Treatment of Metastatic Breast Cancer. Prof RCCoombes Imperial College London

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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, psychooncologists, 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 ERα AF-1 DBD LBD/AF-2 17ß-estradiol Tamoxifen ERE 5 AGGTCA NNN TGACCT 3 3 TCCAGT NNN ACTGGA 5

5 Differences in AI and Tamoxifen Mechanisms of Action Androstenedione Testosterone Aromatase AIs Aromatase AIs Estrone Estradiol Tamoxifen ER ER EREs ER target genes Proliferation EREs, estrogen response elements. Johnston. Nat Rev Cancer. 2003;3: Adapted with permission: 3

6 Aromatase Inhibitors: Enzyme Interaction Type I Exemestane Type II Anastrozole Letrozole Fe Fe N NC CN IRREVERSIBLE REVERSIBLE Adapted from Lang M, et al. J Steroid Biochem Mol Bio. 1993;44: ; Furet P, et al. J Med Chem. 1993;36:

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11 Resistance to Endocrine Therapies o o o o o De novo endocrine resistance may be due to breast tumours being independent of a requirement for estrogen, despite being ERα-positive. Acquired endocrine resistance may be due to growth promotion of initially estrogendependent tumours, by other mitogenic pathways. In a proportion of cases endocrine resistance is accompanied by loss of ERα protein. However, in the majority of cases ERα 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 ERα Mutations cause estrogenindependent ERα activation in vitro studies and predicted to cause resistance to aromatase inhibitors

13 Progression-free survival (PFS) in SoFEA by ESR1 mutation status. MUT + MUT - Fribbens C et al. J Clin Oncol. 2016;34:

14 Baselga J, et al. New Engl J Med 2012;366: BOLERO-2 Phase III trial: second-line everolimus + exemestane ER+ menopausal patients progressing to nsai N= Exemestane 25 mg daily + Everolimus 10 mg daily Exemestane 25 mg daily + placebo 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

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

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= 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: Finn RS et al. Lancet Oncol. 2015;16: Cristofanilli M, et al. Lancet Oncol 2016

17 Benefit of Palbociclib When Combined with Fulvestrant: PALOMA-3 PAL + FUL (n=347) PLACEBO + FUL (n=174) PFS (%) 100 Number at risk Palbociclib + fulvestrant Placebo + fulvestrant Palbociclib + fulvestrant Placebo + fulvestrant Median PFS, mos (95% CI) 9.5 ( ) 4.6 ( ) HR (95% CI) 0.46 ( ) P value < Time (months) Cristofanilli M, et al. Lancet Oncol 2016

18 Progression-free survival (PFS) in PALOMA-3 by ESR1 mutation status Turner N et al. J Clin Oncol 34, 2016 (suppl)

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21 HER-2 Immunostaining

22 Herceptin

23 Pertuzumab and Trastuzumab: Mechanisms of Action Trastuzumab binds to subdomain IV and inhibits downstream signalling HER2 Pertuzumab binds to a specific domain II and inhibits ligand-activated dimerization 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):

24 CLEOPATRA: Trastuzumab + Docetaxel + Pertuzumab or Placebo 808 patients with centrally confirmed HER2+ MBC 1:1 R A N D O M I Z E Trastuzumab + pertuzumab until progressive disease 6 cycles of docetaxel recommended 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/m 2, escalating to 100 mg/m 2 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 Improvement: 15.7 months HR=0.68 P<.0002 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. LoRusso P M et al. Clin Cancer Res 2011;17: 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 Median OS (interim analysis) NE 14.9 months HR=0.528 P<.0001 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 1 st line 25 to 45% 5 to 8 m 2 nd line 15 to 30% 2 to 5 m 3 rd line 0 to 20% 1 to 4 m 4 th line Few data 5 th line Fewer data 6 th 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 MAPK inhibitors; NOTCH inhibitors Anti- Angiogenesis Bevacizumab MAP Kinase Pathway Transcriptional Control Cell Cycle Akt Pathway PARP inhibitors; Trabectedin DNA Repair pathways Cell Death After Cleator S et al. Lancet Oncol. 2006:8:

34 Gem/Carbo +/- BSI-201 in Triple Negative Metastatic Breast Cancer MBC Triple Negative Prior Chemo N=120 Gemcitabine 1000 mg/m 2 d 1,8 Carbo AUC 2 d 1,8 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 ASCO m 6.9 m NEJM m 5.9 m OS ASCO m 9.2 m NEJM 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