ASCO heterogeneity presentation El-Deiry 6-4-17

Emerging Complexity of Tumor Heterogeneity and Clinical PracticeWafik El-Deiry, MD, PhD, FACPDeputy Cancer Center Director for Translational ResearchCo-Leader, Molecular Therapeutics Program Fox Chase Cancer Center

Tumor and Clinical Heterogeneity Educational SessionJune 4, 2017

Disclosures

Presented by: Wafik El-Deiry, MD, PhD, FACP

• Oncoceutics: Founder, Shareholder (no research funding)– Clinical stage company developing ONC201/TIC10 as cancer therapeutic– El-Deiry Lab performs basic research on cell death, TRAIL signaling and ONC201

• P53-Therapeutics: Founder, Shareholder (no research funding)– Early stage company developing small molecules targeting mutant p53– El-Deiry Lab performs basic research on p53 mechanisms and therapeutics

• Morphotek: Sponsored Research Funding– Supports 3D organoid cultures as predictive assays in immune suppressive microenvironments

• Caris Life Sciences: Co-Chair National Steering Committee for Centers of Excellence Network (no research funding)

– Precision medicine company

Learning ObjectivesAfter reading and reviewing this material, the participant should be able to:

• Appreciate clinical and molecular heterogeneity of cancer– Focus on colorectal cancer (lessons relevant to other tumors)

• Understand complexities and issues for patient care with tumor heterogeneity


Presentation Outline• Landscape of clinical and molecular heterogeneity

in colorectal cancer• Issues in care of patients with heterogeneous

tumors and treatment responses• Open questions in the field and future directions


Clinical heterogeneity of CRC• Landscape of clinical and molecular heterogeneity

in colorectal cancer





Age, Stage (I-IV), Location (right, left, rectal), Risk (family history, IBD)

WT, KRAS/NRAS, BRAF, MSI




Age, Stage (I-IV), Location (right, left, rectal), Risk (family history, IBD)

WT, KRAS/NRAS, BRAF, MSI

Operable Inoperable

Landscape of host & tumor heterogeneity


• Clinical heterogeneity• Host heterogeneity

• drug metabolism• MicrobiomeCellular & Molecular Heterogeneity

• Inter-patient tumor heterogeneity• Intra-tumoral heterogeneity

• within primary tumor• within metastases• within a metastasis

• Intergenic heterogeneity• TME heterogeneity; immune, stroma• Response heterogeneity

• Tumor evolutionVogelstein et al. Science 239:1546-1558, 2013




In early stage CRC we currently do not assess molecular heterogeneity beyond universal testing for MMR protein expression and genetic risk in those with family history or early age-of-onset disease

Molecular heterogeneity of CRC• Landscape of clinical and molecular heterogeneity



• In CRC, including advanced disease, no two tumors are exactly alike

• Drivers• Passengers

From Volgelstein and colleagues:

Wood et al. Science 318:1108-1113, 2007

Host heterogeneity in CRC treatment• Landscape of clinical and molecular heterogeneity



Host heterogeneity in 5-FU metabolism described in late 1990’s

• Landscape of clinical and molecular heterogeneity in colorectal cancer


PK-guided dosing of 5-FU allows for more cycles before adverse side effects including in early stage CRC

Kline et al., Clinical Colorectal Cancer 13:119-126, 2014

Host heterogeneity in CRC treatment

• Landscape of clinical and molecular heterogeneity in colorectal cancer


PK-guided dosing of 5-FU in CRC remains as an opportunity for personalized therapy given the large variation among individuals in 5-FU metabolism

More work is needed for prospective validation but it is important

Host heterogeneity in CRC treatment

Molecular heterogeneity of mCRC


A series of well-described molecular genetic and epigenetic changes occur leading to colorectal cancer



Nearly 50% of CRCs are driven by KRAS or NRAS mutations while ~10% have BRAF mutations; the rest are wild-type for Ras and BRAF

Louisa Lo, Timothy Price, Joanne Young and Amanda Townsend (2016). BRAF Mutation in Colorectal Cancer, Colorectal Cancer - From Pathogenesis to Treatment, Prof. Luis Rodrigo (Ed.), InTech, DOI: 10.5772/62226. Available from: https://www.intechopen.com /books/col orectal-cancer-from-pathogenesis-to-tr eatment/br af-m utati on-i n-col or ectal-cancer



Low intra-patient inter-metastatic genetic heterogeneity and genomic complexity are associated with favorable patient outcome

Sveen A, et al. Intra-patient Inter-metastatic Genetic Heterogeneity in Colorectal Cancer as a Key Determinant of Survival after Curative Liver Resection. PLOS Genetics 12(7): e1006225, 2016. https://doi.org/10.1371/journal.pgen.1006225http://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1006225

Limited heterogeneity in treatment-naïve tumors


• Passenger mutations accounted for all intra-tumoralheterogeneity

• Genetic similarity among founding cells of metastases was higher than expected for any two cells from a normal tissue

• Uniformity of drivers among metastases encouraging

Response heterogeneity of mCRC


Chemotherapy plus cetuximab is associated with improved OS (vs chemo alone) in (extended) WT RAS mCRC; OS worse if mutant Ras with combination

Van Cutsem et al., Journal of Clinical Oncology 33:692-700, 2015 Follow-up of CRYSTAL study



Misale et al., Cancer Discovery 4:1269-1280, 2014

• Response to anti-EGFR therapies accompanied by selection of preexisting resistant clones.

• Resistant clones can emerge with therapy

• Clones carrying distinct alterations in KRAS, NRAS, EGFR, BRAF mutations or KRAS, HER2, or MET amplifications can coexist in the same metastatic site or in different metastatic sites.

Bardelli and colleagues:

EGFR and Ras mutations in mCRC following cetuximab


Mutation in the extracellular domain of EGFR in patients who have been treated with cetuximab: S492R is still sensitive to panitumumab. Other mutations described at 2014 ASCO include R451C and K467T. In some but not all patients, mutations preexisted at the time of diagnosis.

Resistance to anti-EGFR in mCRC is heterogeneous


Resistance mechanisms identified from 116 KRAS WT PDX models: ERBB2, MET, EGFR mutation, FGFR1, PDGFRA, Ras pathway, PI3K pathway

Nature 2015

Heterogeneous response following resistance to anti-EGFR in mCRC


Russo et al., Cancer Discovery 6:147-153, 2016

• Corcoran and colleagues identified MEK1 pK57T as a resistance mechanism

• A heterogeneous response was observed to panitumumab plus trametinib

v Serial analysis of plasma ctDNA during therapy v Known MAP2K1 p.K57T mutation decreased v A KRAS p.Q61H mutation emerged in plasma v Segment 5 liver lesion biopsied after progression

and NGS detected KRAS p.Q61H seen in ctDNAv The MAP2K1 p.K57T mutation in segment 8 was

not detected in biopsy of segment 5, suggesting independent evolution of distinct resistance mechanisms in these two metastatic lesions.

Heterogeneity of metastatic sites in CRC


• Her2 overexpressed in ~4% of lung mets (Odds ratio 2.247); note HERACLES trial

• Based on Topo1 and ERCC1, irinotecan preferred for peritoneal metastases

• Anti-c-MET worth further testing in liver mets

Heterogeneity of Ras mutations in CRC


• A number of hotspots are observed in various Ras genes

• More work is needed to understand differences in biology and implications for therapy

ASCO 2016

Evolution of treatments for BRAF mutant CRC


• The knowledge of differences between BRAF-mutant melanoma and CRC has been evolving for several years as has the progress for therapy of BRAF-mutant mCRC

• Data from 2015 ASCO

Not all BRAF mutations are the same in mCRC


How should they be treated?

There is immune heterogeneity in CRC and variability in tumor mutation burden


• MMR-deficient CRCs have immune infiltrates and can respond to immune checkpoint therapy; these tumors have a high mutation burden

• Non-MMR-deficient tumors do not generally respond to single agent immune checkpoint therapeutics; these tumors typically do not have a high mutation burden

Potentially actionable mutations in MMR-deficient CRC


• Of 1104 profiled CRCs from a 2nd cohort (COSMIC), MSH2/MLH1-mutant CRCs showed higher mutation rates in BRCA2 vs non-MMR-deficient tumors (38% vs 6%, P < 0.0000001)

• Some BRCA2 mutations predicted to disrupt interactions with partner proteins DSS1 & RAD51 • EGFR was mutated in 45.5% of MSH2/MLH1-mutant vs 6.5% of non-MMR-deficient tumors (P

< 0.0000001). 15% of EGFR mutations found may be actionable including N700D, G719D, T725M, T790M, and E884K

• NTRK gene mutations identified in MSH2/MLH1-mutant CRC including NTRK1 I699V, NTRK2 P716S, and NTRK3 R745L

What to do beyond resistance to immunotherapy; need trials based on the new insights

Treatment options based on molecular heterogeneity in mCRC


First-line therapy:• Unknown status: FOLFOX, FOLFIRI, or FOLFOXIRI plus bevacizumab• KRAS/NRAS WT: FOLFIRI (or FOLFOX) plus cetuximab

Second-line therapy:• KRAS/NRAS WT: FOLFIRI + cetuximab (following FOLFOX + bevacizumab)• KRAS/NRAS mutant: FOLFIRI + bevacizumab (following FOLFOX plus

bevacizumab in first-line setting)

Therapy for refractory disease:• V600E BRAF mutant: Vemurafenib + irinotecan + cetuximab or dabrafenib

+ trametinib + panitumumab (not all BRAF mutants are the same); not yet approved by FDA

• MSI: Immune checkpoint therapy (e.g. pembrolizumab)• FOLFIRI + zaltrap, regorafenib, lonsurf, clinical trial, genomic profiling

There are many open questions regarding managing heterogeneous colorectal tumors


• When and how often to do extensive tumor profiling (and using what platform), and will it help the patient

• How to better predict relapse or resistance• Liquid biopsy versus tumor tissue biopsy• What to do with multiple actionable targets• How to combine immune checkpoint therapy & targeted agents• How to manage mixed responses• How to overcome therapy resistance• How to manage heterogeneous resistance mechanisms

Summary• Molecular heterogeneity and tumor evolution

present a challenge to effective colorectal cancer therapy

• Knowledge is rapidly evolving to allow precise therapies and algorithms for molecular subtypes

• More work is needed to unravel resistance mechanisms, to monitor tumor evolution, and to target therapy escape mechanisms

Presented by:

ASCO heterogeneity presentation El-Deiry 6-4-17

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