Colangiocarcinoma: ¿otro reto terapéutico?

Manuel Benavides

Agenda

- Introduccion: Aspectos generales

- Tratamiento- Sistémico: Adyuvante / Metastásico- Local

- Aspectos moleculares / Resultados

Klatskin

Distal

N. Goldaracena et al. Liver Transplantation 2018

Cáncer de la vía biliar

Carcinoma vesícula biliar

Colangiocarcinoma (CC)- CC intra- hepático (10-20%)

- CC extra- hepático- Hilar / Perihilar ; Klatskin*- Distal

Ampolla de Vater

*Bifurcación del conducto hepático común (extrahepático)

SEER 1973 -2012

Saha SK et al. The oncologist 2016

Iincidence vary according to geographic regions related to the

distribution of the risk factors (Thailand, highest incidence:Liver fluke O. Viverrini)

Ve

sícu

la B

iliar

2.1

14

Las Cifras del cáncer en España 2018. SEOM

De Angelis et al. Lancet Oncol 2014

EUROCARE-5 (1999-2007)

449 pts (1973 – 2010)

M.C. de Jong et al. J Clin Oncol 2011

R0MultifocalityVascular invasionLN +

Factores Pronósticos tras resección iCC

AgeTumor diameterLN +Vascular invasiónMultifocalityCirrhosis

O. Hyder et al. JAMA Surg. 2014

Agenda

- Introduccion: Aspectos generales

- Tratamiento- Sistémico: Adyuvante / Metastásico- Local

- Aspectos moleculares / Resultados

Horgan AM et al. J Clin Oncol 2012

Adjuvant therapy

- A systematic review and meta-analysis of 20 studies including 6712 resected BTCspatients (GBC, iCC, eCC)

- Non-significant improvement in OS compared with surgery alone

- Non-significant when analyzed independently for patients with GBC, iCC or eCC

- Nonetheless and because of the grim prognosis, adjuvant therapy is oftenrecommended … … … high-risk features (node and/or margin-posi- tive).

- Current data do not support its use after BTC resection (Level of Evidence IIb, Grade ofRecommendation C).

BILCAP: Study Design

▪ Open-label, randomized, controlled phase III trial

Primrose JN , et al. ASCO 2017. Abstract 4006.

▪ Primary endpoint: OS

▪ Secondary endpoints: RFS, toxicity, QoL, health economics

Capecitabine 1250 mg/m2 BID

Days 1-14 of 21-day cycle for 8 cycles

(n = 223)

Observation

(n = 224)

Histologically confirmed

biliary tract cancer*; radical

and macroscopically

complete surgery; ECOG

PS ≤ 2; no previous

chemotherapy or

radiotherapy for biliary

tract cancer

(N = 447)

Primary

analysis after

minimum 2-yr

follow-up

Resection

*Included: intrahepatic CC, hilar CC, muscle-invasive gallbladder cancer, and lower common bile duct CC Excluded: pancreatic, ampullary, mucosal (T1a) gallbladder cancers; incomplete recovery from prior surgery

Stratified by surgical center,

R0 vs R1 resection, ECOG PS

Presented by: Professor John Primrose

Assessed for eligibility, n=753

Randomized, n=447

Observation, n=224

Capecitabine, n=223

Primary analysis population, n=224

Primary analysis population, n=223

Excluded, n=306 Ineligible n=153 Patient declined trial n=133 Other n=20

First centre opened March 2006 First patient recruited July 2006 Accrual completion December 2014 Primary analysis (commenced) February 2017

Premature withdrawal from study, n=6 Disease related, n=1 Patient choice, n=5

Lost to follow-up, n=3

Withdrawal from trial treatment, n=14 Disease related, n=2 Patient choice, n=6 Toxicity, n=4 Other, n=2

Premature withdrawal from study, n=9 Disease related, n=2 Patient choice, n=7

Lost to follow-up, n=4

Participant flow

BILCAP: Baseline Characteristics

Primrose JN , et al. ASCO 2017. Abstract 4006.

Characteristic, % Capecitabine Arm

(n = 223)

Observation Arm

(n = 224)

Male 50 50

Median age, yrs (IQR) 62 (55-68) 64 (55-69)

Tumor site

▪ Intrahepatic CC

▪ Hilar CC

▪ Muscle-invasive gall bladder carcinoma

▪ Lower common bile duct CC

19

29

17

34

18

28

18

36

Resection status, R0/R1 62/38 63/38

ECOG PS, 0/1/2 5/52/3 45/52/3

Tumor size, mm (IQR) 25 (19-45) 25 (20-44)

Lymph node status, N0/N1/not evaluable 45/48/7 48/46/6

BILCAP: OS

Primrose JN , et al. ASCO 2017. Abstract 4006. Reproduced with permission.

ITT Population

Treatment Median OS, Mos

(95% CI)

HR (95% CI)

Capecitabine 51.1 (34.6-59.1) 0.81 (0.63-1.04)

P = .097Observation 36.4 (29.7-44.5)

Sensitivity analyses adjusting for further prognostic factors (gender, nodal status, disease grade) HR 0.70 (95% CI: 0.55-0.91; P = .007)

Treatment Median OS, Mos

(95% CI)

HR (95% CI)

Capecitabine 52.7 (40.3-NR) 0.75 (0.58-0.97)

P = .028Observation 36.1 (29.6-44.2)

Per Protocol Population

> 80% pts followed-up for 36 mos

0

25

50

75

100

Pts

Aliv

e (

%)

0 12 24 36 48 60Mos Since Randomization

0

25

50

75

100

Pts

Aliv

e (

%)

0 12 24 36 48 60Mos Since Randomization

Estudios en curso en AdyuvanciaACTICCA-1Phase III Gemcitabine + CDDP vs CAPECITABINETwo different cohorts: Cholangiocarcinomas and Gall-bladder carcinomaCompletion date: April 22

JapanBCAT: Gemcitabine vs Surgery aloneASCOT: S-1 vs Surgery

PRODIGE 12-ACCORD 18 (J. Edeline et al. J Clin Oncol 2017;#225)

Phase III: Gemox vs Observation(intra-hepatic, perihilar, extra-hepatic cholangiocarcinoma or gallbladder cancer)N: 190No difference in RFS (p=0.31, HR 0.83 [95%CI: 0.58-1.19]

Pooled analysis:

104 trials / 2810 pts

F Eckel et al. BJC 2007

… Based on published results of predominately phase II trials, gemcitabinecombined with platinum compounds represents the provisional standard ofchemotherapy in advanced biliary tract.

Subgroup analysis GBC CC

Median OS (m) 7.2 9.3

Chemotherapy in advanced biliary tract carcinoma: a pooled

analysis of clinical trials

F Eckel* ,1 and RM Schmid1

1Department of Internal Medicine II, Klinikum rechts der Isar, Technical University of Munich, Munich, Germany

Owing to the lack of randomised controlled trials no standard of chemotherapy exists in the treatment of advanced biliary tract

carcinoma. 5-fluorouracil or gemcitabine is recommended based on small and predominately phase II trials. The aim of this analysis

wasto analyse existing trials, even small and nonrandomised, and identify superior regimens. Chemotherapy trialspublished in English

from 1985 to July 2006 were analysed aswell asASCO abstracts from 1999 to 2006. Response rate (RR¼CRþ PR), tumour control

rate (TCR¼CRþ PRþ SD), time to tumour progression (TTP), overall survival (OS), and toxicity were analysed. One hundred and

four trialscomprising 112 trial armsand 2810 patients, thereof 634 respondersand 1368 patientswith tumour control were analysed.

Pooled RR and TCR were 22.6 and 57.3%, respectively. Significant correlations of RR and TCR with survival times were found.

Subgroup analysis showed superior RRs for gallbladder carcinoma (GBC) compared with cholangiocarcinoma, but shorter OS for

GBC. Furthermore, superior RRsand TCRsof gemcitabine and platinum containing regimens were found with highest RRsand TCRs

in the combination subgroup. Based on published results of predominately phase II trials, gemcitabine combined with platinum

compounds represents the provisional standard of chemotherapy in advanced biliary tract cancer, unless a new evidence-based

standard has been defined.

British Journal of Cancer (2007) 96, 896–902. doi:10.1038/sj.bjc.6603648 www.bjcancer.com

Published online 27 February 2007

& 2007 Cancer Research UK

Keywords: bile duct carcinoma; biliary tract carcinoma; cholangiocarcinoma; gallbladder carcinoma; gemcitabine; platinum compounds

Biliary tract carcinomas (BTC) are uncommon but highly fatalmalignancies in the United States and Europe. BTC comprisegallbladder carcinoma (GBC) and cholangiocarcinoma (CC) (bileduct cancer), which arise from the epithelial cells of theintrahepatic and extrahepatic bile ducts. The anatomic locationof CC can bedescribed as intrahepatic, distal extrahepatic, or hilar.Lesions can be described as mass-forming, periductal or intra-ductal, or as mixed mass-forming and periductal (Patel, 2006).

Approximately 5000 cases of GBC and 2500 cases of CC arediagnosed annually in the USA (de Groen et al, 1999). Theincidence of CC (particularly, intrahepatic CC) has been risingover the past two decades in the United States, United Kingdom,and Australia (Rajagopalan et al, 2004). Worldwide, the highestprevalence of GBC is seen in India, Pakistan, Ecuador, Israel,Mexico, Chile, Japan, and among Native American women,particularly those living in New Mexico. Mortality rates in theseareas can reach 5–10 times that in the United States (Lazcano-Ponce et al, 2001; Randi et al, 2006). Worldwide, CC accounts for3% of all gastrointestinal cancers and is the second commonestprimary hepatic tumour (Khan et al, 2005). Incidence of CC ishighest in Israel, Japan, among Native Americans, and in Southeast

Asia, where it can reach 87 per 100000 (Rajagopalan et al, 2004).This indicates the global significance of both GBC and CC.

The reported incidence of ‘surprise’ or ‘incidental’ GBC variesfrom 0.35 to 2% (Misra and Guleria, 2006). Even in patientsundergoing aggressive surgery, the general outcome of patientswith BTC has been disappointing. Five-year survival rates are5-10% for GBC and 10–40% for CC (de Groen et al, 1999).Unfortunately, most biliary tract carcinomas are diagnosed atadvanced stages when the tumour is unresectable. Median survivalof patients with advanced disease is in the range of only a fewmonths.

Owing to the lack of randomised phase III studies, there is nostandard regimen for palliative chemotherapy of GBC and CC.Depending on thepatient’s general condition best supportive care,a clinical trial, 5-fluorouracil, or gemcitabine is recommendedaccording to guidelines of the National Comprehensive CancerNetwork.

The aim of this study was to extensively analyse existing data ofpublished clinical trials, even small and non-randomised, and, ifpossible, identify superior regimens, which may represent astandard of care of palliative chemotherapy in this disease.

METHODS

Data for this analysis were identified by searches of PubMed andreferences from relevant articles using the search terms ‘biliarytract neoplasms’, ‘bile duct neoplasms’, ‘cholangiocarcinoma’, and‘gallbladder neoplasms’. Only papers reporting the results of

Received 20 November 2006; revised 26 January 2007; accepted 29January 2007; published online 27 February 2007

*Correspondence: Dr FEckel, II. Medizinische Klinik, Klinikum rechts derIsar, Ismaninger Str. 22, 81675 Munchen, Germany;E-mail: florian.eckel@lrz.tum.de

Brit ish Journal of Cancer (2007) 96, 896–902

& 2007 Cancer Research UK All rights reserved 0007– 0920/07 $30.00

www.bjcancer.com

Clin

ical

Stu

die

s

J. Valle et al. NEJM 2010

58% CC

11.7 m

8.1 m

Fase IIINo inferioridad

N: 350

Gemcitabina + CDDP

vs

Gemcitabina + S1

13.4 m

HR 0.95; 90%CI, 0.78-

1.15; p .046

15.1 m

Obj. PrincipalSG

Vía Biliar metastásico

M. Ueno et al. #4014 ASCO 2018

J. Valle et al. NEJM 2010med. SG: 11.7 m

MMR-d across 12,019 tumors.

D.T. Le et al. Science 2017

11,6

9,08,3

9,2

7,4 7,2

5,4

9,9

5,76,7

5,0

6,4

0

2

4

6

8

10

12

14

Average of TML per MB

TM

B p

er M

B (

Me

an

)

12% 11%

8%6%

4%3% 3% 3% 3% 2%

1%0%

0%2%4%6%8%

10%12%14%

TM

B ≥

17 (

%)

Percent With TMB ≥ 17

Mean TMB per MB

SalemME,etal.ASCOGI2017

02

468

101214

TumorMutationBurdenAcrossGICancers

Tumor Mutation Burden across GI Cancers

Salem ME, et al. ASCO GI 2017

TACEMed.. OS: 9 – 18 meses(Gem, MMC, ADM, CDDP, Oxa.)

Deb TACEMed.. OS: 11 – 30 meses(ADM, Oxa. CPT-11)

Y90-REMed.. OS: 7 –22 meses

Tratamientos intra-arteriales (pacientes irresecables, conversión, paliación)

L.J. Savic et al. HepatoBiliary Surg Nutr 2017

Ablative Radiotherapy

R. Tao et al. J Clin Oncol 2015

High-dose hypofractionatedproton therapy

Th.S. Hong et al. J Clin Oncol 2015

Unresectable iCC

NCT02232932: Liver Resection Versus Radio-Chemotherapy- Transplantation for Hilar CCNCT02878473: Liver Transplantation for Early Intrahepatic Cholangiocarcinoma

N. Goldaracena et al. Liver Transplantation 2018, G. Sapisochin et al. Hepatology 2016, S. Darwish et al. Gastroenterology 2012

… early iCCA on explant afterundergoing LT for anotherindication …

Darwish Murad et al. Page 14

Gastroenterology. Author manuscript; available in PMC 2013 December 02.

NIH

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IH-P

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anuscrip

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IH-P

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anu

scrip

t

Neoadjuvant QT-RT followed by LT eCC (perihilar)

Ch.P. Wardell et al. Journal of Hepatology 2018

Cell of origin analysis on BTCs and liver cancers.

Agenda

- Introduccion: Aspectos generales

- Tratamiento- Sistémico: Adyuvante / Metastásico- Local

- Aspectos moleculares / Resultados

Driver gene landscape in BTC

H. Nakamura et al. Nature GeNetics 2015

cases with significant enrichment of a somatic TP53 p. Arg249Ser

mutation, which is a typical mutation of aflatoxin B1-exposed HCC.

Letouze et al23 further analyzed WGS of European HCC cases and

identified 10 mutational signatures (COSMIC signatures 1, 4, 5, 6,

12, 17, 16, 22, 23, and 24). Of note, they affirmed a significant asso-

ciation between COSMIC signature 16 and epidemiological back-

grounds such as male gender, alcohol intake, and tobacco

consumption. They also reproduced the significant association

between the presence of CTNNB1 mutation and the frequency of

COSMIC signature 16.

Recently, Ng et al24 reported broad prevalence of the AA signa-

ture (COSMIC signature 22) in HCC cases in Taiwan. They under-

took WES of 98 HCC cases from two hospitals in Taiwan, and found

that 78% of cases harbored the AA signature. Further searching in

1400 HCCs from diverse geographic regions found that 47% of Chi-

nese HCCs and 29% of HCCs from Southeast Asia showed the AA

signature, which is somewhat consistent with exposure through

known herbal medicines. The AA signature was also but infrequently

detected in 13% and 2.7% of HCCs from Korea and Japan, respec-

tively, as well as in 4.8% and 1.7% of HCCs from North America and

Europe, respectively. The TCGA HCC group reported 4.6% of cases

with significant contribution of the AA signature.8 Although the fre-

quency of AA-associated HCC is low in Japan and Western coun-

tries, exposure to AA or their derivatives would play an important

role in HCC globally, especially in East Asia, implying substantial

opportunities for prevention and intensive screening of HCC in these

endemic areas.

5 | DRIVER GENE LANDSCAPE OF BTC

Nakamura et al25 reported the first large-scale WES and transcrip-

tome sequencing of 260 BTC cases that contained three anatomical

subtypes (145 ICC cases, 86 ECC cases, and 29 GB cases). Three

top diver genes were TP53 (26% of all cases), KRAS (18%), and

ARID1A (11%), followed by SMAD4, BAP1, PIK3CA, ARID2, and

GNAS. Similar to HCC, most driver genes were altered in a fraction

(<5%) of cases, suggesting of genetic heterogeneity in BTC. TERT

promoter mutations were detected in 21% of GB cases, whereas

only one ICC case had these mutations. This is quite a contrast with

the high frequency of TPMs in HCC as described above.

The list of frequently mutated driver genes in BTC cases looks

partly similar to that of HCC (TP53, ARID1A, and ARID2) and pancre-

atic cancer (TP53, KRAS, and SMAD4) (Figure 4). By contrast, charac-

teristically, alterations in WNT signaling and TERT were infrequent

and IDH1 mutations (3%) were unique in BTC. Nakamura et al fur-

ther classified driver genes among anatomical subtypes, and reported

subtype-specific and shared driver genes (Figure 4). For example,

IDH1 and BAP1 mutations were ICC-specific, whereas ELF3 and

ARID1B mutations were more common in ECC. EGFR, ERBB2, PTEN,

and ARID2 mutations with TPMs occurred more frequently in GB

cases. The molecular mechanisms underlying the selection of specific

driver genes along anatomical locations and characteristic differences

between HCC and ICC remain completely unknown. It could be pos-

sible that cell type-specific expression levels or signaling cascades, or

carcinogenic causes, might affect the selection of driver genes.

Whole genome sequencing of liver cancer displaying biliary pheno-

types revealed a mixture genetic profiles of HCC and ICC, suggesting

that this category could be a marginal mixture of two tumor types.26

Activation or inactivation of some driver genes might exert cytotoxi-

city or a differentiation switch in specific lineages of liver and bile

duct cancer, as reported in the case of IDH1 mutations.27

The Cancer Genome Atlas CCA project analyzed 34 CCA sam-

ples that were fluke-negative and HBV/ HCV-negative.28 Due to the

limited size of the cohort, frequencies of driver genes were variable

compared to other large-scale studies; however, notably, this cohort

FI GU RE 4 Specific driver genes across anatomical subtypes of biliary tract cancer (BTC), and comparison with core driver genes in

hepatocellular carcinoma (HCC) and pancreatic cancer. ECC, extrahepatic cholangiocarcinoma; GB, gallbladder cancer; ICC, intrahepatic

cholangiocarcinoma

1286 | SHIBATA ET AL.

T. Shibata et al. Cancer Science 2018

Genes accionables

Cáncer V. Biliar

Hepatocarcinoma

Cáncer de Páncreas

Genetic, epigenetic and gene expression features of CCA clusters

Significantly mutatedgenes in Fluke-Pos andFluke-Neg CCA

A. Jusakul et al. Cancer Discov 2017

required. There would exist some overlap in molecular signatures of

subtypes between HCC and ICC despite distinctive core driver gene

sets between the two tumor types.

8 | FUTURE PERSPECTIVES

Comprehensive molecular and genomic analyses of large cohorts of

hepatobiliary cancers have now uncovered landscapes of driver

genes, characteristic mutational signatures, and molecular classifica-

tions of these tumor types. To apply this knowledge for better

treatment, diagnosis, and prevention of these intractable cancers,

genetic screening of each tumor sample, so-called clinical sequenc-

ing, for optimized and individualized choice of treatment , clinical tri-

als, and translational research of new drugs, and novel approaches

for early diagnosis, such as liquid biopsy, are expected. Furthermore,

deeper and broader genomic and basic research, together with inter-

national collaborat ions, are required to understand the biological

roles of each or combinations of identified driver genes in the car-

cinogenesis processes of these tumor types, and to uncover intratu-

moral, interpatient, and inter-ethnic diversities of genomic profiles in

more detail.

(A)

(B)

FI GU RE 6 Molecular classifications of hepatocellular carcinoma (HCC) and biliary tract cancer (BTC) by integrative molecular analyses. (a)

Clinical and molecular features in subtypes of HCC reported in three studies8,42,43 are summarized. TPM, TERT promoter mutation. (b) Clinical

and molecular features in subtypes of BTC or cholangiocarcinoma (CCA) reported in four studies24,27,30,43 are summarized. Subtypes colored

green showed better prognosis; those colored orange showed poorer prognosis. ECC, extrahepat ic cholangiocarcinoma; ICC, intrahepatic

cholangiocarcinoma; JP-UM, Japanese-specific ICC subtype; TCGA, The Cancer Genome Atlas

SHIBATA ET AL. | 1289

Molecular classifications of HCC and BTC

T. Shibata et al. Cancer Science 2018

STARTRK-2

iCC / eCC

Basket Trials

Publicado

Basket Trials

CDDP + Gem. vs CDDP + Gem. + Panitumumab

A. Vogel et al. European Journal of Cancer 2018

Kras wt

- BGJ398 (selective pan-FGFR kinaseinhibitor)

- N: 61 pts whose disease hadprogressed

- FGFR2 fusion (n=48), mutation(n=8) or amplification (n=3)

Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced Cholangiocarcinoma

Javle M et al. J Clin Oncol 2018

med. PFS: 5.8 m

L. Goyal et al. Cancer Discov. 2017

cfDNA, primary tumors, and metastases

3 pts with advanced FGFR2-fusion+ ICC

Marked inter- and intra-lesional heterogeneity, with different FGFR2 mutations

Primary and Secondary resistance to BGJ398 (FGFR pathway)

Conclusiones

- Cáncer de Vía Biliar: Localizado Resecado: Adyuvancia con capecitabina (hasta cuando ….) Metastásico: Gemcitabina + CDDP

- Inv. Vascular / N+ / R1 muy alto riesgo. Papel de la neoadyuvancia

- Creciente información molecular sin actual aplicación en práctica clínica (como en páncreas)

- Tratamientos locales y sistémicos precisan mayor nivel de evidencia e integración

Muchas gracias