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Biological and clinical heterogeneity of breast cancer Antonio Frassoldati Oncologia Clinica - Ferrara Heterogeneity, … that is, what we have tried to ignore Facing tumor heterogeneity Looking changes by re-biopsy? Mean discondance 29,7% Kasraw, Curr Oncol Rep 2011 Biological heterogeneity is the key problem in precision medicine Santarpia, The Oncologist, 2016 Implication of the concept that tumors are composed of evolving clones • Existence of clonal genotypes (i.e., not all mutations occur in the same cells) • Expansion and decline of clonal populations over time • Existence of internal spatial variation in tumor composition • Partial tumor responses to therapy and the emergence of drug-resistant malignant cells • Seeding of metastatic cells from subclones (which may be rare or common in the originating population) • Absence of an observable clonal structure based on genome aberrations in some cancers • Existence of neutral clonal relationships (e.g., arising from random genetic drift) without discernible phenotypic consequences. Mutation, Selection, and Drift are the Three Basic Processes Shaping Cancer Evolution Clonal selection Multiple intratumoral subclones harboring different driver mutations, displaying distinct phenotypes, and evolving with branched phylogenies were identified; spatial constraints most likely limit clonal competition to the immediately neighboring subclones Mutation are the prerequisite for evolution, but their rates, the genomic regions that are prone to mutagenesis, and the timing when particular mutagenic processes operate can vary significantly between but also within individual cancers. Genetic drift each cell in a newly generated cancer subclone has a certain probability of dying as a result of random factors and occasionally all cells of a small subclone die, even if this clone harbors a highly beneficial mutation. Lipinski, Trends in Cancer 2016 Mutation rate increases with increase in tumor size Lipinski, Trends in Cancer 2016 Major cancer susceptibility loci identified in breast cancer Santarpia, The Oncologist, 2016 Somatic mutations in breast cancer and molecular subtypes according to COSMIC database Santarpia, The Oncologist, 2016 Significantly Mutated Genes (SMG) and correlations with genomic and clinical features The Cancer Genome Atlas Network, Nature 2012 Frequencies of the most commonly mutated cancerrelated genes across breast cancer subtypes according to the Cancer Genome Atlas Santarpia, The Oncologist, 2016 Frequencies of the most commonly mutated cancerrelated genes across breast cancer subtypes according to the Cancer Genome Atlas Santarpia, The Oncologist, 2016 The dark side of genome • Besides the importance of variants in protein-coding regions, the majority of the alterations occur in noncoding portions of the genome. • Like somatic variants, germline noncoding affects gene expression through several mechanisms (e.g., promoter mutations, single-nucleotide polymorphisms in enhancers and noncoding RNAs and their binding sites, and variants in introns) • Breast cancer seems to harbor more alterations in the noncoding regions compared with other tumors • Noncoding driver mutations/alterations remains crucial to enable therapeutic approaches that target the specific linked proteins. Cancer Evolution Features • Tumor microenvironmental features, such as blood vessel densities or immune cell infiltrates, can be responsible for some relevant selection pressures. • Cancer cells colonizing metastatic sites are also likely to encounter altered selective landscapes. Lipinski, Trends in Cancer 2016 Clinical consequences of biological heterogeneity Santarpia, The Oncologist, 2016 Cancer as a society of neoplastic cells (an anthropologic view…) • Several variables have to be considered – The composition of society • Young or elderly people prevalence, foreign people, families or singles,…. – The time point of observation • Which idea dominates the society at that point • Trying to understand the film looking at a picture – The space dimension of society • Site and space and time effects on society evolution – The drivers of society • Matriarcal or patriarcal society, culture, politics, religions…. – The relationships between societies • Guests and hosts Which effects of tumor heterogenity for the clinicians? Limits or opportunities? • Knowledge and prognostication of the disease behavior (aggressiveness, specific site of localization, …) • Prediction of response to therapies • Possibility to adapt disease monitoring and treatment • Possibility to modulate treatment based on tumor characteristics and their changes Inter-tumor heterogeneity and response to therapy Co-expression of HR, or p95 positivity in HER2 positive BC reduce the probability of response to antiHER2 agents Guarneri, JCO 2012 Response to primary therapy in HER2pos BC by PIK3CA mut status Loibl, Ann Oncol 2016 Mutation load affects PFS Benefit With Everolimus in ER+ BC resistant to AIs Subgroup N Events (%) Median PFS (d) EVE: WT PBO: WT EVE: Single PBO: Single EVE: multiple PBO: multiple 43 18 76 35 38 17 19 (44%) 14 (78%) 48 (63%) 31 (89%) 27 (71%) 14 (82%) 356 203 214 77 138 128 HR* (95%CI) 0.24 (0.11 - 0.54) 0.26 (0.16 - 0.43) 0.78 (0.39 - 1.54) *HR adjusted with imbalanced covariates Subgroup Definition Size, % WT No alteration in PIK3CA AND PTEN AND FGFR1/2 AND CCND1 Single Single alteration only in PIK3CA OR PTEN OR FGFR1/2 OR CCND1 Two or more alterations in PIK3CA OR PTEN OR FGFR1/2 OR Multiple CCND1 genes Multiple Minimal 27% 76% 49% 24% 24% Hortobagyi, SABCS 2013 ESR1 mutation (by cf-DNA) can predict sensitivity to different hormonal drugs* *SoFEA cohort ESR1 mutant ESR1 wild type Fribbens, JCO 2016 No difference in effect of palbociclib + fulvestrant ESR1wt or ESR1mut (by circulating cf-DNA) *Paloma3 cohort ESR1 mutant in ESR1 wild type Fribbens, JCO 2016 Challenges for clinician related to breast cancer heterogeneity • Understanding heterogeneity – Looking to the tree or to the wood? • Measuring heterogeneity – Dissecting high-throughput data to pick-up the relevant ones • Monitoring heterogeneity – Rebiopsy, liquid biopsy, targeted imaging • Treating heterogeneity – Patient selection, target’s selection, selective or multitarget drug, horizontal or vertical multiple blocks, sequence strategies, … Addressing heterogeneity in clinical practice • Decrease heterogeneity by dissecting tumors by just one homogeneous characteristic – unrealistic, due to the number of variations and to the imprecision of tecniques Screening breast cancer for actionable molecular alterations About 400 MBC pts screeened for genomic alterations Andre’, Lancet Oncol 2013 Personalised therapy is really possible in a minority of patients, positive results just in fews. 13% of pts with actionable targets; RR 1% Andre’, Lancet Oncol 2013 Addressing heterogeneity in clinical practice • Decrease heterogeneity by dissecting tumors by just one homogeneous characteristic (unrealistic, due to the number of variations and to the imprecision of tecniques) • Accept heterogenity, and pick-up the master regulator of the tumor society to induce a catastrophic crash – large failure of clinical trials, due to redundance of escape pathways Molecular subtyping breast cancer could be useful to select the right patient for the right drug Response to primary therapy by intrinsic subtype in CALGB 40601 neoadjuvant trial Carey, ASCO 2013 Targeting cell-cycle regulators in hormone-resistant BC Turner, NEJM 2015 Addressing heterogeneity in clinical practice • Decrease heterogeneity by dissecting tumors by just one homogeneous characteristic (unrealistic, due to the number of variations and to the imprecision of tecniques) • Accept heterogenity, and pick-up the master regulator of the tumor society to induce a catastrophyc crash (large failure of clinical trials, due to redundance of escape pathways) • Accept heterogeneity, and hit multiple targets simultaneously or in sequence – many ongoing trials, thougthly marginally improving the results Multiple block strategy in neoadjuvant setting had limited fallout in adjuvant Different size effect related to hormonal status Addressing heterogeneity in clinical practice • Decrease heterogeneity by dissecting tumors by just one homogeneous characteristic (unrealistic, due to the number of variations and to the imprecision of tecniques) • Accept heterogenity, and pick-up the master regulator of the tumor society to induce a catastrophyc crash (large failure of clinical trials, due to redundance of escape pathways) • Accept heterogeneity, and hit multiple targets simultaneously (many ongoing trials, thougthly marginally improving the results) • Limit heterogeneity effects, by monitoring the changes in tumor composition and the onset of new master regulator and rapidly adapting therapies, both by functional imaging and by molecular analysis – very difficult for possible divergent behavior of different metastases cf-DNA PIK3ca mutations are predictive of efficacy of BKM120* * Belle-2 population Baselga, SABCS 2015 Evolution of heterogeneity (the case of 60 yr-old BC pt, treated with PIK3CA inhibitor) variation of allele frequencies (VAF) of the listed gene mutations in the three lesions Juric, Nature 2015 Heatmap of the non-silent genetic alterations across the primary tumour and the 14 metastases Phylogenetic evolution of the metastases, with bi-allelic loss of PTEN leading patient to death Juric, Nature 2015 Don’t miss host heterogeneity • At individual level (PK, PD, SNPs, …) and at tissue level (immune response and inflammation, angiogenesis, stromal reaction) pCR by TILs in the CherLOB study (Dieci, Ann Oncol 2016) Conclusions • Heterogenity is a natural evolutionary needs of cancer • Mutation, drift and selection represent the key mechanisms regulating heterogeneity • In BC, whole genome analysis revealed high degree of mutations, insisting at different levels in different cell pathways. • Main mutations occur at non coding DNA regions, but their significance has been not yet elucidated • Heterogeneity is the limiting-effect of current therapies, both at a static and a dynamic level • Better understanding of the development and of the role of different clones, as well as of their relationships and fate, is needed to rationally use anticancer drugs