Heterogeneity in hormone receptor

positive breast cancerTomás 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

Quality or state of being diverse in character or content

•ResistanceAbility not to be affected, especially adversely

•EvolutionGradual development , specially from a simple to a more complex form

Oxford dictionary

• Heterogeneity• Inter-tumor• Intra-tumor

• Spatial• Temporal

• Resistance

• Evolution

• The example of the Estrogen Receptor gene (ESR1) mutation

• Incorporating these concepts into clinical practice

• Heterogeneity• Inter-tumor• Intra-tumor

• 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 – 1896SOFT trial - 2015

Beatson GW. Lancet 1896Francis 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 ProjectNext-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• Inter-tumor• Intra-tumor

• 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 2008Geyer and Reis-Filho. J Path 2010

Intra-tumor spatial (geographic) heterogeneity

Shah SP et al. Nature 2010Collison 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• Intertumor• Intratumor

• 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 actionTargeting 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• Intertumor• Intratumor

• 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• Intertumor• Intratumor

• Spatial• Temporal

• Resistance

• Evolution

• The example of the Estrogen Receptor gene (ESR1) mutation

• Incorporating these concepts into clinical practice

ESR1 mutationEstrogen 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 2015Toy 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• Intertumor• Intratumor

• 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

• Patient• 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 2015Cardoso F et al – Ann Oncol 2015

Suggested endocrine therapy sequencing alternatives in patients with HR+ advanced breast cancer

De novo diseaseEndocrine 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

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]

• Exemestane + everolimus[6]

• Fulvestrant + palbociclib[7]

• Tamoxifenc[9]

Define according to the previous two lines

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]

• 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

Reinert T, Barrios CH. Ther Adv Med Onc 2015

• Thank you for your attention!

tomasreinert@hotmail.com