents in PAC
Meta analysis of overall survival

25. DNA Repair Pathways
Normal cells have intact base-
excision repair and
homologous recombination
‒ Single-strand breaks
repaired by base-excision
repair (PARP1)
‒ Double-strand breaks
repaired by homologous
recombination (BRCA1/2)
Iglehart. NEJM. 2009;361:189.
Normal Cells Cells With BRCA Mutation
Base-excision
repair
Homologous
recombination
Repair
PARP1 BRCA
Base-excision
repair
Homologous
recombination
Repair
PARP1 BRCAX

26. Maintenance Olaparib (300mg x2/d) for Germline
BRCA-Mutated Metastatic Pancreatic Cancer
- Maintenance olaparib delay progression in patients with
metastatic pancreatic cancer that harbor germline BRCA
mutations
- However, there is no detectable impact on survival
N Engl J Med 2019;381:317-27.

27. Secondary mutations in BRCA alleles and other
mechanisms may prevent synthetic lethality limiting the
duration of cytostatic effects of PARP inhibitors

28. HOW MUCH DOES THIS IMPACT
MEDICAL CARE?
PARP inhibition
XI CURSO DE ENTRENAMIENTO INTENSIVO
PARA EL MANEJO INTERDISCIPLINARIO DE LOS TUMORES DIGESTIVOS
Organizado por el Intergrupo Argentino para el Tratamiento
de los Tumores Gastro-Intestinales

29. Screening for gBRCA mutations is associated with a
high attrition rate
100%
7.4%
5%
4.6%
With a hazard ration of
0.53 we may consider
that about 2.3% of
screened patients will get
benefits from PARP
inhibition
To get 2 patients with
benefit, we shall screen
100 patients
- 100 x 1000USD for gBRCA testing
with associated delay in responses
of analyses = 100,000 USD
- To get 4-5 treated at the average
price of 5,000 USD/months for 3-6
months (delay in responses) =
60,000-120,000 USD
N Engl J Med 2019;381:317-27.

30. Summary
• Pancreatic adenocarcinoma still stands as a
highly lethal disease
• From diagnosis, pancreatic adenocarcinoma
display aggressive carcinogenesis and high
potential for metastases and drug resistance
• Despite real progresses in multimodality
therapies, pancreatic adenocarcinoma
remains with unmet medical needs

31. Thanks for your attention