What is new in HR+ Breast Cancer? Olivia Pagani Breast Unit and Institute of oncology of Southern Switzerland

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1 What is new in HR+ Breast Cancer? Olivia Pagani Breast Unit and Institute of oncology of Southern Switzerland

2 Outline Early breast cancer Advanced breast cancer Open questions

3 Outline Early breast cancer Advanced breast cancer Open questions

4 Definition of HR+ breast cancer Hormone receptor-positive and HER2-negative Luminal A-like Luminal B-like ER and/or PgR positive 1% High ER/PR and clearly low Ki-67 or grade. Lower ER/PR clearly high Ki-67, histological grade 3. Ki-67 scores should be interpreted in the light of local laboratory values: as an example, if a laboratory has a median Ki-67 score in receptor-positive disease of 20%, values of 30% or above could be considered clearly high; those of 10% or less clearly low. San Gallen 2017 Ann Oncol. 2017;28(8):

5 Postmenopausal women: what s still open? Always aromatase inhibitors? Sequence with Tamoxifen? Aromatase inhibitors after tamoxifen? Overall Duration?

6 San Gallen recommendations Postmenopausal women High receptor, low tumor burden (pt1a, pt1b), no nodal involvement (pn0), low proliferation, low grade or low genomic risk High/Intermediate degree of ER and PgR expression, intermediate tumor burden pt1c, pt2, pn0 or pn1 (1-3), intermediate or high proliferation or grade, and/or intermediate genomic risk Tamoxifen or AI for 5 years The majority of the panel recommended against extended adjuvant endocrine therapy beyond 5 years AI up front Extended adjuvant AI according to risk and tolerability Ann Oncol ;28(8):

7 Aromatase inhibitors versus tamoxifen in early breast cancer: patient-level meta-analysis of the randomised trials TAM 5 vs AI 5 TAM 2-3 AI 2-3 vs AI 5 EBCTCG. Lancet 2015;386:

8 S U R G E R Y Stratify Institution CT (Adjuvant/ Neoadjuvant) -Prior -None -Concurrent BIG 1-98 Overall Design R A N D O M I Z E R A N D O M I Z E A B A B C D Tamoxifen Letrozole 2-Arm Option Tamoxifen Letrozole 4-Arm Option Tamoxifen Letrozole Letrozole Tamoxifen YEARS N=911 N=917 N=1548 N=1546 N=1548 N=1540 N=1,828 Enrolled N=6,182 Enrolled N=8,010* *Intent-to-treat population excludes 18 patients who withdrew consent and did not receive study treatment N Engl J Med 353: , 2005

9 STEPP: 5-year DFS by Composite Risk Proportional benefit of AI v tam seems greater among tumors with higher risk biology Viale, Regan, et al., Ann Oncol 2011; 22(10):2201-7

10 Annual Hazard Rates of Recurrence for Breast Cancer after Primary Therapy by ER status Saphner T et al: J Clin Oncol 14: 2738, 1996

11 Prognostic markers of recurrence in ER+ breast cancer Factor Risk Early recurrence years 0-5 Late Recurrence years 5-10 Tumor size Larger > Smaller Nodal status Positive > Negative Intrinsic subtype Luminal B > Luminal A Grade Higher > Lower Proliferation (Ki67) Higher > Lower ER / PgR expression Lower > Higher Courtesy H Burstein

12 Major trials of extended adjuvant ET Treatment MA17 NSABP B-33 ABCSG 6a ATLAS ATTOM MA17R NSABP B-42 IDEAL DATA Years since diagnosis TAM AI

13 Summary of Trials of Extended Adjuvant AI after AI therapy Endpoint MA17R NSABP B-42 DATA IDEAL DFS hazard ratio DFS Δ absolute % 4% 3.5% 3.7% (0.5%) Contral hazard ratio Contral - Δ absolute % 1.8% 1.5% 1.0% DDFS hazard ratio 0.72 DDFS - Δ absolute % 1.1% 1.9% Fracture - Δ absolute % 5% 0.6% Courtesy H Burstein

14 To extend or not to extend AIS? Data neither conclusive nor convincing DFS benefit only in one trial so far (MA.17R) No survival benefit Patients populations not homogeneous across trials as regards upfront therapy and total duration of AI Up-escalation strategy not fashionable

15 Some Potential Factors to Support Discussion of Extended Adjuvant Endocrine Therapy Higher stage at diagnosis Limited or absent toxicity during first 5 years Absence of life-threatening comorbidities Younger age Patient preference Biomarkers for late recurrence?

16 Premenopausal women

17 San Gallen recommendations Premenopausal women High receptor, low tumor burden (pt1a, pt1b), no nodal involvement (pn0), low proliferation, low grade or low genomic risk High/Intermediate degree of ER and PgR expression, intermediate tumor burden pt1c, pt2, pn0 or pn1 (1-3), intermediate or high proliferation or grade, and/or intermediate genomic risk Tamoxifen for 5 years No role for extended adjuvant tamoxifen beyond 5 years No OFS OFS + Tam or OFS + Exemestane Extended Tam in some cases Ann Oncol. 2017;28(8):

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19 T+OFS significantly improves DFS vs T-alone in the overall population SOFT DFS 8 years median follow-up

20 SOFT Secondary Endpoints: No Chemo Distant Recurrence-Free Interval Overall Survival No Chemo cohort remains at low risk of distant recurrence with T alone; 12 of 24 deaths were in setting of no distant recurrence

21 SOFT Secondary Endpoints: Prior Chemo Distant Recurrence-Free Interval Overall Survival Prior Chemo cohort has small absolute OS improvements in OFS arms at 8 yrs

22 TEXT Sustained Improvement in DFS 4.0% absolute improvement in 8-yr DFS for E+OFS after 9 years median follow-up

23 TEXT Overall Survival E+OFS did not improve Overall Survival vs T+OFS, after 9 years median follow-up

24 DFS DRFI TEXT HER2-negative Patients (N=4035) Consistent treatment effects in cohorts Different absolute benefits of E+OFS at 8 years

25 Very young women

26 All women < 35 years of age in SOFT and TEXT 385 HER2- pts < 35 93% received CT Saha P e al JCO 35, June 27, 2017

27 Timing of OFS Regan MM, Ann Oncol. 2017;28(9):2225

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29 Outline Early breast cancer Advanced breast cancer Open questions

30 ER POSITIVE / HER-2 NEGATIVE MBC Endocrine therapy (ET) 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. (LoE: 1 A)

31 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. Available options include AI, tamoxifen, fulvestrant, AI/fulvestrant + CDK4/6 inhibitor, AI/tamoxifen/fulvestrant + everolimus. In later lines also megestrol acetate and estradiol, as well as repetition of previously used agents, may be used. (LoE/GoR : I/A) (95%) It is currently unknown how the different combinations of endocrine + targeted agents compare with each other, and with single agent CT. Trials are ongoing.

32 AI Combining Targeted Agents and Endocrine Therapy 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 HDAC Inhibitor Entinostat TANDEM electra P Cell Growth

33 PRIMARY: - Relapse while on the first 2 years of adjuvant ET - PD within first 6 ms of initiating 1 st line 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 (LoE: Expert opinion) ENDOCRINE RESISTANCE Ann Oncol. 2014;25(10):

34 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. (LoE/GoR : I/A) (90%) CDK4/6 INHIBITORS

35 PFS Benefit in 1 st Line AI + CDK 4/6 inhibitor Phase III Trials PALOMA-2 MONALEESA-2 MONARCH-3 mpfs (months) Palbociclib letrozole: 24.8 Placebo letrozole: 14.5 Finn R, et al. NEJM. 2016;375(20): Hortobagyi G, et al. NEJM 2016; 375(18): Goetz MP, et al. J Clin Oncol Courtesy Dr Johnston

36 The addition of a CDK4/6 inhibitor to Fulvestrant, in patients previously exposed to an AI, 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. (LoE/GoR : I/A) (90%)

37 PFS Benefit in 2 nd Line Fulvestrant + CDK 4/6 inhibitor Phase III Trials PALOMA-3 MONARCH-2 Turner N, et al. SABCS 2016 (Abstract P ); Sledge GW, et al JCO 2017;35:

38 The addition of everolimus to an AI is a valid option for some patients previously exposed to endocrine therapy, since it significantly prolongs PFS, albeit without OS benefit. The decision to treat must take into account the toxicities associated with this combination, lack of statistical significant OS benefit, cost and country availability. (LoE/GoR : I/B) (88%) Tamoxifen or Fulvestrant can also be combined with everolimus. (LoE/GoR : II/B) (80%) Adequate prevention, close monitoring and proactive treatment of adverse events is needed, particularly in older patients treated with everolimus due to the increased incidence of toxic deaths reported in the Bolero-2 trial. (LoE/GoR : I/B) (97%)

39 Neither everolimus nor CDK4/6 inhibitors should be used postprogression. (LoE/GoR : NA/E) (74%) 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. (LoE/GoR: I/E) (95%)

40 For pre-menopausal women, for whom ET was decided, ovarian suppression/ablation combined with additional endocrine therapy is the preferred choice. (LoE: 1 B) Ovarian ablation by laparoscopic bilateral oophorectomy ensures adequate estrogen suppression and contraception, avoids potential initial tumor flare with LHRH agonist. (LoE: Expert Opinion) Ovarian irradiation is also a method of permanent ovarian ablation. This is not always effective and therefore is the least preferred option.

41 Open questions Early breast cancer Who will benefit from adjuvant chemotherapy Endocrine resistance Drugs addressing endocrine resistance to be incorporated in adjuvant therapy In postmenopausal women the exact sequence and duration is still unclear In premenopausal women several options now available, according to risk (individualized treatment!!!) Quality of life should be taken into consideration when proposing ET

42 Open questions Advanced breast cancer Several new drugs and approaches! When switching to CT? How new drugs compare to CT? Bolero 6 trial: everolimus + exemestane vs. capecitabine PEARL trial: palbociclib + exemestane vs. capecitabine Cost issues and availability New endpoints important in indolent disease Harmonized integration with supportive care

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