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Biomarkers and Molecular Pathways in Endometrial Cancer Donal Brennan Queensland Centre for Gynaecological Cancer Plan • Why we need biomarkers in EAC • Serum biomarkers in pre-operative triage • The rationale for targeted therapeutics in advanced / recurrent disease Plan • Why we need biomarkers in EAC • Serum biomarkers in pre-operative triage • The rationale for targeted therapeutics in advanced / recurrent disease Type 1 v’s Type 2 endometrial cancer Loss of PTEN KRAS mutations MSI p53 mutations Genomic instability Type 1 G1/2 EAC Risk Factors Excess Estrogen – endogenous and exogenous Tamoxifen Diabetes Nulliparity Type 2 G3 EAC Serous Clear Cell Risk Factors Age Obesity ?BRCA Pre-operative triage Increasing incidence of endometrial cancer in women < 50 years old Arora et al . Best Pract Res Clin Obstet Gynaecol. 2012 Jun;26(3):311-24. Plan • Why we need biomarkers in EAC • Serum biomarkers in pre-operative triage • The rationale for targeted therapeutics in advanced / recurrent disease Biomarkers in EAC • Limited use • None utilised for triage of patients as diagnosis • CA-125 associated with extra-uterine disease – Lacks sensitivity and specificity – Threshold – 35 v’s 65 iu – NPV < 90% • MRI to assess myometrial invasion – Cost issues, access issues, inter-observer variability • Lymph nodes????????? Predicting Extra-Uterine Disease Salvesen HB et al Lancet Oncol 2012 8(13) e353 - e361 HE4 in endometrial cancer • • • • Identified in Human Epididymis Secreted protein ? role in innate immunity Upregulated in a number of cancers – ovary, endometrial, lung • FDA approved in EOC • HE4 is increased in EC compared to normal endometrium • A number of single institution retrospective studies have demonstrated HE4 associated with – advanced stage – myometrial invasion – poor prognosis • No data from population based studies Australian National Endometrial Cancer Study (ANECS) • • • • • • Population based, case control study 1497 patients recruited between 2005 and 2007 Peri-operative serum available for 373 patients CA-125 and HE4 quantified using Abbott Architecture kits Analysis performed in clinically accredited lab Non-parametric Mann Whitney U test, ROC analysis, Kaplan Meier and Cox Porportional Hazards applied. ANECS HE4 study Manuscript submitted Association with Clinicopathological Factors Median HE4 (IQR) [pmol/L] P Value Median CA125 (IQR) [U/ml] P Value All women FIGO Stage (2009) Stage I & II (n =339) Stage III & IV (n=30) 72·7 (53·2-106·3) 134·6 (83-237·7) <0·001 14·9 (11-23) 29·4 (15·1-76·5) <0·001 Grade Grade I & II (n=291) Grade III (n=76) 73·1 (53·5-114·7) 82·7 (53·3-113·4) 0·572 15·4 (11·1-24·1) 15·5 (11·3-28·5) 0·431 Endometrioid Histology Non Endometrioid (n=57) Endometrioid (n=316) 81·8 (56·0-110·7) 73·7 (53·6-113·4) 0·765 14·9 (11-30·5) 15·5 (11·2-24·2) 0·496 LVSI Absent (n=276) Present (n=57) 74·2 (53·1-111·2) 77·9 (51·8-114·3) 0·908 14·9 (11·2-24·8) 15·4 (9·9-25·9) 0·853 Myometrial Invasion ≤ 50% (n=289) > 50% (n=84) 68·0? (52-93·6) 115·3 (81·7-178·9) <0·001 14·6 (11·1-21·8) 25·1 (11·8-43·5) <0·001 Age < 62 (n=184) ≥62 (n=189) 64·0 (48·1-91·2) 85·2 (61·8-136·2) <0·001 15·5 (11·6-26·1) 15·2 (10·5-26) 0·295 BMI (kg/m2) < 30 (n=184) >/= 30 (n=189) 68·4 (52·5-101·3) 81·6 (55·1-122) 0·024 15·0? (10·9-26·8) 15·6 (11·4-24·2) 0·723 Diabetes No (n=309) Yes (n=64) 73·1 (53·2-106·5) 91·1 (57·3-152·3) 0·023 15·4 (11·2-26) 15·9 (11·8-26·3) 0·781 Hypertension No (n=231) Yes (n=137) 69·8 (50-101·6) 82·7 (60-131·1) 0·001 15·2 (11·2-24·9) 15·8 (11·6-26·6) 0·653 Manuscript submitted Predicting Outer Half Myometrial Involvement All Patients (n=373) AUC HE4 – 0.76 (0.70-0.81) CA-125 – 0.65 (0.57-0.72) Endometrioid Histology, Grade 1 and 2 (n = 280) Endometrioid Histology (n = 316) AUC AUC HE4––0.76 0.77(0.70-0.83) (0.70-0.83) HE4 CA-125––0.62 0.64(0.53-0.71) (0.55-0.73) CA-125 Applying 70pmol/L as a threshold Manuscript submitted HE4 as a Prognostic Marker P = 0.05 P = 0.001 Manuscript submitted Multivariate Analysis of RFS Manuscript submitted HE4 Summary • Largest study of HE4 in EC to date • First population based study • Elevated HE4 is associated with an aggressive phenotype • HE4 is a superior to CA125 in predicting outer-half myometrial invasion – HE4 < 70 pmol/L, ? avoid lymphadenectomy • HE4 is an independent predictor of OS and RFS Manuscript submitted Where next? • What is the functional role of HE4 in endometrial cancer. • What effect does progesterone treatment have on HE4? • Can HE4 be used to monitor patients on hormonal therapy • Are age-specific references needed? HE4 may be beneficial in pre-operative triage weelevated apply targeted in advanced / • Can Is HE4 in recurrenttherapeutic disease ? recurrent disease – Particularly if it was normal at initial presentation • Can HE4 be used to monitor for recurrence? Plan • Why we need biomarkers in EAC • Serum biomarkers in pre-operative triage • The rationale for targeted therapeutics in advanced / recurrent disease Historical Perspective • • • • 18th century – Biology 19th century – Chemistry 20th century – Physics / Computer Science 21st century – Molecular Medicine Principles of Molecular Medicine • Successful new therapies will be based on a foundation of precise molecular understanding of disease • Translational science must adopt a multidisciplinary approach that requires substantial infrastructure • Human subjects are an essential early component in the evaluation of new drug candidates Charles Sawyers J Clin Invest 2009 The Targeted Therapeutic Era to Date • Molecular Diagnostics are urgently required • Oncogene addiction – Only relevant in certain tumour types • Repeat analysis during treatment – Inclusion of translational arm in early phase trials – Pathway diagnostics Somatic Mutations in Endometrial Cancer Adv Genomics Genet. ; 2012(2): 33–47 Classification of EAC based on somatic mutation profiling Type 1 – PTEN, KRAS common TypePI3K, 1 Type 2 Grade III – higher incidence of p53 and PI3K mutations , less CTNNB1, KRAS Type II – p53 mutations common, PTEN mutations rare Alterations in PI3K pathway seen in 80% of endometrioid cancers Loss of MMR protein expression associated with higher mutation prevalence Cheung L W et al. Cancer Discovery 2011;1:170-185 Somatic Mutations in Endometrial Cancer Type 1 Type 2 FGFR2 Her2 PI3K KRAS PI3K PTEN CTNNB1 p53 What does and unsupervised approach add ? • Similar mutation frequencies for normal candidates - PTEN, p53, PI3K, CTNNB1 • 10 novel tumour suppressor genes – ARID1A, INHBA, KMO, TTLL5, GRM8, IGFBP3, AKTIP, PHKA2, TRPS1, and WNT11 • 2 novel oncogenes – ERBB3 and RPS6KC1 Liang H et al. Genome Res. 2012;22:2120-2129 Wu J N , and Roberts C W Cancer Discovery 2013;3:35-43 Loss of ARID1A expression in primary human cancers ? Haploinsufficient effect ARID1A regulates PI3K activity in Endometrial Cancer Liang H et al. Genome Res. 2012;22:2120-2129 RAS and PI3K pathways www.biooncology.com Downstream Effects of PI3K and KRAS mutations Distinct downstream signaling events are activated in PI3K pathway- and KRAS-mutant EC Cheung L W et al. Cancer Discovery 2011;1:170-185 KRAS as a therapeutic target • Best molecular targets are aberrantly activated kinases that are inhibited by selective smallmolecule inhibitors. • Oncogenic Ras proteins have reduced GTPase activity • Restoring enzymatic function is a major challenge • Prognostic relevance of KRAS mutation remains inconsistant • MEK inhibitors have shown some promise in other tumour types PI3K Pathway as a therapeutic target Salvesen H B et al. PNAS 2009;106:4834-4839 Slomovitz B M , and Coleman R L Clin Cancer Res 2012;18:5856-5864 How do we define activity of PI3K pathway? • Major issue for trial design • Clinically valid molecular diagnostic is urgently required • Options include – – – – – PTEN IHC pAKT Stathmin IHC Sequence based assay Combination assay Djordjevic et al Mod Pathology 2012 Targeting PI3K / AKT / mTOR Slomovitz B M , and Coleman R L Clin Cancer Res 2012;18:5856-5864 Temsirolimus in recurrent o4 metastatic EAC 62 patients, weekly temsirolimus 25mg • Chemo-Naïve group (Group A) – – • Chemo-treated group (Group B) – – • 48% SD or better Median PFS 3.2 months Toxicity – – • 69% SD or better Median PFS – 9.7 months Rash, fatigue, mucositis, pneumosisitis Higher dose reduction in chemo-treated group Unable to identify any predictor of response Oza A M et al. JCO 2011;29:3278-3285 Phase 1 and phase 2 trials of targeted therapies for endometrial cancer >100 trials registered investigating PI3K inhibition 26 trials open in endometrial cancer 4 are biomarker enriched Rapalogues / PI3K inhibitors in breast and gynae cancers Combined with various other regimens Response rate 30% in patients with PI3KCA mutation Response rate 10% in patients with wild type PI3KCA Predicting response to PI3K inhibition PI3K inhibitors p85 p110 PTEN AKT inhibitors AKT mTORC2 Rapalogs mTORC1 Dual mTOR Inhibitors 4EBP1 S6K Approach to identify predictive biomarkers Coexistent KRAS mutation predicts resistance Coexistent Her2 amplifcation predicts response PTEN mutant cells are sensitive to PI3Kb inhibitors PTEN loss may predict response to AKT inhibitors Must identify addicted v’s dependent populations Brennan et al Nat Rev Cancer 2010 Future for Targeted Therapies in Endometrial Cancer • Biomarker enriched, adaptive trial design • Repeat biopsy • Tumour heterogeneity • Circulating free DNA • Confirmation of pathway inhibition • Identify mechanisms of resistance • Combination therapy – – – – Vertical – RAF / MEK inhibition in melanoma Horizontal – MEK + PI3K / PI3K + PARP Endocrine therapy Cytotoxics Leary et al Sci Tran Med 2012 ER Signalling E2 Growth Factor e.g. EGF or IGF-1 ER MISS MAP Kinase Activation Classical Ligand Dependent Pathway Ligand Independent Pathway P P mRNA Protein ER ER ERE Genomic Pathway ER Responsive Gene Tissue Response P ER Fos mRNA Protein Jun AP-1 Target Gene Brennan et al Oncogene 2012 Rationale for combining PI3K inhibition and endocrine therapies IGF 1/II P IGF-R PTEN PI3K LKB1 E2 AKT AMPK Metformin mTOR p-S6K ER PR ER response genes PR, PS2 PR response genes Inhibition of proliferation Conclusions • Why we need biomarkers in EAC • Fertility sparing therapy, • Obesity • Serum biomarkers in pre-operative triage • HE4 shows some promise • The rationale for targeted therapeutics in advanced / recurrent disease • PI3K inhibitors are unlikely to have a role as single agents • Combination, biomarker enriched studies may offer best chance of clinical response