1. Heterogeneity in hormone receptor positive breast cancer
Tomás Reinert

2. 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

3. 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

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

5. Key concepts
Heterogeneity
Resistance
Evolution

6. 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

7. 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

8. 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

9. Breast cancer timeline

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

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

12. Lett H et al. BMJ 1905

13. 1970 : Discovery of estrogen receptor

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

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

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

17. The Human Genome Project Next-generation sequencing (NGS)

18. 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

19. 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

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

21. 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

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

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

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

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

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

27. 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

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

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

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

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

32. Evolution

33. Evolution

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

35. Polyak K. J Clin Invest 2011

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

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

41. The Cancer Genome Atlas
The Cancer Genome Atlas. Nature 2010

42. 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

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

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

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

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

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

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

50. 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

51. 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

52. 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

53. 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

54. Thank you for your attention!