Current Optimal Sequence and Duration of Endocrine Treatment

[Symposium 7] Present and Future of Endocrine Therapy 07 Apr, 2018@GBCC Current Optimal Sequence and Duration of Endocrine Treatment Breast Oncology Center The Cancer Institute Hospital of JFCR Shinji Ohno, M.D., Ph.D., FACS.

Disclosure Slide Honoraria: AstraZeneca, Novartis, and Chugai, Pfizer, Taiho, Eisai, Kyowa Hakko Kirin Research funding: Chugai, Daiichi-Sankyo, and Taiho.

Research Needs in Breast Cancer Ann Oncol 28:208-217, 2017 Although significant advances have been made in some areas of breast cancer research resulting in improvements in therapies and outcomes over the last few decades, other areas have not benefited to the same degree. This article summarizes the 12 clinical research needs in breast cancer deemed as priorities by a panel of experts, in an attempt to focus and accelerate future research in the most needed areas

Research needs in breast cancer 1. de-escalate breast cancer therapies in early breast cancer without sacrificing outcomes 2. explore optimal adjuvant treatment durations 3. develop better tools and strategies to identify patients with genetic predisposition 4. improve care in young patients with breast cancer 5. develop tools to speed up drug development in biomarker-defined populations 6. identify and validate targets that mediate resistance to chemotherapy, endocrine therapy and anti-her2 therapies 7. evaluate the efficacy of local-regional treatments for metastatic disease 8. better define the optimal sequence of treatments in the metastatic setting 9. evaluate the clinical impact of intra-patient heterogeneity (intra-tumor, inter-tumor and inter-lesion heterogeneity) 10. better understand the biology and identify new targets in triple-negative breast cancer 11. better understand immune surveillance in breast cancer and further develop immunotherapies 12. increase survivorship research efforts including supportive care and quality of life Ann Oncol 28:208-217, 2017

Current Optimal Sequence and Duration of Endocrine Treatment Early breast cancer Advanced breast cancer

Kennecke H et al. JCO 2010;28:3271-3277 Risk of recurrence and subtype Median follow-up time among 3,726 eligible patients was 14.8 years Late recurrence

Optimal sequence and duration of endocrine therapy (ET) Optimal duration of tamoxifen (1, 2, 5 years) Optimal drug and sequence for 5 years Tamoxifen versus Aromatase inhibitor (AI) Tamoxifen vs Tamoxifen AI Tamoxifen AI vs AI Optimal duration after 5 years ET 10 years tamoxifen Extended AI after 5 years tamoxifen Extended AI after 5 years ET

Optimal sequence and duration of endocrine therapy (ET) Optimal duration of tamoxifen (1, 2, 5 years) Optimal drug and sequence for 5 years Tamoxifen versus Aromatase inhibitor (AI) Tamoxifen vs Tamoxifen AI Tamoxifen AI vs AI Optimal duration 10 years tamoxifen Extended AI after 5 years tamoxifen Extended AI after 5 years ET

Reduction of the risk Duration of tamoxifen for 37,000 women in 55 trials Early Breast Cancer Trialists Collaborative Group (EBCTCG) 50 Recurrence 47 Mortality 40 30 20 10 21 29 12 17 26 0 1 year 2 years 5 years 1 year 2 years 5 years Lancet 351: 1451-1467, 1998

Recurrence (%) Breast mortality (%) Tamoxifen versus AI for 5 years Early Breast Cancer Trialists Collaborative Group (EBCTCG) 9,885 women RR=0.80 (95%CI0.73-0.88) 10-year gain 3.6% Log-rank 2p<0.00001 RR=0.85 (95%CI0.72-0.96) 10-year gain 2.1% Log-rank 2p=0.009 Lancet. 2015;386(10001):1341-1352

Recurrence (%) Breast mortality (%) Tamoxifen vs tamoxifen AI Early Breast Cancer Trialists Collaborative Group (EBCTCG) 11,798 women RR=0.82 (95%CI0.75-0.91) 10-year gain 2.0% Log-rank 2p<0.0001 RR=0.84 (95%CI0.72-0.96) 10-year gain 1.5% Log-rank 2p<0.01 Lancet. 2015;386(10001):1341-1352

Recurrence (%) Breast mortality (%) Tamoxifen AI vs AI Early Breast Cancer Trialists Collaborative Group (EBCTCG) 12,799 women RR=0.90 (95%CI0.81-0.99) 7-year gain 0.7% Log-rank 2p=0.045 RR=0.89 (95%CI0.78-1.03) 7-year gain 1.1% Log-rank 2p=0.11 Lancet. 2015;386(10001):1341-1352

Cumulative incidence (%) 10 versus 5 years of adjuvant tamoxifen ATLAS 5-9y:RR 0.90 (0.79-1.02) >10y:RR 0.75 (0.62-0.90) All yes: log-rank p=0.002 5-9y:RR 0.97 (0.79-1.02) >10y:RR 0.71 (0.62-0.90) All yes: log-rank p=0.01 Cristina R et al. Lancet 2013;381:805-816

Extended Aromatase inhibitor after 5 years tamoxifen Trial Study arms No. of patients DFS (RFS) OS MA. 17 5 y Letrozole vs Placebo after 5y tam 5157 HR 0.58 [0.45-0.84] p<0.001 HR 0.82 [0.57-1.19] P=0.3 NSABP B-33 5 y Exemestane vs Placebo after 5y tam 1598 RR 0. 68 P=0.07 ABCSG 6a 3 yrs anastrozole vs No therapy after 5y tam 856 HR 0.62 [0.40-0.96] P=0.031 (RFS) HR 0.89 [0.59-1.34] P=0.57 Goss P et al. NEJM 2016; 375: 209-219. Mamounas P et al. JCO 2008; 26:1965-1971. Jakesz R et al. JNCI 2007; 99: 1845-1853.

Extended Aromatase inhibitor after 5 years endocrine therapy including AI Wimmer K et al. Ther Adv Med Oncol 2017, 9: 679-692 DFS HR 0.66 p=0.01 HR 0.85 p=0.048[ns] HR 0.79 p=0.07 OS HR 0.66 p=0.01 HR 1.15 HR 0.91 p=0.60 ABCSG16 HR 0.96 p=0.70 HR 1.08 p=0.31 HR 1.007 p=0.925 HR 1.08 p=0.59 HR 0.88 HR 1.007 p=0.947

Factors predicting late recurrence for ER+ breast cancer

Recurrence after 5 years adjuvant hormone therapy Early Breast Cancer Trialists Collaborative Group (EBCTCG) 62,923 women The risk of distant recurrence was strongly correlated with the original TN status T1 Stage T2 Stage Pan H et al. N Engl J Med. 2017;377(19):1836-1846

PAM50 Risk of Recurrence Score Predicts 10-Year Distant Recurrence in a Comprehensive Danish Cohort of Postmenopausal Women Allocated to 5 Years of Endocrine Therapy for Hormone Receptor Positive Early Breast Cancer Negative node 1positive node 2 positive nodea 3 positive nodea Laenkholm AV et al. 2018;36:735-740

Utility of testing as predictive factors St Gallen Consensus Conference 2015 Oncotype DX MammaPrint 70 Early recurrence 1~5 years? PAM-50 EndoPredict Breast Cancer Index 82.9% 81. 0% 92. 9% 70. 3% 58. 3% Late recurrence >5 years? 43. 19.0% 63.2% 38. 2% 30. Yes No Abstain Coates AS et al. Ann Oncol 2015; 26: 1533-1546

Current Optimal Sequence and Duration of Endocrine Treatment Early breast cancer Advanced breast cancer

Goal and treatment for patients with ABC Goal: ABC is a treatable but still generally incurable disease. The goal of care is to optimize both length and quality of life. Treatment: ER positive ABC is responsive to endocrine therapy, whereas the majority of patients with ABC eventually develop resistance. Recently, promising target therapeutic drugs have been produced to overcome the endocrine resistance.

Treatment strategy for ER+ ABC before the era of target therapy Hormone-responsive disease and No life-threatening disease Hormone-unresponsive or life-threatening disease 1 st line hormonal therapy 1 st line chemotherapy (AC) Response then Progression No response Progression of disease 2 nd line hormonal therapy 2 nd line chemotherapy (Taxanes) Response then Progression No response Progression of disease 3 rd line hormonal therapy 3 rd line chemotherapy No response Hortobagyi G NEJM 339; 974, 1998 Supportive care

CDK4/6i in patients naïve or pre-exposed to ET Progression-Free Survival, % 100 90 80 70 60 50 40 30 20 10 PALOMA 2 (2:1) Median PFS MONALEESA 2 (1:1) Palbociclib + NSAI: 24.8 m PAL+LET (N=444) placebo + NSAI: 14.5 m Number of Events, n (%) Median (95% CI) PFS HR (95% CI); 1- sided P value 194 (44) 24.8 (22.1- NR) PCB+LET (N=222) 137 (62) 14.5 (12.9-17.1) HR (95% CI): 0.58 (0.46, 0.72) p =<0.000001 0.58 (0.46-0.72); P<0.000001 0 0 3 6 9 12 15 18 21 24 27 30 33 Number of patients at Time, months PAL risk + 44 39 36 32 29 26 23 15 LET 69 29 10 2 4 5 0 8 5 3 8 4 PCB + 22 17 14 13 11 98 81 54 22 12 4 2 LET 2 1 8 1 6 MONARCH 3 (2:1) Median PFS Ribociclib + NSAI: 25.3 m placebo + NSAI: 16 m HR (95% CI): 0.568 (0.457, 0.704) p = 0.000000096 Median PFS abemaciclib + NSAI: not reached placebo + NSAI: 14.7 m HR (95% CI): 0.543 (0.409, 0.723) p = 0.000021 Rugo HS et al. Ann Oncol. 2018 Jan 19. doi O'Shaughnessy J et al. Breast Cancer Res Treat. 2018 ;168:127-134 Goetz MP et al. J Clin Oncol. 2017, 35:3638-3646.

CDK4/6i in patients previously exposed to ET PALOMA 3 1,2 MONARCH 2 3 HR (95% CI): 0.46 (0.36, 0.59) p =<0.0001 HR (95% CI): 0.55 (0.45, 0.68) p =<0.001 Cristofanilli M et al. Lancet Oncol. 2016; 17: 425-439 Sledge GW Jr et al. J Clin Oncol. 2017, 35(25):2875-2884

Probability of Event, % BOLERO-2 (exemestane + evelorimus) 100 80 60 40 Progression free survival HR=0.45 (95% CI, 0.38-0.54) Log-rank P <0.0001 Kaplan-Meier medians EVE+EXE: 7.8 mo PBO+EXE: 3.2 mo Overall survival 20 0 Censoring times EVE+EXE (n/n=310/485) PBO+EXE (n/n=200/239) 0 6 12 18 24 30 36 42 48 54 60 66 72 Time, wk Patients at risk EVE+EXE 485436 366 304257 221185 158 124 91 66 50 35 PBO+EXE 239190 132 96 67 50 39 30 21 15 10 8 5 Yardley et al, Adv Ther 2013; Baselga et al, NEJM 2012

ASCO Guideline : Postmenopausal HR+ ABC No prior adjuvant endocrine therapy Prior adjuvant endocrine therapy Prior treatment with tamoxifen Prior treatment with an Al Early relapse ( 12 months since adjuvant therapy) Late relapse (> 12 months since adjuvant therapy) Early relapse ( 12 months since adjuvant therapy) Late relapse (> 12 months since adjuvant therapy) First line Al, nonsteroidal preferred Al + fulvestrant Al + palbociclib Al (nonsteroidal) Fulvestrant Al + palbociclib Al (nonsteroidal) Al + fulvestrant Al + palbociclib, Tam Fulvestrant + palbociclib Al + everolimus Al (steroidal), Tam Al (nonsteroidal) Fulvestrant Al + palbociclib Tamoxifen Second line Fulvestrant + palbociclib Al + everolimus Al (steroidal) Tamoxifen Fulvestrant + palbociclib Al + everolimus Al (steroidal) Tamoxifen (late relapse) Depending on prior therapy: Fulvestrant ± palbociclib Al + everolimus Al (steroidal), Tamoxifen 29 Third line or greater Sequential therapy based on prior exposure and response to hormone therapy Estradiol (2 mg three times per day) Megestrol acetate Fluoxymesterone Reintroduction of prior therapy Rugo, H.S. et al.: J Clin Oncol 34(25): 3069, 2016

Advanced Breast Cancer Consensus Conference November 2011, 2013, 2015, 2017 @ Lisbon Bridging the gap Too little attention Few therapeutic standards No international consensus guidelines Treatable, but Incurable Fatima Cardoso Cardoso F et al. Breast. 2012;21:242-52

Optimal sequence of endocrine therapy The optimal sequence of endocrine-based therapy is uncertain. It depends on which agents were previously used (in the (neo)adjuvant or advanced settings), the burden of the disease, patients preference, costs and availability. 94.7% 0.0% 5.2% YES NO ABSTAIN

1 st line endocrine therapy The preferred 1st line ET depends on type and duration of adjuvant ET as well as time elapsed from the end of adjuvant ET; it can be an aromatase inhibitor, tamoxifen or fulvestrant. Total votes:(44) 84.0%(37) 9.0% 6.8% (4)(3) YES NO Abstention or I don t know Cardoso F, Ohno S et al. Ann Oncol. 2017;28:16-33

CDK4/6 inhibitor to an aromatase inhibitor, in patients naïve or pre-exposed to ET The addition of a CDK4/6 inhibitor to an aromatase inhibitor, in patients naïve or pre-exposed to ET, provided a significant improvement in median PFS (~10 months), with an acceptable toxicity profile, and is therefore one of the preferred treatment options*. Patients relapsing < 12 months from the end of adjuvant AI were not included in the published studies and may not be suitable for this combination. OS results are still awaited. QoL was comparable to that with ET alone. 89.7% 0.0% 10.2% YES NO ABSTAIN

CDK4/6 inhibitor to Fulvestrant, in patients previously exposed to ET The addition of a CDK4/6 inhibitor to Fulvestrant, in patients previously exposed to ET, provided significant improvement in median PFS (6 to 7 months) as well as improvement of QoL, and is one of the preferred treatment options, if a CDK4/6 inhibitor was not previously used. OS results are awaited. 90.0% 0.0% 10.0% YES NO ABSTAIN

Endocrine therapy for premenopausal women Many trials in ER+ ABC have not included pre-menopausal women. Despite this, we recommend that young women with ER+ ABC should have adequate ovarian suppression or ablation (OS/OA) and then be treated in the same way as post-menopausal women with endocrine agents with or without targeted therapies. 94.5% 0.0% 5.4% Future trials exploring new endocrine-based strategies should be designed to allow for enrollment of both pre- and post-menopausal women. 91.8% 2.7%5.4% YES NO ABSTAIN

Predictive biomarker At present, no validated predictive biomarker other than hormone receptor status exists to identify patients who will/will not benefit from the addition of a targeted agent (i.e. CDK4/6 inhibitor, mtor inhibitor) to endocrine therapy and none of the studied biomarkers is ready for use in clinical practice. Research efforts must continue. 0.0% 95.0% 5.0% YES NO ABSTAIN

Treatment strategy?(48y.o. premenopausal woman) Left invasive breast cancer(3cm) cn0 bone metastasis(scalp rib lumbal) Stage IV ER+/PgR+,/HER2- Ki67 10% NG1 LHRHa+Tam LHRHa+ Tam/AI LHRHa+AI LHRHa+Flu +CDK4/6i ChemoTx ChemoTx

Treatment strategy?(58y.o. post-menopausal woman) Left invasive breast cancer(3cm) cn0 bone metastasis(scalp rib lumbal) Stage IV ER+/PgR+,/HER2- Ki67 10% NG1 AI Fluvestrant Fluvestrant AI Letrozole + CDK4/6i Fluvestrant AI Fluvestrant + CDK4/6i Exemestane+ Everolimus Exemestane+ Everolimus Exemestane+ Everolimus Exemestane+ Everolimus ChemoTx ChemoTx ChemoTx ChemoTx

Hormone sensitivity DFI/PFS Optimal timing and Optimal drug for ER+HER2- ABC (before targeting therapy Era) Endocrine monotherapy Tumor burden Chemotherapy 化学療法 Bone Lung Liver

Hormone sensitivity DFI/PFS Optimal timing and Optimal drug for ER+HER2- ABC (targeting therapy Era) Endocrine monotherapy Hormone + targeting therapy Tumor burden Chemotherapy 化学療法 Bone Lung Liver

Value of the treatment for patients with ABC The value of any new therapeutic strategy or treatment is determined by the magnitude of its clinical benefit balanced against its cost. Value considerations have become increasingly important in an era of rapid expansion of new, expensive cancer medicines.

Evidence Blocks (NCCN guideline) 5 4 3 2 1 E=Efficacy of Regimen/Agent S=Safety of Regimen/Agent Q=Quality of Evidence C=Consistency of Evidence A=Affordability of Regimen/Agent E S Q C A https://www.nccn.org/professionals/physician_gls/pdf/breast_blocks.pdf

Evidence Blocks for each regimen/drug Anastrozole/Letrozole Everolimus+exemestane Tamoxifen Palbociclib+letrozole Ribociclib+letrozole fulvestrant Palbociclib+fulvestrant https://www.nccn.org/professionals/physician_gls/pdf/breast_blocks.pdf

Summary Early breast cancer Physicians take a number of factors into account when deciding whether to recommend that a patient extend adjuvant hormone therapy. These factors include the patient s age and nodal status, existing comorbidities, bone mineral density, and overall AI tolerance during her initial 5 years of therapy. Advanced breast cancer Endocrine therapy is the preferred option for hormone receptor positive disease, even in the presence of visceral disease, unless there is visceral crisis or concern/proof of endocrine resistance. Tremendous progress in new potential agents to improve response to hormone therapy, such as CDK4/6 inhibitors and mtor inhibitor. The optimal sequence of endocrine-based therapy is uncertain. It depends on which agents were previously used (in the (neo)adjuvant or advanced settings), the burden of the disease, patients preference, costs and availability. Biomarkers to identify tumors most likely to benefit is essential.

HOPE Thank you for your attention.