1. Treatment of Metastatic Breast Cancer
Prof RCCoombes
Imperial College
London

2. Metastatic Breast Cancer: General Guidelines
 Specialized oncology nurses (if possible specialized breast nurses) should be part of the multidisciplinary team managing ABC pts. In some countries this role may be played by a physician assistant or another trained and specialized health care practitioner. 
 There are few proven standards of care in ABC management. After appropriate informed consent, inclusion of patients in well-designed, prospective, independent trials must be a priority whenever such trials are available and the patient is willing to participate.

3. General Guidelines (2)
 The management of ABC is complex and, therefore, involvement of all appropriate specialties in a multidisciplinary team (including but not restricted to medical, radiation, surgical oncologists, imaging experts, pharmacologists, pathologists, gynecologists, psycho-oncologists, social workers, nurses and palliative care specialists), is crucial.
 From the time of diagnosis of ABC, patients should be offered appropriate psychosocial care, supportive care, and symptom-related interventions as a routine part of their care. The approach must be personalized to meet the needs of the individual patient.
 Following a thorough assessment and confirmation of MBC, the potential treatment goals of care should be discussed. Patients should be told that MBC is incurable but treatable, and that some patients can live with MBC for extended periods of time (many years in some circumstances)

4. Tamoxifen: binding to The Estrogen Receptor
ER
AF DBD LBD/AF-2
5’ AGGTCA NNN TGACCT 3’
3’ TCCAGT NNN ACTGGA 5’
ERE
17ß-estradiol Tamoxifen

5. SPEAKER'S NOTES
Tamoxifen and AIs interfere with the supply of estrogen to breast cancer cells in distinct ways.1
AIs inhibit estrogen synthesis, causing estrogen deprivation in postmenopausal women.1
Tamoxifen binds to the estrogen receptors, blocking estrogen from binding.2
References
1. Johnston SRD, Dowsett M. Aromatase inhibitors for breast cancer: lessons from the laboratory. Nat Rev Cancer. 2003;3:
2. Hayes DF, Robertson JFR. Overview and concepts of endocrine therapy. In: Robertson JFR, Nicholson RI, Hayes DF, eds. Endocrine Therapy of Breast Cancer. London, England: Martin Dunitz; 2002:3-10.

6. SPEAKER'S NOTES
The 2 different types of AIs, steroidal and nonsteroidal inhibitors, are also known as Type I and Type II, respectively.1
Type I AIs, such as exemestane, are converted to intermediates and bind irreversibly to the substrate binding site of aromatase.1
Type II inhibitors reversibly interact with the heme group of the cytochrome P450 moiety of the enzyme, and interference with estrogen biosynthesis is dependent on the continued presence of the nonsteroidal agent. The nonsteroidal AIs, anastrozole and letrozole, bind at their triazole groups.1
References
Miller WR, Dixon JM. Antiaromatase agents: preclinical data and neoadjuvant therapy. Clin Breast Cancer. 2000;1(suppl 1):S9-S14.
Lang M, Batzl C, Furet P, Bowman R, Hausler A, Bhatnagar AS. Structure-activity relationships and binding model of novel aromatase inhibitors. J Steroid Biochem Mol Biol. 1993;44:
Furet P, Batzl C, Bhatnagar A, Francotte E, Rihs G, Lang M. Aromatase inhibitors: synthesis, biological activity, and binding mode of azole-type compounds. J Med Chem. 1993;36:

11. Resistance to Endocrine Therapies
De novo endocrine resistance may be due to breast tumours being independent of a requirement for estrogen, despite being ER-positive.
Acquired endocrine resistance may be due to growth promotion of initially estrogen-dependent tumours, by other mitogenic pathways.
In a proportion of cases endocrine resistance is accompanied by loss of ER protein.
However, in the majority of cases ER is not lost and the ER is mutated or Enhanced by other signalling pathways.
A large proportion of patients who become resistant to Tamoxifen, respond to another anti-estrogen (Faslodex) or to aromatase inhibitors.

12. The ESR1 Gene is Mutated in Endocrine Resistant Breast Cancer
80% of mutations target helix 12 critical for estrogen-dependent transcriptional activity of ERa
Mutations cause estrogen-independent ERa activation in vitro studies and predicted to cause resistance to aromatase inhibitors

13. Progression-free survival (PFS) in SoFEA by ESR1 mutation status.
Progression-free survival (PFS) in SoFEA by ESR1 mutation status. (A) PFS of patients with ESR1 mutant cancers who received exemestane or a fulvestrant-containing regimen. (B) PFS of patients without detected ESR1 mutation who received exemestane or a fulvestrant-containing regimen. HR, hazard ratio.
Fribbens C et al. J Clin Oncol. 2016;34:

14. BOLERO-2 Phase III trial: second-line everolimus + exemestane
Exemestane 25 mg daily + Everolimus 10 mg daily
ER+ menopausal patients progressing to nsAI
N=724
Exemestane 25 mg daily + placebo 1
84% of patients sensitive to prior endocrine therapy:
DFI >24 months if relapse occurs during/after adjuvant AI, or clinical benefit to the prior line of AI for advanced disease
ER+=estrogen receptor positive; DFI=disease-free interval; AI=aromatase inhibitor; nsAI=non-steroidal aromatase inhibitor
Baselga J, et al. New Engl J Med 2012;366:520–529

15. BOLERO-2: progression-free survival analysis
Baselga J, et al. New Engl J Med 2012;366:520–529

16. Palbocicib: first-in-class CDK 4/6 inhibitor
In the Phase 2 PALOMA-1 trial in endocrine-therapy sensitive patients the addition of palbociclib to letrozole significantly improved PFS in advanced ER+, HER2-negative breast cancer
PFS: 20.2 months vs 10.2 months p=0.0004
The Phase 3 PALOMA-3 trial assessed the addition of palbociclib to fulvestrant (vs fulvestrant alone) in endocrine therapy-resistant ER+ HER2- patients
Finn RS et al. Lancet Oncol. 2015;16: Cristofanilli M, et al. Lancet Oncol 2016  
Finn RS et al. Lancet Oncol. 2015;16:25-35.

17. Benefit of Palbociclib When Combined with Fulvestrant: PALOMA-3
PAL + FUL
(n=347)
PLACEBO + FUL
(n=174)
Median PFS, mos (95% CI)
9.5 (9.2─11.0)
4.6 (3.5─5.6)
HR (95% CI)
0.46 (0.36─0.59)
P value
<0.0001
PFS (%)
Time (months) 10 20 30 40 50 60 70 80 90
100 1 2 3 4 5 6 7 8 9 15 11 12 13 14
Placebo + fulvestrant
Palbociclib + fulvestrant
347
333
281
273
247
244
202
197 91 85 32 23
174
165
112
105 83 59 58 22
Number at risk
Cristofanilli M, et al. Lancet Oncol 2016

18. Progression-free survival (PFS) in PALOMA-3 by ESR1 mutation status
Progression-free survival (PFS) in PALOMA3 by ESR1 mutation status. (A) PFS for patients with ESR1 mutant cancers who received fulvestrant and placebo or fulvestrant and palbociclib. (B) PFS for patients without detected ESR1 mutation who received fulvestrant and placebo or fulvestrant and palbociclib. HR, hazard ratio.
Turner N et al. J Clin Oncol 34, 2016 (suppl)

21. HER-2 Immunostaining

22. Herceptin

23. Trastuzumab binds to subdomain IV and inhibits downstream signalling
Pertuzumab and Trastuzumab: Mechanisms of Action
Pertuzumab binds to a specific domain II and inhibits ligand-activated dimerization
Trastuzumab binds to subdomain IV and inhibits downstream signalling
HER2
HER1-4
Cell membrane
The combined regimen of pertuzumab and trastuzumab offers the potential for a more comprehensive HER blockade
Franklin MC, et al. Cancer Cell. 2004;5(4): 23

24. CLEOPATRA: Trastuzumab + Docetaxel + Pertuzumab or Placebo
RANDOMIZE
Trastuzumab + pertuzumab until progressive disease
808 patients with centrally confirmed HER2+ MBC
≥ 6 cycles of docetaxel recommended
1:1
Trastuzumab + placebo until progressive disease
≥ 6 cycles of docetaxel recommended
Study dosing every 3 weeks
Pertuzumab/Placebo: 840 mg loading dose, 420 mg maintenance
Trastuzumab: 8 mg/kg loading dose, 6 mg/kg maintenance
Docetaxel: 75 mg/m2, escalating to 100 mg/m2 if tolerated
Baselga J, et al. N Engl J Med. 2012;366(2):

25. CLEOPATRA: Updated Survival Results
Pertuzumab + Trastuzumab + Docetaxel
(n=402)
Placebo + Trastuzumab + Docetaxel
(n=406)
P value
Median PFS
18.7 months
12.4 months
HR=0.68
P<.0001
Improvement: 6.3 months
Median OS
56.5 months
40.8 months
P<.0002
Improvement: 15.7 months
PFS = progression-free survival
Swain SJ, et al. ESMO Abstract 350O_PR.

26. The Addition of Pertuzumab to Herceptin and Docetaxel

27. Structure of T-DM1 and mechanisms of action.
Structure of T-DM1 and mechanisms of action. After T-DM1 binds HER2, the HER2/T-DM1 complex undergoes internalization, followed by lysosomal degradation. This process results in the intracellular release of DM1-containing catabolites that bind to tubulin and prevent microtubule polymerization as well as suppress microtubule dynamic instability. T-DM1 has also been shown to retain mechanisms of action of trastuzumab, including disruption of the HER3/PI3K/AKT signaling pathway and Fcγ receptor–mediated engagement of immune effector cells, which leads to antibody-dependent cellular cytotoxicity.
LoRusso P M et al. Clin Cancer Res 2011;17:
©2011 by American Association for Cancer Research

28. TH3RESA: T-DM1 in Heavily Pretreated MBC
600 patients previously treated with ≥ 2 prior therapies (trastuzumab, lapatinib, taxane) randomly assigned (2:1) to T-DM1 or treatment of physician’s choice*
T-DM1
Physician’s choice
P value
ORR
31.3%
8.6%
P<.0001
Median PFS
6.2 months
3.3 months
HR=0.528
Median OS (interim analysis) NE
14.9 months
HR=0.552
P=.0034
*Single-agent chemotherapy, hormonal therapy, or HER2-directed therapy, or a combination of a HER2-directed therapy with a chemotherapy, hormonal therapy, or other HER2-directed therapy.
NE = not estimable
Krop IE, et al. Lancet Oncol ;15(7):

29. Goals of Chemotherapy for Advanced Breast Cancer
Relieve symptoms associated with advanced cancer, such as pain, fatigue, or dyspnea
Prevent symptomatic progression of tumor
Prolong survival
Enhance quality of life
To make advanced breast cancer a “chronic” condition

30. St Gallen Chemotherapy Guidelines: Breast Cancer 2017
 In the absence of medical contraindications or patient concerns, anthracycline or taxane based regimens, preferably single agents, would usually be considered as first line CT for HER-2 negative MBC, in those patients who have not received these regimens as (neo)adjuvant treatment and for whom chemotherapy is appropriate. Other options are, however, available and effective, such as capecitabine and vinorelbine, particularly if avoiding alopecia is a priority for the patient
 In patients with taxane-naive and anthracycline-resistant MBC or with anthracycline maximum cumulative dose or toxicity (i.e. cardiac) who are being considered for further CT, taxane-based therapy, preferably as single agents, would usually be considered as treatment of choice. Other options are, however, available and effective, such as capecitabine and vinorelbine, particularly if avoiding alopecia is a priority for the patient.

31. Typical Clinical Outcomes with Single-agent Chemotherapy for Advanced Breast Cancer
Response rate
Time to Progression
1st line
25 to 45%
5 to 8 m
2nd line
15 to 30%
2 to 5 m
3rd line
0 to 20%
1 to 4 m
4th line
Few data
5th line
Fewer data
6th line etc
No data

32. Eribulin mesylate (E7389) Synthetic analogue of halichondrin B
Binds to unique site on tubulin
Suppresses microtubule polymerization
Sequesters tubulin into nonfunctional aggregates
Creates irreversible mitotic block
Inhibition of breast cancer cell line growth in vitro
MCF7
Jordan M A et al. Mol Cancer Ther 2005;4:

33. Triple-Negative Breast Cancers: Potential Therapeutic Targets
Cetuximab
EGFR Tyrosine Kinase
C-KIT tyrosine kinase
Dasatinib Sunitinib
MAP Kinase Pathway
Akt Pathway
MAPK inhibitors; NOTCH inhibitors
Transcriptional Control
PARP inhibitors; Trabectedin
Anti-Angiogenesis
Cell Cycle
DNA Repair pathways
Bevacizumab
After Cleator S et al. Lancet Oncol. 2006:8:
Cell Death

34. Gem/Carbo +/- BSI-201 in Triple Negative Metastatic Breast Cancer
Gemcitabine 1000 mg/m2 d 1,8
Carbo AUC 2 d 1,8
MBC
Triple Negative
Prior Chemo
N=120
CYCLES EVERY 21 DAYS
Gemcitabine 1000 mg/m2 d 1,8
Carbo AUC 2 d 1,8
BSI mg/kg d 1,4,8, 11
RESTAGE EVERY 2 CYCLES
O’Shaugnessy et al, ASC0 2009

35. Iniparib Data Oral Presentation vs Publication Results
Endpoint
Venue
GC alone
GC + BSI201
Response rate
ASCO ’09
16%
48%
NEJM ‘11
32%
52%
PFS
3.3 m
6.9 m
3.6 m
5.9 m OS
5.7 m
9.2 m
NEJM ’11
7.7 m
12.3 m

36. Conclusions
Metastatic or locally advanced breast cancer, although not curable, is amenable to treatment
Lifespan can be extended by sequential use of therapies
The disease should be treated by a multidisciplinary team
Access to Estrogen receptor and HER 2 testing is essential since the receptor status can change
throughout treatments