Heterogeneity in hormone receptor positive breast cancer Tomás Reinert

Hormone receptor positive (HR+) breast cancer Most common Major cause of death “Luminal” disease  uncertainty commonly arises Oncologists seek to avoid both under-treatment and over-treatment

Hormone receptor positive (HR+) breast cancer Endocrine therapy (ET) is the mainstay of treatment ET might have the greatest global impact among all of available oncology treatments, considering breast cancer prevalence and substantial benefit associated with this treatment Significant benefit in the adjuvant setting Still, 25% early stage ER+ will develop recurrence within 10 years In the metastatic setting, initial regression ~30% and clinical benefit in the majority of patients However, resistance and disease progression invariably occurs

Why study heterogeneity ? Prognostic – predictive biomarker for stratification Tool to trace back tumor evolution –relevant for prevention Development of better experimental models Personalized therapy

Key concepts Heterogeneity Resistance Evolution

Key concepts Heterogeneity Resistance Evolution Quality or state of being diverse in character or content Resistance Ability not to be affected, especially adversely Evolution Gradual development , specially from a simple to a more complex form Oxford dictionary

Heterogeneity Resistance Inter-tumor Intra-tumor Evolution Spatial Temporal Resistance Evolution The example of the Estrogen Receptor gene (ESR1) mutation Incorporating these concepts into clinical practice

Heterogeneity Resistance Inter-tumor Intra-tumor Evolution Spatial Temporal Resistance Evolution The example of the Estrogen Receptor gene (ESR1) mutation Incorporating these concepts into clinical practice

Breast cancer timeline

Ma CX, Reinert T, Ellis MJ. Nature Rev Cancer 2015

Dr George Beatson – 1896 SOFT trial - 2015 Beatson GW. Lancet 1896 Francis PA et al. NEJM 2015

Lett H et al. BMJ 1905

1970 : Discovery of estrogen receptor

Inter-tumor heterogeneity Sorlie T, Perou CM et al. Proc Nat Acad Sci USA 2001

Inter-tumor heterogeneity Ades F et al. J Clin Oncol 2014

Breast cancer survival according to subtypes Sorlie T, Perou CM et al. Proc Nat Acad Sci USA 2001

The Human Genome Project Next-generation sequencing (NGS)

Genetic heterogeneity among luminal tumors MAPK3  hormone sensitivity TP53  hormone resistance GATA3  predictive of ET sensitivity Ellis MJ, Ding L, Shen D et al. Nature 2012

Heterogeneity Resistance Inter-tumor Intra-tumor Evolution Spatial Temporal Resistance Evolution The example of the Estrogen Receptor gene (ESR1) mutation Incorporating these concepts into clinical practice

Intra-tumor spatial (geographic) heterogeneity Allred et al. Clin Canc Res 2008 Geyer and Reis-Filho. J Path 2010

Intra-tumor spatial (geographic) heterogeneity Shah SP et al. Nature 2010 Collison EA et al. Nature Rev Clin Onc 2012 Hortobagyi G et al. AACR 2013

Intra-tumor heterogeneity Babayan A et al. PLOS One 2013

Inter-tumor and intra-tumor heterogeneity Polyak K. J Clin Invest 2011

Inter-tumor and intra-tumor heterogeneity Zardavas D, Swanson C, Piccart M. Nature Rev Clin Onc 2015

Heterogeneity Resistance Intertumor Intratumor Evolution Spatial Temporal Resistance Evolution The example of the Estrogen Receptor gene (ESR1) mutation Incorporating these concepts into clinical practice

Estrogen receptor pathway = mainstay of ET Ma CX, Reinert T, Ellis MJ. Nature Rev Cancer 2015

Endocrine therapy mechanism of action Targeting the estrogen receptor (ER) pathway Estrogen deprivation  Aromatase inhibitors (anastrozole, letrozole and exemestane) Selective estrogen receptor (ER) modulation/downregulation  tamoxifen and fulvestrant

Mechanisms of resistance Ma CX, Reinert T, Ellis MJ. Nature Rev Cancer 2015

Mechanisms of resistance Ma CX, Reinert T, Ellis MJ. Nature Rev Cancer 2015

Mechanisms of resistance Ma CX, Reinert T, Ellis MJ. Nature Rev Cancer 2015

Heterogeneity Resistance Intertumor Intratumor Evolution Spatial Temporal Resistance Evolution The example of the Estrogen Receptor gene (ESR1) mutation Incorporating these concepts into clinical practice

Evolution

Evolution

Darwin and cancer evolution Greaves C, Marley CG. Nature 2010

Polyak K. J Clin Invest 2011

Heterogeneity Resistance Intertumor Intratumor Evolution Spatial Temporal Resistance Evolution The example of the Estrogen Receptor gene (ESR1) mutation Incorporating these concepts into clinical practice

ESR1 mutation Estrogen Receptor Alluri PG et al. Breast Cancer Research 2014

The Cancer Genome Atlas The Cancer Genome Atlas. Nature 2010

ESR1 mutation in hormone-resistant cohorts Jesensohln R et al. Nat Rev Clin Onc 2015 Toy et al. Nature 2013 Hortobagyi G et al. AACR 2013

Mutations, translocations and amplifications ESR1 Ma CX, Reinert T, Ellis MJ. Nature Rev Cancer 2015

Pre-existing rare mutation X De novo acquired mutation Jesensohln R et al. Nat Rev Clin Onc 2015

Ligand-independente ER pathway activation in ESR1 mutation Jesensohln R et al. Nat Rev Clin Onc 2015

ESR1 mutation: heterogeneity, resistance and evolution Jesensohln R et al. Nat Rev Clin Onc 2015

Heterogeneity Resistance Intertumor Intratumor Evolution Spatial Temporal Resistance Evolution The example of the Estrogen Receptor gene (ESR1) mutation Incorporating these concepts into clinical practice

Zardavas D, Swanson C, Piccart M. Nature Rev Clin Onc 2015

Optimal management of HR+ advanced breast cancer in 2015 HR+ advanced breast cancer remains an incurable disease Lack of biomarkers Our objective  Tailored treatment Predict which particular ET will benefit more the individual patient  realistic and clinically meaningful goal

Factors to consider when selecting endocrine therapy for patients with HR+ advanced breast cancer Age, menopausal status, PS, comorbidities, adherence Tumor Histological subtype, HR expression, HER2 amplification, intrinsic subtype Disease Previous ET, DFI on adjuvant ET, response to previous line, tumor burden, visceral metastasis Agent Mechanism of action, toxicities, cost, availability Other issues Availability of clinical research, financial hardship, existing guidelines Reinert T, Barrios CH. Ther Adv Med Onc 2015

Different populations of patients with HR+ advanced breast cancer De novo disease : endocrine therapy naive Long DFI on adjuvant AI or long PFS on previous line as surrogate for acquired (secondary) resistance Shot DFI on adjuvant AI or short PFS on previous line as surrogate for intrinsic (primary) resistance Reinert T, Barrios CH. Ther Adv Med Onc 2015 Cardoso F et al – Ann Oncol 2015

Suggested endocrine therapy sequencing alternatives in patients with HR+ advanced breast cancer Short DFI on adjuvant AI (or short PFS on previous Line) as surrogate for intrinsic resistance 1ST LINE for ABC (previously exposed to AI) 2ND LINE for ABC 3RD and further LINES Exemestane + everolimus[6] Fulvestrant + palbociclib[7] This group of patients probably represents a less endocrine sensitive population, and chemotherapy should be considered at an earlier point depending on the clinical course Long DFI on adjuvant AI (or long PFS on previous Line) as surrogate for acquired resistance 1ST LINE for ABC (previously exposed to AI) 2ND LINE for ABC 3RD and further LINES Fulvestranta[5] Exemestane + everolimus[6] Fulvestrant + palbociclib[7] TamoxifenC[9] Fulvestrant[5] Tamoxifenc[9] Define according to the previous two lines De novo disease Endocrine Therapy naive 1ST LINE 2ND LINE 3RD and further LINES Fulvestrant a [1] Letrozole + palbociclib b[2] Aic[3] Tamoxifenc[4] Fulvestrant[5] Exemestane + everolimus[6] Fulvestrant + palbociclib[7] Aic[8] Tamoxifenc[9] Define according to the previous two lines Reinert T, Barrios CH. Ther Adv Med Onc 2015

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