Luminal Advanced Breast Cancer

From Bench to Bedside

Septiman
Human breast cancer is highly heterogeneous
On the level of histopathology On the molecular level

Stage (in situ/invasive)

Differentiation
Nuclear Grade Shift to A New Approach Based on the
LVI Biology of the Disease
HR
HER2
LVI, lymphovascular invasion

2 Sorlie T et al, PNAS 2001; Sotiriou C et al, Proc Natl Acad Sci USA, 100; 2003
Breast cancer gene expression subtypes

3 Sorlie T et al, PNAS 2001

Surrogate definitions of intrinsic subtypes of
breast cancer (2013 St Gallen)

4 Ades F. JCO 2014; Goldhirsch. Ann Oncol. 24:2206, 2013

Genomic classifiers vs IHC
PAM50 vs St Gallen IHC

N= 797 patients with ER, PR, HER2 and Ki-67 data available

Although IHC and transcriptomic subtypes correlate,

they are not synonymous

5 Bastien et al. BMC Med Genomics 2012

Distinct subtypes have different repertoires of mutations,
but no mutation or gene is subtype-specific

6 Stephens et al, Nature 2012; Shah et al. Nature 2012; Ellis et al. Nature 2012; Banerji et al. Nature 2012
Subtype distribution within
HR+/HER2-negative disease

7 Prat et al. Breast 2015.

Correlation Between Intrinsic Subtype Classification by PAM50
and OncotypeDX and MammaPrint Prognostic Signatures

8 Ades et al, J Clin Oncol 2014

The prognostic role of the intrinsic subtypes in
metastatic HR+ breast cancer

- EGF3008: Phase III clinical trial

- First-line therapy
- 1,286 patients with HR+ disease
- Survival Benefit of lapatinib in HR+/HER2+ disease, but not in HR+/HER2-

9 Johnston et al. JCO 2009.

EGF30008
Distribution of the intrinsic subtypes

4% 11%
27%

29%

29%

HR+/HER2+ (N= 157)

10 Prat et al. JAMA Oncol 2016.
Studying the Biological Differences Between
Primary and Metastatic Breast Cancer

11 Cejalvo et al. Cancer Res 2017.

Studying the Biological Differences Between
Primary and Metastatic Breast Cancer

12 Cejalvo et al. Cancer Res 2017.

 NCCN v3. 2017 Breast Cancer
Treatment Guidelines
Systemic Treatment of Recurrent or De Novo Metastatic Disease
Continue ET until progression
or unacceptable toxicity
Progression
No clinical benefit after 3 sequential ET
regimens
Or
Symptomatic visceral disease
Yes
Chemotherapy Trial of new ET
• Many premenopausal and postmenopausal women
with hormone-responsive breast cancer benefit from
sequential use of endocrine therapies at disease
progression
• Definitive recommendation on optimal ET cascade is
unavailable
• Recommend 3 consecutive ET regimens before
switching to CT
• If no response is observed after 3 sequential lines of
CT or ECOG PS ≥3 achieved, patients should be
transitioned to palliative care
No
• There is no compelling evidence that combined CT
regimens are superior to single agents

CT, chemotherapy; ECOG PS, Eastern Cooperative Oncology Group Performance Status; ET, endocrine therapy; NCCN, National
Comprehensive Cancer Network.

13 National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V3.2017.
1st Line Hormonal Therapy vs Chemotherapy

14 Chang et al, ASCO 2011 (abstr 622)

Sequential use of endocrine therapies

15 Iwase H; IntJClinOncol. 20(2):253-61, 2015

Mechanisms of Endocrine Therapy Resistance
(ER-Growth Factor Signaling ‘Cross-Talk’)

16 Arpino G, et al. Endocrine Rev, 2008, 29(2):217–233

Definition of endocrine resistance

 Primary (intrinsic)
- Relapse while on the first 2 years of adjuvant ET
- PD within first 6 months of 1st ET for MBC, while on ET
 Secondary (acquired)
- Relapse while on adjuvant ET but after the first 2 years
- Relapse within 12 months of completing adjuvant ET
- PD ≥6 months after initiating ET for MBC, while on ET

17
Growth Factor Receptor Inhibitor + HT

18 Arpino G, et al. Endocrine Rev, 2008, 29(2):217–233

First-line HER2 inhibitor plus HT
in HER2+/HR+ metastatic breast cancer

19 Kaufman et al, JCO2009, Johnston et al, JCO2009, Huober et al, The Breast 2012
Inhibition of Common Down Stream Effector

20 Arpino G, et al. Endocrine Rev, 2008, 29(2):217–233

 Targeted Agents in HR+, HER2– Advanced BC
EXEMESTAN
Receptor PIP3 E
Estrogen
PIP2 FULVESTRANT &
tyrosine TAMOXIFEN
kinase LETROZOLE &
PTEN ANASTROZOLE
Estrogen
AKT receptor
PI3K
mTOR S6K Restriction point
ALPELISIB,
BUPARLISIB,
PICTILISIB, & EVEROLIMUS
TASELISIB Cell cycle Tumor growth
CDK4/6 Cyclin D and
proliferation
G1
Angiogenesis
PALBOCICLIB E2F Gene
Inhibition of
, RIBOCICLIB RB transcription
Cell cycle eg, Cyclin D apoptosis
ABEMACICLI progression and E2F
B
G1/S

BC, breast cancer; CDK, cyclin-dependent kinase; HER2–, human epidermal growth factor receptor 2-negative; HR+, hormone receptor-positive; mTOR, mammalian target
of rapamycin; PI3K, phosphatidylinositol 4,5-bisphosphate 3-kinase; PIP2, phosphatidylinositol 4,5-bisphosphate; PIP3, phosphatidylinositol 3,4,5 trisphosphate; PTEN,
phosphatase and tensin homolog; RB, retinoblastoma protein; S6K, S6 kinase.
Figure generated based on data from 1. Baselga J, et al. Oncologist. 2011;16(suppl 1):12-19; 2. Bosch A, et al. Sci Transl Med. 2015;7(283):283ra51; 3. Campbell RA, et al. J Biol Chem. 2001;276(13):9817-9824; 4. Carracedo A, et al. J Clin Invest.
2008;118(9):3065-3074; 5. Ciruelos Gil EM. Cancer Treat Rev. 2014;40(7):862-871; 6. Courtney KD, et al. J Clin Oncol. 2010;28(6):1075-1083; 7. Crowder RJ, et al. Cancer Res. 2009;69(9):3955-3962; 8. Dienstmann R, et al. Mol Cancer Ther.
2014;13(5):1021-1031; 9. Faivre S, et al. Nat Rev Drug Discov. 2006;5(8):671-688; 10. Hart CD, et al. Nat Rev Clin Oncol. 2015;12(9):541-552; 11. Hosford SR, et al. Pharmgenomics Pers Med. 2014;7:203-215; 12. Isakoff SJ, et al. Cancer Res.
2005;65(23):10992-11000; 13. Jerusalem G, et al. Cancer Treat Rev. 2015:41(2):94-104; 14. Lukas J, et al. Mol Cell Biol. 1996;16(12):6917-6925; 15. Mayer IA, et al. J Clin Oncol. 2014;32(12):1202-1209; 16. Meric-Bernstam F, et al. J Clin
Oncol. 2009;27(13):2278-2287; 17. Miller TW, et al. J Clin Oncol. 2011;29(33):4452-4461; 18. Miller TW, et al. J Clin Invest. 2010;120(7):2406-2413; 19. O’Reilly KE, et al. Cancer Res. 2006;66(3):1500-1508; 20. Shapiro GI. J Clin Oncol.
2006;24(11):1770-1783; 21. Zoncu R, et al. Nat Rev Mol Cell Biol. 2011;12(1):21-35.
 Current first-line treatment guidelines
for HR+, HER2– ABC

 ET (tamoxifen, AI, FUL)

NCCN 1,a  EVE+EXE (PMW with disease refractory to NSAI)
 CDKi+LET

 ET (preferably AI)
 AI+FUL (patients with no prior exposure to ET)
ASCO2  EVE+EXE or PAL+FUL (patients with disease refractory
to NSAI)
 PAL+AI

 ET (tamoxifen, AI, high-dose FUL)

ABC33  EVE+EXE (PMW with disease refractory to NSAI)
 PAL+AI

ABC, advanced breast cancer; AI, aromatase inhibitor; CDKi, cyclin-dependent kinase inhibitor; ER, estrogen receptor; ET, endocrine therapy; EVE,
everolimus; EXE, exemestane; FUL, fulvestrant; HER2–, human epidermal growth factor receptor-2–negative; HR+, hormone receptor-positive; LET, letrozole;
NSAI, nonsteroidal aromatase inhibitor; PAL, palbociclib; PMW, postmenopausal women.
a
For premenopausal patients: Selective ER modulators (tamoxifen or toremifene) or ovarian ablation or suppression plus ET as for postmenopausal women.

22 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V.2.2017;
2. Rugo H, et al. J Clin Oncol. 2016;34(25):3069-3103; 3. Cardoso F, et al. Ann Oncol. 2017;28(1):16-33.
 Rationale for Combination Approaches in
HR+, HER2– Advanced Breast Cancer
 Endocrine therapy (ET) is the standard of care for advanced HR+ BC 1,2
• However, the majority of patients with metastatic disease experience
progression, necessitating alternate treatment approaches3,4
 Combination of ET with targeted agents such as EVE and CDK4/6
inhibitors has shown efficacy in phase 3 trials and clinical practice
Combination With mTOR
Inhibitors: Combination With CDK4/6
Key Clinical Trials Inhibitors: Key Phase 3 Clinical
• Phase 3: EVE + EXE (BOLERO- Trials
2)5 • RIBO + LET (MONALEESA-2)9
• Phase 2: EVE + other ET agents • PAL + LET (PALOMA-2)10
– EVE + TAM (TAMRAD)6 • PAL + FUL (PALOMA-3)11
– EVE + LET → EVE + EXE • ABE + FUL (MONARCH-2)12
(BOLERO-4)7 • ABE + NSAI (MONARCH-3)13
– EVE + FUL (PrECOG 0102)8
BC, breast cancer; EVE, everolimus; EXE, exemestane; FUL, fulvestrant; HR+, hormone receptor-positive; LET, letrozole; mTOR, mammalian target of
rapamycin; TAM, tamoxifen; PAL, palbociclib; RIBO, ribociclib.

1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. V.2.2017; 2. Gnant M, et al. Curr Oncol
Rep. 2013;15(1):14-23; 3. Osborne CK, et al. Annu Rev Med. 2011;62:233-247; 4. Fox EM, et al. Front Oncol. 2012;2:145;
5. Yardley DA, et al. Adv Ther. 2013;30(10):870-884; 6. Bachelot T, et al. J Clin Oncol. 2012;30(22):2718-2724; 7. Royce M, et al. ESMO 2016. Abstract
222O [oral]; 8. Kornblum, et al. SABCS 2016. Abstract S1-02 [oral]; 9. Hortobagyi G, et al. N Engl J Med. 2016;375(18):1738-1748; 10. Finn R, et al. N
232016;375:1925-1936; 11. Cristofanilli M, et al. Lancet Oncol. 2016;17(4):425-439; 12. Sledge GW, et al. J Clin Oncol. 2017;35(25):2875-
Engl J Med.
2884; 13. Di Leo A, et al. ESMO 2017. Abstract 236O-PR [oral].
 Summary

 Breast cancers display complex repertoire of somatic mutations

- Few highly recurrently mutated genes; most of the highly recurrently mutated
driver genes have been identified

 Luminal A and luminal B subtypes have different outcomes

- Modest agreement for the classification of individual patients

 HR+/HER2-negative disease is clinically and biologically heterogeneous

- These molecular entities might change over time, specially primary Luminal A
tumors converting into non-Luminal A disease

 Guidelines specify the use of sequential ET, including ET in combination

with targeted therapy, for the treatment of luminal ABC
- Combination approaches of a targeted agent and an endocrine therapy agent
are showing significant efficacy benefit over endocrine monotherapy
approaches
24