interuniversitair postgraduaat onderwijs heelkunde oncologie · pancreatic cancer head and neck...
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Sevilay Altintas, MD, PhD
Staff member at the multidisciplinary breast clinic, gynecological oncology and urogenital oncology, Antwerp University Hospital. Belgium
Interuniversitair postgraduaat onderwijs Heelkunde
Oncologie
31 januari 2020
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Incidentie
In 2017, 68.702 new diagnoses of cancer were registered in Belgium
The disease affects approximately 1/3 men and 1/4 women before they reach the age of 75.
Cancer mainly affects older people. Respectively 67% of women and 79% of men are aged 60 years or older when diagnosed.
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Incidentie
• 03
Cancer Statistics 2019
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Oorzaak van kanker: theorieën
Kanker = combinatie van genetische en epigenetische afwijkingen in hetgenoom van de cel
Carcinogenese = complex proces dat verschillend verloopt voorverschillende tumoren
- chemische, fysische en biologische noxen;
- genetische eigenschappen van het individu spelen een modulerende rol
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Een aantal begrippen
• Transformatie = celveranderingen onttrekken aan normale groeiregulerendmechanismen
• Mutatie = verandering in base-paar compositie van DNA
• Oncogenese = proces van ontstaan van maligne tumoren
• Carcinogenese = ontstaan van maligne tumoren
• Carcinogene factoren = omgevingsfactoren, die een rol spelen bij het ontstaan
• Mutagene factoren = factoren die afwijkingen in het genoom induceren
• Initiatie = proces dat in het genoom mutaties induceert
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Het ontstaan van kanker (carcinogenese)
• De meeste tumoren ontstaan door omgevingsfactoren. Een veel kleiner aantal is het gevolg van erfelijke afwijkingen in het genoom.
• Het is gebleken dat niet één enkele, maar meer afwijkingen (mutaties) in het genoom van de cel nodig zijn om een cel te transformeren tot een tumorstamcel.
• Carcinogenese is dus een meerstapsproces. Daarbij spelen ook gastheerfactoren een rol (bv. hormonale of immunologische factoren).
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Oorzaken
M. Peeters
Voeding Leeftijd
Overgewicht Familie
Tabak Voorgeschiedenis
Alcohol
Beroepsfactoren,
fysische (stralen) en
biologische (virussen)
carcinogenen
Milieu Verontreiniging
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M. Peeters
oorzaken van darmkanker: de leeftijd
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M. Peeters
oorzaken van darmkanker: de familie
Hoog (5 – 10 %) Verhoogd (15 – 20 %) Globaal (75 %)
Lynch SyndroomFamiliaal, Persoonlijke
voorgeschiedenis
3.5 %Familial Polyposis Coli IBD (colitis)
Centrum voor GeneticaPopulatie Screening
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Screening
• Screening is het onderzoeken van een in principe gezonde populatie om asymptomatische gevallen van een ziekte of
aandoening op het spoor te komen, in de veronderstelling dat deze aandoening in een vroeg stadium misschien beter te
behandelen is. Screening op zoek naar ziekten in een vroeg stadium valt onder de secundaire preventie van ziekten. Om voor
screening in aanmerking te komen moet een aandoening aan een aantal voorwaarden voldoen:
• Er moet een test bestaan met een hoge specificiteit en sensitiviteit, zodat het percentage fout-positieven laag is, evenals het
percentage fout-negatieven.
• De aandoening in kwestie moet een asymptomatisch voorstadium hebben.
• De aandoening moet bij behandeling in een vroeg stadium een duidelijke betere prognose hebben dan bij latere ontdekking.
• De test mag zelf niet tot merkbare ziekte of bijwerkingen aanleiding geven
• Het onderzoek moet betaalbaar zijn (er moeten in relatie tot de kosten van het onderzoek voldoende vaak gevallen worden
gevonden om het de moeite waard te maken).
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M. Peeters
♀ + ♂, 50-74 jaar Post Huisarts
Screenning
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In 2016 werden 571.034 Vlamingen uitgenodigd, waarvan er 54,5 % deelgenomen hebben. Bij 6,6 % bleek de test afwijkend te zijn.In 2017 daalde de deelname tot 51,757 op 1000 mensen hebben afwijkend stoelgangtest
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Screenning
• Borstkankerscreening elke 2 jaren Mammografie vanaf 50-69 j
• Baarmoederhalsscreening elke 3 jaren vanaf 25-64 j
• Longkankerscreening (Low dose CT)
• Prostaatkankerscreening
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Oncologische Behandelingsstrategieen
CHIRURGIE ORGAAN GERICHT SYSTEMISCH
primaire tumor RFA, RadioFrequentieAblatie
chemotherapie
(platinumderivaten,
anthracyclines, ea)
metastasen chemoembolisatie
drug eluting beads
doelgerichte therapie
(TKI, Antilichamen)
radioembolisatie
(tomo) radiotherapie
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M. Peeters
Doelstelling
Curatief
Palliatief
OS
OS
QOL
- Adjuvante therapie
- Neo-adjuvante
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Behandeling colorectaal carcinoom
M. Peeters
Combinaties Monotherapie
• De Gramont • 5-Fluorouracil +/- Folinic Acid
• Folfox, Capox • Capecitabine, UFT
• Folfiri • Cetuximab, Panitumumab
• Beva, Aflib + Chemotherapy • Irinotecan
• EGFRi + Chemotherapy • Regorafenib
Chemotherapie Biologicals
• 5-Fluorouracil, Capecitabine • Bevacizumab
• Oxaliplatin • Aflibercept
• Irinotecan • Regorafenib
• Mitomycin C • Cetuximab
• Panitumumab
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Metastatisch
Beperkt
Resecabel Neo-Adjuvant
MogelijksResectabel
Inductie
Diffuus Palliatief
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Neoadjuvante chemotherapie
• Identificatie van patiënten die zullen reageren op de ingestelde behandeling• Gevoeligheid ingestelde therapie
• Biologie van tumor
• In vivo test voor nieuwe moleculaire therapie
• Borstsparende chirurgie/Cosmetica bij borstca
• Inoperabel Operabel (bv levermeta’s)
• Bij non-responders therapie aanpassen en bijsturen
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Neoadjuvante chemotherapie
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Beoordeling van therapie
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M. Peeters
PATIENT
Huisarts
Patholoog
Radiotherapeut
Radioloog
Nuclearist
Chirurg
Oncoloog
Andere
Multidisciplinair Oncologisch Consult
Therapeutische Beslissing
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Conventional Cancer therapy
• Surgery
• Chemotherapy
• Radiotherapy
Based on classical clinicopathological featuresTumorgrade, tumorsize, age…
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Interindividual Variability
One size fits all?
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Treatment Strategies related to Cancer Function
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Multipathway inhibition
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Personalized Medicine
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Biomarkers: Definition
• Biomarker: A distinctive biological or biologically derived indicator of a process, event, or condition.
• Prognostic biomarkers: biomarkers that provide information aboutthe patients overall cancer outcome, regardless of therapy
• Predictive biomarkers: Biomarkers that can be used in advance of therapy to estimate response or survival of a specific patient on a specific treatment compared with another treatment
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Biomarkers: definition
• Predictive biomarkers
• Identify patients who will/will not respond to treatment
• Goal: Enrich treatment population to maximize benefit and minimize costs
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Metastatisch
RAS
Wild Predictief
Mutant Predictief
BRAF
Wild Prognose
Mutant Prognose
Target & Trends in de Oncologie – gepersonaliseerd
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The Efficacy of Targeted Therapy Is Affected by . . .
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Tumor heterogeneity
IMPORTANCE OF MULTIPLE BIOPSIES OF MULTIPLE SITES IN CASE OF RECURRENT DISEASE
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Molecular subtypes (Predictive markers) of breast cancer and their targets
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Farmacogenomics: PARP inhibitors in BRCA mutated BC and ovarian cancer
Many trials running with PARPi in BC and OC with longlasting responses
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Her-2 positive breast cancer
Her-2 overexpressing BC: poorly differentiated tumorshigh proliferative ratepositive axillary lymph nodesdecreased expression of estrogen and progesterone receptors. increased risk of disease recurrence and death
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Other anti-HER therapy
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Evolution HER-2 therapy in breast cancer
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Farmacodynamics: Molecular imaging
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89 Zr-trastuzumab-PET/CT
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Farmacodynamics: blood-based markers
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CTC’s in Breast Cancer patients
Mario Giuliano et al. Breast Cancer Research, 2014
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ctDNA
• virtually all cancers carry
somatic DNA mutations
• dying tumor cells release small
pieces of their DNA into the
bloodstream
• patient-friendly method for the
detection, monitoring and
treatment of cancer
• ctDNA can correlate with the
stage of cancer
• Prognostic/Predictive
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ctDNA
Bettegowda et al. Sci Trasl. Med. May 2014
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Diagnosis
Treatment Response Relapse
Circulating tumor cells
Circulating tumor DNA
CT/PET scan
CTCs
and
ctD
NA leve
ls in
plasm
a
Tum
or burd
en
Disease Progression in time (from diagnosis to relapse)
Rolfo, Castiglia, Russo, Peeters et al. In press 2014
‘Vloeibare Biopsie’
Target & Trends in de Oncologie – gepersonaliseerd
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Immunotherapy
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(Cancer)Immunotherapy
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Immunotherapy
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Long-term data from the CheckMate 067 study
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Estimated Frequency of NTRK Fusions Across Tumor Types
Hong. ESMO Asia Congress 2016. Abstr 1500.
NTRK Fusion Frequency
< 5% of patients 5% - 25% of patients > 75% of patients
CNS Astrocytoma Brain low-grade glioma Glioblastoma
GI CRC Cholangiocarcinoma GIST Pancreatic cancer
Head and Neck Squamous cell
carcinoma
Lung Adenocarcinoma Large cell
neuroendocrine
Other Acute myeloid leukemia Breast cancer Melanoma Sarcoma
Congenital mesoblastic nephroma
Papillary thyroid cancer
Pontine glioma
Spitz tumors
Mammary analogue secretory carcinoma (MASC) of the salivary gland
Secretory breast carcinoma
Infantile fibrosarcoma
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Larotrectinib in a Pediatric Patient With ETV6-NTRK3 Fusion–Positive Secretory Breast Cancer
Shukla. JCO Precis Oncol. 2017;2017.
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First TRK Fusion–Positive Cancer Treated With Larotrectinib
• 42-yr-old female with LMNA-NTRK1fusion soft tissue undifferentiated sarcoma
• Treated with epirubicin, ifosfamide, and sorafenib prior to resection and doxorubicin while awaiting study entry
• Received 100 mg BID larotrectinib
• Resolution of dyspnea and hypoxemia and confirmed partial response
Doebele. Cancer Discov. 2015;5:1049. Hong. ESMO Asia 2016. Abstr. 1500.
Baseline Study Cycle 13 Day 1
Study Cycle 3 Day 1
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Larotrectinib Efficacy in Patient With ETV6-NTRK3 Infantile Fibrosarcoma
• 2-yr-old female patient with infantile fibrosarcoma
• Previously received 2 cycles of vincristine/actinomycin-D/cyclophosphamide and continued to progress
• Leg amputation was remaining alternative option
• Received 4 cycles of larotrectinib followed by surgery
• Pathologic complete response, clear margins, and no functional deficit following surgery
Hyman. ASCO 2017. LBA2501.
Baseline Cycle 3
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1980 1990 2020
Times have changed...
EMPIRICAL ONCOLOGY MOLECULAR ONCOLOGY
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Our New Way to Work . . . Molecular Tumor Board
Molecular Tumor Board
Patient case is derived from his doctor
Mol. Pathol PediatGeneticistOncologist Gyneco Thorax
Molecular Tumor BoardReport with therapeutic
proposal
Referral Doctor Discussion
Nav. nurse
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• Evolving therapeutic concepts in oncology basedon molecular biology understanding
- Precision medicine
- Cancer immunotherapy
From clinical oncology to molecular and immunological therapeutic approaches
Chemotherapy
Molecular-targeted agents
Immunotherapy
Evolving cancer treatments and concepts
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Data Tsunami
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Clinical trials and
collaboration
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Traditional vision of Drug Development
Courtesy of David Hong
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The inverted Pyramid of Biomarker-Driven Trials
Garrido-Laguna et al, Nat Rev Clin Oncol 2011
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Research
Clinical Trials
Collaboration and Sharing Experiences
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TKI and toxicity profile
RTK
nRTK
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Skin rash
A Typical Rash Associated With EGFR TK
Inhibitors.A Typical Rash Associated With PI3K
Inhibitors.
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Onycholysis and Paronychia
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Hand foot syndrome
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Pulmonary toxicity: Noninfectious Pneumonitis
• mTOR inhibitors: 14-45%
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Dermatologic Toxicity: Cutaneous squamous cell cancer/keratoacanthoma
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Conclusion
“ I stopped taking the medication because I prefer the original
disease to the side effects”
Diarree
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Dosing
Appropriate/Optimal individual dose
Maximum
Efficacy Duration
of treatment
as long as clinical
benefit is observed
Management
of side effects
Pro-active approach +
close monitoring of
the patient
USE OF THE AGENT WITH THE HIGHEST EFFICACY Improves
tumor/disease control before resistance occurs
MAXIMIZING EFFICACY
Individualizing treatment
Individual Dose management
1. Negrier .Oncology 2012 Mar 21 vol 82(4) 189-196
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