Young-onset Cancer in GI Oncology-

An Evolving entity

Prof. Irit Ben-Aharon MD, PhDHead, Division of Oncology

Rambam Health Care Campus,

Haifa, Israel

Head, Young-onset Task Force, GI Group, EORTC

Disclosure:

None

Digestive tract CancersLong-Term Trends in SEER Incidence Rates, 1975-2015<50y

http://seer.cancer.gov/statfacts/html/

Young-onset CancerCancer is only part of the

Equation….

Late-term Toxicities

Biology and

Etiology

Unmet Needs

Young-Onset Cancer – Relevant Domains

Late-term Toxicities

Biology and

Etiology

Unmet Needs

Young-Onset Cancer – Relevant Domains

▪ The incidence data for invasive cancers among people aged 25–84 years diagnosed from 1995-2014 was obtained.

▪ The authors used age-period-cohort modelling to estimate average annual percentage change in incidence rates by 5-year age group and incidence rate ratios (IRR) by birth cohort.

▪ Incidence significantly increased for six of 12 obesity-related cancers in young adults (25–49 years) with steeper rises in successively younger generations.

Sung et al., Lancet Public Health, 2019

Sung et al., Lancet Public Health, 2019

Early-Onset CRC across the world:

- The trend observed in Europe is not homogenous:▪ Increased incidence in Western Europe

▪ Mixed trends in Middle Europe

▪ Stable trend in Mediterranean countries

Guren et al., In Preparation

- In Far East trend is not homogenous

Colorectal Cancer

Meester et al. JAMA 2019

EOCRC is diagnosed at later stages

Trends in CRC Incidence by Stage in Adults Aged 40-49Y

• SEER data was age-standardized to the 2000 US standard population

• There were a total of 29,532 CRC cases diagnosed among 40-49y from 1975-2015

• This suggests that there has been a real increase in risk and not a shift in age at diagnosis attributable to earlier detection.

Average annual percentage changes were:

• 2.9 (95%CI,2.4-3.4) for distant disease

• 1.4 (95%CI,1.0-1.7) for localized disease

• 1.3 (95%CI,0.7-1.9) for regional disease

▪ Young-onset cancer is a hallmark of inherited cancer predisposition.

▪ Yet, Only 10-17% of EOCRC are hereditary….

Environmental factors??

▪ Obesity

▪ Antibiotic use

Current Evidence:

▪ Obesity

▪ Antibiotic use

Current Evidence:

▪ Body fatness during childhood and adolescence was assessed usinga validated 9-level somatotype scale in the NHS study

▪ Among women, the RR (95% CI) for childhood body fatness oflevel 5 or higher versus level 1 was 1.28 (1.04–1.58) and foradolescent body fatness, it was 1.27 (1.01–1.60)

▪ Increased body fatness in early life, independent of adult obesity,might be a risk factor for colorectal cancer in women, but a weakerassociation was observed in men

Zhang et al., Cancer Epidemiol Biomarkers Prev 2015

Early Life Body Fatness and Risk of CRC

▪ In a prospective cohort study (The NHS-II) of 85,256 women, thosewith obesity (BMI≥30) had a nearly doubled risk of early-onsetcolorectal cancer compared with women with a body mass index of18.5 to 22.9

▪ In another study, cancer incidence was significantly increased for sixof 12 obesity-related cancers in young adults (25–49 years), amongwhich CRC

Liu et al. JAMA Onc 2018Sung et al., Lancet Public Health 2019

Obesity and Young-onset CRC – is there a link?

▪ Obesity

▪ Antibiotic use

Current Evidence:

▪ Former evidence suggests that antibiotic use, which alters the gutmicrobiome, is associated with an increased risk of CRC

▪ Long-term antibiotic use in early-to-middle adulthood wasassociated with increased risk of colorectal adenoma

▪ Studies have suggested antibiotic use during infancy or childhood,which increased dramatically during the 1970s and 1980s, mayinfluence microbial diversity and increase risk of cancer in adults.Does it play a role in young-onset CRC?

Associations between antibiotic use and CRC

Cao et al., Gut 2018Dik et al., Dig Dis Sci 2016Pérez-Hernández et al., Frontiers in Endocrinology 2014

▪ Obesity

▪ Antibiotic use

Current Evidence:

What is the role of epigenetic modifications?

▪ Diet?

▪ Microbiome?

1Dos Santos et al., ESMO 20182Ben-Aharon et al., ESMO 2016

▪ Recent high-resolution genome-wide studies confirm that DNA hypomethylation was the initial epigenetic abnormality recognized in human tumors

▪ The role in the context of EOCRC remains to be elucidated

▪ The genomic landscape of MSS EOCRC does not differ significantly from AOCRC1

▪ An analysis of DNA methylation profiles comparing EOCRC and AOCRC revealed striking methylation differences between these two groups. EOCRC exhibited hypomethylation beyond naturally occurring variation in normal tissue2

Early onset colorectal cancer – does the difference lie in epigenetics?

Pancreatic Cancer

Waddel et al., Nature 2015Bailey et al., Nature 2016

• State-of the art genomic analyses of pancreatic adenocarcinoma has yielded insights into signaling pathways underlying carcinogenesis.

• PDAC is characterized by substantial genomic heterogeneity.

Early-onset Pancreatic Cancer –A different entity?

Subgroups: <55y (EOPC)>70y (AOPC)

•TCGA - PDAC•MSKCC-IMPACT•Nature 2015

Datasets included in the

analysis:N=3

EOPC=90AOPC=203

Ben-Aharon et al., Clin Cancer Res 2019

Mutational Profile

Ben-Aharon et al., Clin Cancer Res 2019

Ben-Aharon et al., Clin Cancer Res, 2019

www.broadinstitute.org/gsea

Upregulated pathways:EOPC AOPC

-1.0

-0.5 0.

00.

51.

0

GSK3A/GSK3B_PS21

GSK3A/GSK3B_PS9

NDRG1_PT346

PDK1_PS241

PKC_PS660

PRKAA1_PT172

PRKCA_PS657

PRKCD_PS664

RICTOR_PT1135

RPS6KA1_PT359

RPS6KB1_PT389

RPS6_PS235

RPS6_PS240

TSC2_PT1462

FRAP1_PS2448

AKT1S1_PT246

AKT1/AKT2/AKT3_PS473

AKT1/AKT2/AKT3_PT308

FOXO3_PS318

MAP2K1_PS217

MAPK14_PT180

SRC_PY416

SRC_PY527 YOUNG

OLD

AK

Tm

TO

RP

KC

PD

KW

NT

p=0.0317

p=0.07

MA

PK

SR

C

Z Score

Upregulated pathways in EOPC

Volcano plot of expressed genes in EOPC versus AOPC

AOPC EOPC

Protein (RPPA) profile

Late-term Toxicities

Biology and

Etiology

Unmet Needs

Young-Onset Cancer – Relevant Domains

Female patients at risk of treatment-induced infertility

•Embryo cryopreservation•Oocyte cryopreservation•Oophoropexy

???

Investigational:•Ovarian cryopreservation • Ovarian suppression

▪ Lack of evidence for counselling for GI cancers

▪ Radiation?

▪ GnRH analogues?

Radiation-induced uterine toxicity

▪ Survivors treated with abdominal radiotherapy were at threefold risk of delivering offspring with a low birthweight compared with survivors treated without radiotherapy

▪ Lack of evidence regarding uterine toxicity of new RT techniques.

• Survivors of stage I-III CRC, diagnosed at age > 65 years between 2000-2011 from the Medicare DB (n = 72,408) were compared with a matched cohort without cancer (n = 72,408).

• Median age at CRC Dx was 78 years (66-106y), and median FU was 8 years.

• The 10-year cumulative incidence of new-onset CVD and CHF were 57.4% and 54.5% compared with 22% and 18% for control, respectively (P < .001).

• The authors concluded that older patients with CRC are at increased risk of developing CVD and CHF.

Kenzik et al., JCO 2018

Chemotherapy-induced vascular toxicity

No evidence regarding young patients… Can we detect the seed of evil?

• A population-based cohort study using SEER and Medicare risk analyses included 1619 tMDS/AML cases among 700,612 adults (age, 20-84years) who were diagnosed with first primary solid cancer during 2000-2013, received chemotherapy and survived >1y.

• Based on 1619 tMDS/AML cases in the SEER database, risks for MDS/AML were statistically significantly elevated after chemotherapy.

• RR ranged from 1.5-10 and excess absolute risks from 1.4-15 cases per 10000 person-years compared with the general population.

• In the SEER-Medicare database, use of known leukemogenic agents, particularly platinum compounds, increased substantially since 2000, most notably for GI tract cancers ((10% in 2000-2001 to 81% during 2012-2013).

Can we detect the seed of evil?

Late-term Toxicities

Biology and

Etiology

Unmet Needs

Young-Onset Cancer – Relevant Domains

*

*

0

0.5

1

1.5

2

2.5

3

Work School Copingwith

children

Interactionwith

spouse

Socialactivity

baseline

During treatment

Post treatment

Ben-Aharon et al., Lancet Onc 2019

• Patient-patient interaction• Research• Education

The role of the social media

• We systematically reviewed all available digital social platforms for young cancer patients.

• The review yielded four major social digital platforms that represent the major web-based social “community” tools.

• A pilot survey aiming to characterize the user profile was delivered via one of the biggest social network, 512 young patients/survivors participated in the survey in 5 days.

Ben-Aharon et al., Lancet Onc 2019

The role of the social media

• The majority of participants had a non-metastatic disease

• Breast cancer, lymphoma, cervical cancer and CRC were the common diagnoses.

• Seventy-eight percent reported they had considered the platform for both medical and social resources.

Emotional coping

Patient/survivor social rights

Emotional coping of the patient’s familyMedical information

Ben-Aharon et al., Lancet Onc 2019

▪ Registry with Biobanking / Translational Research

▪ Quality of life issues

▪ Causation: Diet, Ethnicity

▪ Long-term toxicities

▪ Future design of clinical trials

Young-Onset Colorectal Cancer Task Force (GITCG)

• Registry (prevalence + clinical data)• Tissue sample storage

CRC patients <50

Female patients <43Male patients <45

Curable disease –• Non-metastatic• Oligometastatic

Female patients >43Male patients >45

• Fertility• Cardiovascular• QOL• Microbiome• Disease outcome• Dietary Quest.

Survivorship– 10y:Registry of morbidity

• Cardiovascular• QOL• Microbiome• Disease outcome• Dietary Quest.

Late – 5y:Registry of morbidityPregnancies/ARTDisease outcome

StudyProtocol

▪ The incidence of cancer in the GI tract is increasing in the last decade

▪ The short and long term effects of various anti-cancer treatments for GI cancers remain to be studied – for better consulting and practice of fertility preservation, cardiovascular morbidity and QOL issues

▪ There are unmet unique needs, mainly psychosocial, that should be further studied and addressed

▪ Elucidating the possibly unique biology and etiology is essential for potentially superior treatment tailoring in the future

Early-onset GI cancer – closing remarks

We should try to unravel the cultural, medical, biological, socioeconomic and psychosocial factors that may impact patient outcomesBe Agile

And…

Speak the different language

Young-onset cancer

Thank you