Pro: Hormone Therapy in HR positive MBC is the preferred option!

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1 Pro: Hormone Therapy in HR positive MBC is the preferred option! Alexandru Eniu, MD, PhD Medical Oncologist Head, Day Hospital Unit Department of Breast Tumors Cancer Institute Ion Chiricuţă Cluj-Napoca, Romania

2 Personalized ( tailored) cancer therapy Natural history Personalized therapy The right treatment Localised disease CURABLE For the right patient At the right moment Metastatic disease INCURABLE

3 * Pagani et al, JNCI Can M1 cancer be cured? 3

4 To chemo or not to chemo? That is the question! Shakespeare, 1601,in Complete Works, Blount & Jaggart, Eds, 1623 & Cardoso, Ann Onc 2013: Cardoso, The Breast (2012)

5 But is that really the question?

6 Breast Cancer Survival by molecular phenotypes (n= 1945) Dawood et al, Breast Cancer Res Treat (2011) 126:

7 Molecular subtypes / clinical subtypes St Gallen 2013 BREAST CANCER HR POSITIVE HR NEGATIVE Her2 - Her2 + Her2 - Her2 + Ki67 <14% ER>50%, PR>20% Ki67>20% Or PR<20% LUMINAL A LUMINAL B Her2 - LUMINAL B Her2 + Her2 POSITIVE non luminal TRIPLE NEGATIVE HORMONE THERAPY ALONE HORMONE +/- CYTOTOXICS CYTOTOXICS + ANTI HER2 + HORMONE CYTOTOXICS + ANTI HER2 CYTOTOXICS

8 Impact of Hormone Receptor Status HR + predictor of benefit to anti-hormonal 1st-line HT 40-60% of ORR; TTP around months 2nd-line agents: 30% response, TTP around 6 months predictor of low ORR to chemotherapy (? neo, adj ) HR - Good predictor of no response to hormonal manipulations

9 Treatment of Recurrent Breast Cancer? Several small retrospective studies shown receptor discordance between primary and recurrent tumor Biopsy the metastatic lesion! Rate of discordance: - HR 15-40% - HER2 7-26% Change in management: 12-15% Amir, Locatelli, Karlsson, ASCO 2010

10 Cumulative incidence curves of first distant metastasis by breast cancer subtype. Kennecke H et al. JCO 2010;28: by American Society of Clinical Oncology

11 Site Specific Metastases by Subtype 44% 24% 6,5 % 7,5 % 9,8 % 8,5 % Kennecke H et al. JCO 2010;28:

12 Visceral metastases: efficacy of HT Howell et al, Breast Cancer Res Treat 82:215, 2003

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14 Optimal Endocrine Therapy for MBC First-line changed substantially along the time Premenopausal patients Tamoxifen OAS +/- Tamoxifen Postmenopausal patients AI ( fulvestrant an option)- combination AI+fulvestrant? TAM a reasonable option Second line Depends on first line

15 Klijn, et al. J Clin Oncol 2001;19. Premenopausal Advanced Breast Cancer Combined Tamoxifen and LHRH Agonist vs LHRH Agonist Alone in : A Meta-Analysis of Four Randomized Trials End Point LHRH agonist alone N=256 LHRH agonist + Tamoxifen N=250 HR 95%CI p Median survival, years Median PFS, months Objective response % LHRH+TAM LHRH

16 Postmenopausal MBC Randomized Phase III Trials of AIs vs Tamoxifen as First-line Treatment Anastrozole 1 Anastrozole 2 Letrozole 3 Exemestane 4 No. patients 170 vs vs vs vs 189 ORR, % 21 vs vs vs 21* 46 vs 31* CBR, % 59 vs 46* 56 vs vs 38* 66 vs 49* TTP or PFS, months 11 vs 6* 8 vs 8 9 vs 6* 10 vs 6* ER status unknown, % 11 vs vs vs vs 11 ORR = overall response rate; CBR = clinical benefit rate; TTP = time to progression; PFS = progression free survival; ER = estrogen receptor *Statistically significant difference 1. Nabholtz JM, et al. J Clin Oncol. 2000;18: Bonneterre J, et al. J Clin Oncol. 2000;18: Mouridsen H, et al. J Clin Oncol. 2003;21: Paridaens R, et al. J Clin Oncol. 2008;26:4883.

17 OS Trend toward an improved OS not significant (OR, 1.95; 95% CI, ; P.10) Hong-Bin Xu et al Clinical Breast Cancer 11 (4); 246, 2011

18 Hormonal Therapy in MBC; the Place of Aromatase Inhibitors All three AIs : higher RR and longer TTP vs Tam in first line setting; no differences in long term OS (Mouridsen et al JCO 2003; Bonneterre et al Cancer 2001, Paridaens et al, ASCO 2004); The efficacy of AIs after Tam is comparable to the efficacy of Tam after AIs (Thurlimann et al, EJCancer 2003) All three AIs seem to be equally effective with slight differences in untoward effects (Rose et al ASCO 2002, Cameron et al, ASCO 2004, Mayordomo et al, ASCO 2006) Steroid inactivator exemestane is effective after failure to nonsteroidal AIs, nonsteroidal AIs are effective after failure to exemestane (Thurlimann et al, EJCancer 1997, Bertelli G, et al. Oncology. 2005)

19 TTP Combination trials. Fulvestrant + Anastrozol vs Anastrozol in First line : FACT OS 514 patients 67% prior adjuvant antiestrogens Bergh et al, J Clin Oncol 2012:

20 Combination trials. Fulvestrant + Anastrozol vs Anastrozol: SWOG S0226 PFS OS 707 patients 40% prior adjuvant tamoxifen 39% stage IV de novo Mehta et al, NEJM 2012: 367: % pts in anastrozol arm crossed over to fulvestrant

21 Hormonal Therapy in MBC:Place of Fulvestrant Fulvestrant 500 mg showed higher RR and longer TTP compared to fulvestrant 250 mg, with a safety profile consistent to fulvestrant 250 mg recommended dose of fulvestrant is 500 mg. (CONFIRM) First-line fulvestrant 500 mg was associated with longer TTP compared to anastrozole. (FIRST ) The efficacy of fulvestrant 250 mg is comparable to the efficacy of AIs. ( studies 0020 and 0021)) There is survival advantage of adding fulvestrant to anastrozole in firstline therapy, especially for de novo patients (FACT but SWOG S0226 ) Patients progressing on fulvestrant remain sensitive to subsequent endocrine therapy. (FIRST)

22 But progression always occurs What to do?

23 Combining Other Targeted Agents and Endocrine Therapy AI PALOMA -1 PALOMA-3 Growth Factor Estrogen Tamoxifen Plasma Membrane Tam ER Cytoplasm CDK 4/6 Inhibitor PD Nucleus Cell Cycle Cell Survival P P P P ER ER ERE IGFR P P BOLERO TAMRAD HORIZON p160 P P mtor CBP Akt Transcription Silencing EGF30008 P13-K P p90 RSK Basal Transcription Machinery EGFR/HER2 ER Target Gene Transcription P P P SOS RAS RAF MAPK MEK P P HDAC Inhibitor Entinostat TANDEM electra Cell Growth

24 Baselga et al. NEJM. Epub

25 Side effects Clinicians need to be educated about key recommendations for toxicity management and specific guideline dose modifications. Villarreal-Garza, Ann Oncol 23: 2526,2012

26 Slide 2 Presented By Nicholas Turner at 2015 ASCO Annual Meeting

27 PALOMA-1: Phase II,ER+, HER2 Locally Recurrent or mbc Palbociclib (CDK) 4/6 Inhibitor)+Letrozole vs Letrozole Part 1 Part 2 Post- menopausal ER+, HER2 BC status No prior treatment for advanced disease R A N D O M I S A T I O N N = 66 1:1 Palbociclib 125 mg QD a + Letrozole 2.5 mg QD Letrozole 2.5 mg QD 43% 33% Progression Free Survival Probability (%) Post- menopausal 80 ER+, 70 HER2 BC with CCND1 60 amplification and/ or loss 50 of p16 No prior treatment 40 for advanced disease R A N D O M I S A T I O N N = 99 1:1 Palbociclib 125 mg QD a + Letrozole 2.5 mg QD Letrozole 2.5 mg QD Time (Month) Number of patients at risk PAL+LET LET Key Eligibility Criteria Measurable disease (RECIST 1.0) or bone- only disease ECOG PS of 0 or 1 Adequate blood counts and organ function No prior/current brain metastases Stratification Factors Disease site (visceral vs bone only vs other) Disease- free interval (>12 vs 12 months from end of adjuvant to recurrence or de novo advanced disease) aschedule 3/1. ECOG PS, Eastern Cooperative Oncology Group performance status; ER, oestrogen receptor; QD, daily. 27

28 PALOMA3 Study Design Presented By Nicholas Turner at 2015 ASCO Annual Meeting

29 Primary Endpoint: PFS (ITT Population) Presented By Nicholas Turner at 2015 ASCO Annual Meeting

30 Chemo vs no chemo is that really the question? 1. Triple negative? no question- Chemo! ( but AR+?) 2. Her2 + (nonluminal, ER-)- chemo 3. Luminal B ( Her2 +)- when to give HT? 4. Luminal B ( Her2 negative)- when to give chemo? 5. Luminal A Hormone- when to intervene with chemo? ( unfortunately almost all patients will receive chemo at a certain moment)

31 Luminal A (HR +++, Her2 -, Grade 1-2, Low Ki-67 Perfect candidate for endocrine therapy Less vital mets ( liver, brain) Long-time responders ( reliable data?) Choose carefully the agent ( adjuvant treatment, DFI, toxicity, patients preference ) Think forward ( 2 nd or 3 rd successful line probable, especially for lobular carcinoma) Visceral mets not a contraindication for endocrine therapy Compliance??

32 Luminal A Questions Long term outcome? (inference from neoadj?) When to initiate chemotherapy probably when all endocrine manipulations have been exhausted How long to wait for a response? Bone only disease: what to do after endocrine therapy is exhausted? Will everolimus and palbociclib work preferentially?...all patients were Her2 negative, no data on grade

33 Luminal B Her 2+ (HR +, Her2 + ) Her 2 targeting- very important More vital mets ( liver, brain)

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35 Trial Efficacy of HER2-directed Therapy Plus Endocrine/Chemotherapy in MBC Treatment TanDEM, Anastrozole 1 mg daily + trastuzumab 2 mg/kg qw Johnston, Letrozole 2.5 mg daily + lapatinib 1500 mg daily Di Leo et al (ErbB2+ patients only) Lapatinib 1500 mg qd + paclitaxel 175 mg/m 2 q3w ORR (%) PFS (months) OS (months) Slamon et al ; Trastuzumab 2 mg/kg qw + paclitaxel Smith et al mg/m 2 q3w Marty et al Trastuzumab 2 mg/kg qw + docetaxel 100 mg/m 2 q3w Kaufman, JCO Johnston, et al. JCO Di Leo, et al. Clin Oncol 2008;26: Slamon, et al. N Engl J Med 2001;344: Smith, et al. Anticancer Drugs 2001;12 Suppl 4:S Marty, et al. J Clin Oncol 2005;23:4265.

36 Which Luminal B patients In Romania, barriers in are candidate for access to antiher2 AI + anti-her2 therapy, limits this option omitting or delaying chemotherapy?

37 Luminal B Her 2 - (HR +, Her2 -, Grade 3, High Ki-67 More questions than answers How to define this subtype better?

38 Segregation of breast cancer subtypes using a gene expression proliferation module. Piccart-Gebhart M J The Oncologist 2010;15: by AlphaMed Press

39 Maintenance endocrine therapy Author Regimen Pts (n) TTP (months) OS (months) Kloke (1999) MPA 500mg daily vs nil after 6 x E (30 mg/m2) IFO (2 g/m2) d1, 8 q3w 39% vs 30 RH negative! vs 3.7 (0.02) 17.4 vs 18.3 (0.39 ns) Montemurro (2002) MET ( TAM or ANA) vs nil after HDCT (HR+ only) Retrospective vs 19.2 (0.02) 76.5 vs 41.7 (0.11 ns) Dufresne (2008) MET ( TAM or ANA or FULV) vs nil after first line CT (HR+ only) Retrospective vs 7.77 (0.0001) 48.1 vs 30 (0.0001)

40 Luminal B Her 2 - (HR +, Her2 -, Grade 3, High Ki-67 Start with first line hormonal therapy, if ER, PR high (?>50%...data???) No visceral crisis Discourage chemo + endocrine therapy ( ESMO guidelines 2011, ABC2 2014) No rationale for use of combination hormonal therapies ( several negative studies) Second line HT granted if benefit from 1 st If quick PD after HT, offer first line chemo line After chemo, offer maintenance hormonal therapy ( reasonable, but data?)

41 Triple negative Hormone therapy for HR negative?

42 AR Signaling and Triple-Negative Breast Cancer Presented By Tiffany Traina at 2015 ASCO Annual Meeting

43 <0% IHC Study Schema (MDV ) Presented By Tiffany Traina at 2015 ASCO Annual Meeting

44 Clinical Benefit in Evaluable and ITT Populations Presented By Tiffany Traina at 2015 ASCO Annual Meeting

45 PFS in Evaluable and ITT Populations Presented By Tiffany Traina at 2015 ASCO Annual Meeting

46 Principles of treatment Doing the minimum indispensable The objective of treatment of metastatic disease is not cure Obtaining the maximal palliation of symptoms with minimal side effects For asymptomatic patients, do not delay treatment Favor low-toxicity treatments, with less side effects Increase the total duration of the time with no or few disease-related symptoms, with the lowest costs in terms of side effects of treatment

47 ENDOCRINE THERAPY Endocrine therapy (ET) is the preferred option for HR+ disease, even in the presence of visceral disease, unless there is concern or proof of endocrine resistance or rapidly progressive disease needing a fast response The preferred 1st line ET for postmenopausal patients is an aromatase inhibitor or tamoxifen, depending on type and duration of adjuvant ET. Fulvestrant HD is also an alternative option. AI + everolimus is also an option after progression on a non-steroidal AI. At present, no predictive biomarker exists to identify those patients who benefit from this approach. F. Cardoso et al. / The Breast (2014) 489e502 Annals of Oncology 00: 1 18, 2014

48 Typical Endocrine Strategy ( circa June 2015) NO prior therapy Endocrine naïve PRIOR TAM OR AI PRIOR TAM or AI or FULV PRE: OFS+ TAM (OFS + AI option) POST: AI (+/- FULV?) AI OR TAM FULVESTRANT AI + mtori AI +Palbociclib PROGESTINS ESTROGEN CHEMO

49 Summary Management of MBC : complex and multi-disciplinary, main goal of therapy is palliation Whenever possible, biopsy the metastatic lesion! Tailor for the disease(subtype) and the patient! Luminal A- exhaust HT before chemotherapy Luminal B Her2 +: evaluate, explore first HT + antiher2 treatment( if no visceral crisis), switch to chemo at first PD Luminal B Her2 -: offer HT, evaluate, 2 nd line if initial benefit; maintenance HT after chemo Triple negative: stay tuned for more data

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