Comprehensive molecular profiling should be the preferred test rather than a molecular cancer classifier assay? AGAINST: Dr Natalie Cook Senior Clinical Lecturer in Experimental Cancer Medicine, University of Manchester Honorary Consultant in Medical Oncology Christie NHS Foundation Trust

Premise Tissue agnostic therapeutic approaches are too simplistic Context matters

Hereditary cancer syndromes and tissue-specific tumorigenesis The idea is that germline mutations can predispose to very specific cancer types (left) or more broad (right). The fact that APC mutation promote specific cancers suggests that different tissues have different requirements for genes, and therefore knowing the tissue in which the mutation occurs is important. Certain genes have tissue specific roles ………..Context Matters Schneider et al, Nature Reviews Cancer 2017

Tissue-specific genetic alterations and differential responses Tissue-specific genetic alterations and differential responses Different human cancers contain a subset of recurring cancer driver gene mutations and chromosome copy number alterations that are specific for, or enriched in, that tumor type. The underlying tissue-specific epigenetic architecture may differentially determine the responsiveness to oncogenic signals and thus the propensity to acquire alterations that lead to cancer. …….Context Matters Kevin M. Haigis et al. Science 2019;363:1150-1151 Published by AAAS

Vemurafenib activity against BRAFV600E tumours NSCLC Melanoma COAD Other Sosman et al, NEJM 2012 Tissue-specific activity of vemurafenib against BRAF mutant tumours. …….Context matters Hyman et al, NEJM 2015

Oncogene vs. Tumour Suppressor gene Types of context: 1) Tissue 2) Genetic background 3) Tumour stage …….Context matters Proto-Oncogenes with Tumour Suppressor Function Shen et al, Oncogenesis 2018 Some genes have completely different roles in different cancers. Top table is from a paper that tried to systematically identify these genes. Bottom table I made where I take a few examples and show in which tissues they are oncogenes and which are TSG. Gene Oncogene in: Tumour suppressor in: Therapy NOTCH Breast, T-ALL, Ovarian, Lung, Pancreas HNSC, HCC, Bladder, Oesophagus, Small cell lung GSI (various) EZH2 DLBCL, Prostate , CRC, Melanoma Lung, T-ALL, AML Tazemetostat STAT3 GBM, Prostate, Breast, DLBCL CRC, Salivary TTI-101, AZD9150

The SHIVA Trial: The failure of tissue agnostic precision medicine SHIVA trial shows no difference between matched and non-matched therapies. Lots of potential issues with this trial, but at least on the surface it supports the idea that tissue-agnostic precision medicine does not work. LeTourneau et al, Lancet 2015 …….Context matters

NGS ignores the non-cell autonomous compartment Play a critical role in the maintenance of the cancer

Practical Aspects AND……..CONTEXT MATTERS Molecular cancer classifiers are cheaper than NGS Standard of care limited to certain cancer types (e.g. Immunotherapy) Many trials will only accept certain cancer types IDH1 mutation etc on CUPISCO FGFR3 AND……..CONTEXT MATTERS