making sense of individualised molecular data in gynaecological … · avastin rituxan herceptin...
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Making Sense of Individualised Molecular Data in
Gynaecological Cancer
Caris Symposium Palais De Congres February 4th 2014
Hani Gabra Ovarian Cancer Action Research Centre Imperial College London
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• 45 year old Female, presented with abdominal distension
• CT Scan showed disseminated peritoneal disease
• CA125 of 2500 • Proceeded to Laparotomy
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Locoregional peritoneal dissemmination
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Ovarian Cancer is typically a Chronic Disease
Primary Surgery
Platinum + Other drugs
Relapse Therapy
Tumour volume
• Chronic survivability ends with drug resistance
?
? CA-125
Treatment
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Definitions of Platinum Sensitivity/Resistance
(Friedlander 2011)
• Platinum Refractory: Progression while receiving last line of platinum-based therapy or within 4 weeks of last platinum dose
• Platinum Resistant: Progression free interval since last line of platinum greater than 1 month and less than 6 months
• Partially Platinum Resistant (Intermediate Sensitivity): Progression free interval since last line of platinum of 6-12 months
• Platinum Sensitive: progression free interval since last line of platinum greater than 12 months.
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Isogenic paired cell lines from women with ovarian cancer before and after resistance
Patient 2
Patient 1
Patient 3
Pre-treatment 1st relapse
Cisplatin
Resistant relapse
PEA1 PEA2
PEO14 PEO23
PEO1 PEO4 PEO6
Resistance
Sensitive Resistant
(JD Brenton)
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Non-linear evolution of karyotypes Cooke et al Oncogene 2010
Sensitive Resistant
PEA1
PEO14 PEO23 Nataliya Melnyk
PEA2
PEO1 PEO4 PEO6
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Functional genomics of clinical platinum resistance- Expression Microarray
Stronach et al Cancer Res 2011
In vitro models
Expression profiling
Functional screening
HDAC4/ STAT1
PI3K/ AKT
FOLR2
• STAT1 • HDAC4 • FOLR2 • PI3K/AKT
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AKT
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Platinum induces nuclear pAKT in resistant cells
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A new model for Clinically Acquired Resistance-SPECIFIC AKT activation:
Stronach et al Neoplasia 2011
Outside-in activation DNA-damage activation
Akt
pAkt
pAkt-S473
DNA-PK
cisplatin
Survival
Akt pAkt-S473
Survival
PI3K mTOR
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PEO1 Sensitive
PEO4 Resistant
FDG/FLT Imaging as Biomarkers of Therapy Response in Platinum-Resistant Ovarian Cancer
Perumal et al Mol Imaging Biol 2012
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AKTi resensitises clinically resistant cells to platinum in vivo
Tumour size changes
0 1 2 3 4 5 6 7 8 9 10 11 12 14 140
100
200
300ControlCisplatinAPI-2CIS + API-2
Tum
or
volu
me
(m
m3)
0 1 2 3 4 5 6 7 8 9 10 11 12 13 140
100
200
300ControlCisplatinAPI-2Cis +API-2
Tum
or
volu
me
(m
m3)
PEO1 PEO4 i) ii)
Days after treatment Days after treatment
Perumal et al Mol Imaging Biol 2012
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Activity of GSK2141795
• RECIST responses = 1/12 (8%)
• GCIG Responses = 3/11 (27%)
• Clinical Benefit Rate = 3/11 (27%)
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-100
-80
-60
-40
-20
0
20
40
1 2 3 4 5 6 7 8 9 10 11 12
Best CA125 Response
Best RECIST Response
Ca-125 and Radiological responses
AKT inhibitor Monotherapy In Plat resistant Patients 3/12 = 25% GCIG 1/12= 8% RECIST
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• High success rate obtaining biopsies – Confidence in physician – Education both pre- and post biopsy – A dedicated team of interventional radiologists
• Complication rate: 1.72% – hematoma
Paired Tumour Biopsies (n=58)
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Single agent GSK ’795 trial: RPPA analysis (n=170 antibodies)
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Biomarkers associated with clinical activity
validation
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AKTRES Phase Ib (AKT inhibition in Platinum RESistant ovarian cancer)
Carbo-Taxol + GSK2110183: Oral Pan kinase AKT inhibitor
Platinum Resistant Patients
• CT • 3 X Core
Biopsies • Ca-125
• Carboplatin • Paclitaxel • GSK2110183
• 3 X Core Biopsies
• Ca-125
FIVE cycles • Carboplatin • Paclitaxel • GSK2110183
• Feasibility • Activity • Safety
Dr Sarah Blagden EUTROC Clinical CI Dr Euan Stronach EUTROC Translational CI
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Drivers for change in Cancer Care • Prevalence is rising • Costs are rising • Conventional use of anticancer medicines
=waste due to poor selection • Patients have a tough enough time with
chemotherapy: failure is bad for us and very bad for patients
• Our scientific understanding of individual cancer types has dramatically increased
• Molecular profiling the answer?
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How can molecular analysis help?
• Can enhance understand of likely operating pathways for an individual tumour (Not just single biomarkers)
• Can add value to a physician’s intuition (eg which endocrine agent?)
• Can help a tumour board/MDT achieve rational decisions • May avoid toxicity of useless drugs • Can direct patients to clinical trials / help to enrich clinical
trials rationally • Can assist with temporal analysis of sequential changes in
tumours: Darwinotherapy
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High Cost Burden due to Non-responders
Rituxan Herceptin Gleevec Avastin
Taxotere
Revlimid
Alimta Gemzar Tarceva Femara
$3.059B $2.466B $1.526B $1.373B $1.285B
$1.042B0 $975M $723M $661M $650M
Erbitux Leuprolin Velcade Xeloda Arimidex
$646M $598M $508M $494M $483M
Sources: Individual Drug Labels. US Food and Drug Administration. www.fda.gov Market and Product Forecasts: Top 20 Oncology Therapy Brands. DataMonitor, 2011.
Responder Non-responder
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Heterogeneity in clinical cancers
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Mutation Frequencies in Common Cancers
Dancey et al. The Genetic Basis for Cancer Treatment Decisions. Cell 2012
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CARIS
Imperial College Molecular Tumour Board
• Prof Gordon Stamp: Pathologist • Prof Hani Gabra: Oncologist • Dr Steven Moser: Radiologist • Prof Bob Leonard: Oncologist • Prof Christina Fotopoulou: Surgeon
“Selfie”
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Setting up a molecular profiling MDT • Can discuss individual case management in context of
molecular readout • Major input from pathology and radiology drives
intervention, and review of old and new data • Collect outcome data to validate efficacy of approach:
the crucial empirical approach in audit loop format • Potential to explore heterogeneity in metastatic
cancers: Temporal and Spatial • Allows building of a whole clinical pathway for
integration of molecular information
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Caris Molecular Intelligence Services Comprehensive for Solid Tumors
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Each Biomarker Result May Help You Select Therapeutic Options
©2013 Caris Life Sciences and affiliates.
28
How do I treat a patient with ovarian cancer where
standard treatment options have failed?
TOPO1 (IHC)
TS (IHC)
RRM1 (IHC)
BRAF (NGS)
MGMT (IHC)
ER (IHC), HER2 (IHC), HER2 (CISH), PIK3CA (NGS)
SPARC (IHC), TLE3 (IHC), Pgp (IHC)
ER (IHC) or PR (IHC)
HER2 (IHC), HER2 (CISH), PTEN (IHC), PIK3CA (NGS)
cKIT (NGS), PDGFRa (NGS)
TOPO2A (FISH) and HER2 (CISH)
HER2 (IHC) or HER2 (CISH)
RET (NGS)
CONSIDER irinotecan
AVOID fluorouracil, capecitabine, pemetrexed
CONSIDER gemcitabine
AVOID vemurafenib
CONSIDER temozolomide, dacarbazine
AVOID everolimus, temsirolimus
AVOID paclitaxel, docetaxel, nab-paclitaxel
AVOID hormone therapy
CONSIDER trastuzumab
CONSIDER imatinib
CONSIDER doxorubicin, liposomal-doxorubicin, epirubicin
CONSIDER lapatinib, pertuzumab, TDM-1
AVOID vandetanib
Biomarker associated with potential benefit
Biomarker associated with potential lack of benefit
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Currently
• Increasing information using FFPE material-forget about frozen tissue
• Can get answers back in 7-10 working days • Results of profiles with accompanying evidence
level • We have ‘molecular MDT’ meetings to discuss
problem patients • Ideally get re-biopsy for CURRENT disease profile • How much better than guessing? • Audit of results is essential
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25 CASES ASSESSED BY PROFILING
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Be Critical: CARIS are trying to be, but you have to
be too!!
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Distribution of Mutation in Ovarian Cancer
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Case 1 • 48 yr woman second opinion from Egypt • NOVEMBER 2009: TAH/BSO total macroscopic clearance • STAGE IIIC GRADE 3 ENDOMETRIOID CARCINOMA OF OVARY • CA125 at presentation was 2400 • Patient lost to follow up no chemotherapy • Marker progression noted march 2010 to 175 • commenced on carboplatin and taxol (first line, first
recurrence) with good marker regression to end of therapy, July 2010
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Case 1
• August 2011 CA125 started to climb to 134. • Weekly Taxol and Carboplatin • Due to PD at midway scan, avastin was added but
had marker PD after 3 months, when CA125 was 152 • marker rise and PET-CT lesions with gemcitabine
carboplatin starting July 2012 and CA125 responded initially but PDin December 2012
• 2 cycles Caelyx - PD
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Case 1 • Came to Imperial Molecular MDT for second opinion • CT Review showed further progression with new
hepatic metastases • Surgical Review ruled out surgery • Vault biopsy of tumour done • Pathology review indicated Squamous Carcinoma of
Cervix !! • HPV high risk subtypes confirmed by PCR in-situ, p53
wildype! • CARIS analysis undertaken
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CARIS Associations
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Molecular basis for potential benefit
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Outcome
• Cisplatin Topotecan recommended • Patient underwent good partial response after
3 cycles • Returned to Egypt to continue chemotherapy • MDT recommended capecitabine and
Herceptin at PD
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Case 2 • 70 year old Engineer from China • Presented 2005 CA125 388 • Laparotomy total macroscopic clearance • Serous borderline tumour • 3 cycles taxol only • CT Scan 2010 showed pleural disease, spleen and stomach
peritoneal disease • Attended Imperial Molecular MDT for 2nd Opinion
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Case 2 • Repeat CT showed extensive dissemination of disease
including left supraclavicular fossa • Progressive abdominal massive peritoneal disease and new
left hydronephrosis • Surgical clearance ruled out due to widely disseminated
disease • Fresh biopsy by interventional radiologist Dr Moser, and
stenting of Left Hydronephrosis as a one stage procedure • Patient went home same day
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Case 2 • Pathology Review showed METASTATIC
BORDERLINE TUMOUR • No evidence of invasive elements even in
metastatic disease • Question about heterogeneity!! • Biopsy sent to CARIS for analysis
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CARIS Associations
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Molecular basis for potential benefit
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NGS Alterations
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Outcome • Commenced Letrozole • Good pain control with tramadol and paracetamol • PS 0/1 • Good appetite • Patient well after 2 months • Will return from China for CT Scan and CA125 formal
evaluation in 1 month
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CONTINUOUS LOW-FLOW ASCITES-DRAINAGE AND SEQUENTIAL NON-INVASIVE TUMOR-CELL SAMPLING THROUGH THE URINARY BLADDER VIA THE ALFA-PUMP CLOSED SYSTEM IN PLATINUM-RESISTANT-OVARIAN-CANCER
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Alfapump AMAZE randomised trial: A new translational and therapeutic platform for
noninvasive temporal precision oncology
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Patient 1 Patient 2
Days of implant 81 58
Total amount of fluid removed [L]
28.2 12
Average daily volume [L] (range)
370 (121-2343)
200 (0.25-1582)
Mean successful pump cycles (range)
50 (7-163) 25 (0-145)
Days shake mode was active
0 52
Treatment related patients characteristics
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110
115
120
125
130
135
140
145
0 5 10 15 20 25 30 35 40 45 50
Sodium level, blood
35
55
75
95
115
135
155
175
0 5 10 15 20 25 30 35 40 45 50
Creatinine level, blood
10
12
14
16
18
20
22
24
26
28
0 5 10 15 20 25 30 35 40 45 50
Albumin level, blood
Biochemical Follow up during treatment
Patient 1 Patient 2
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Pap x400
p53
CK7
WT1
p53 mutation (R273L) frequency Primary block
Urine at relapse
72%
96%
Histopathological analysis of the urine revealed rich malignant cell content; this was used to create FFPE-cell-blocks for molecular- pathological profiling with sequential Caris-Target-Now-analysis and full exome-sequencing.
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Blood markers- exosomes
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Case 3 • 65 year old woman • 10 year history of initally stage Ic grade 1 serous ovarian
cancer • Multiple recurrences • 8 lines of chemotherapy • Carboplatin, Taxol, Caelyx, Topotecan, gemcitabine,
combinations • Only one stabilsiation : Gemcitabine, which slowed ascites
formation
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CARIS Associations
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Molecular basis for potential benefit
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Outcome • Marker fell from 400 to 125 after 1 month of
Megestrol Acetate 160mg daily • Appetite improved • PS improved to 0/1 • Postural hypotension stopped, peripheral oedema
disappeared! • Ascites dried up • Alfapump Pump went into “sleep” mode • Patient will be formally assessed at 3 months
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Summary
• We have had a favourable experience of Molecular Profiling in the context of moelcular tumour board decision making
• More information abut the tumour in context of the patient allows us to make more sophisticated decisions when no other options exist
• This is increasingly the future, except that the future is now, and is integrated with new technologies
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Ovarian Cancer TSGs
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Ovarian Cancer Oncogenes
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Other promising target pathways