heterogeneity in hormone receptor positive breast cancer
DESCRIPTION
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-treatmentTRANSCRIPT
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
