What is new in HR+ Breast Cancer?

Olivia Pagani Breast Unit and

Institute of oncology of

Southern Switzerland

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

Outline

• Early breast cancer

• Advanced breast cancer

• Open questions

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

Outline

• Early breast cancer

• Advanced breast cancer

• Open questions

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

Definition of HR+ breast cancer

Hormone receptor-positive and HER2-negative

ER and/or PgR positive 1%

Luminal A-like High ER/PR and clearly low Ki-67 or grade.

Luminal B-like 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):1700-1712 17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

Postmenopausal women: what’s still open?

• Always aromatase inhibitors?

• Sequence with Tamoxifen?

• Aromatase inhibitors after tamoxifen?

• Overall Duration?

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

San Gallen recommendations Postmenopausal women

Ann Oncol. 20171;28(8):1700-1712

High receptor, low tumor burden (pT1a, pT1b), no nodal involvement (pN0), low proliferation, low grade or low “genomic risk”

Tamoxifen or AI for 5 years The majority of the panel recommended against extended adjuvant endocrine therapy beyond 5 years

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”

AI up front Extended adjuvant AI according to risk and tolerability

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

Aromatase inhibitors versus tamoxifen in early breast cancer:

patient-level meta-analysis of the randomised trials

EBCTCG. Lancet 2015;386:1341-52.

TAM 5 vs AI 5 TAM 2-3 AI 2-3 vs AI 5

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

BIG 1-98 Overall Design

2-Arm Option

Tamoxifen

Letrozole

Letrozole

Letrozole Tamoxifen

RANDOMI ZE

0 2 5

YEARS

A

B

C

D

Tamoxifen

Tamoxifen

Letrozole

A

B

4-Arm Option

SURGERY

Stratify

Institution

CT (Adjuvant/ Neoadjuvant)

-Prior -None -Concurrent

N=1,828 Enrolled

1998-2000

N=6,182 Enrolled

1999-2003

N=8,010*

RANDOMI ZE

*Intent-to-treat population excludes 18 patients who withdrew consent and did not receive study treatment

N=911

N=917

N=1548

N=1540

N=1548

N=1546

N Engl J Med 353:2747-2757, 2005 17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

STEPP: 5-year DFS by Composite Risk

Viale, Regan, et al., Ann Oncol 2011; 22(10):2201-7

Proportional benefit of AI v tam seems greater among tumors with higher risk biology

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

Annual Hazard Rates of Recurrence for Breast Cancer after Primary Therapy by ER status

Saphner T et al: J Clin Oncol 14: 2738, 1996 17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

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 17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

Major trials of extended adjuvant ET

Treatment

0 2

3 5

10

15

MA17

NSABP B-33

ABCSG 6a

ATLAS

ATTOM

MA17R

NSABP B-42

IDEAL

DATA

TAM AI

Years since diagnosis

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

Summary of Trials of Extended Adjuvant AI after AI therapy

Endpoint MA17R NSABP B-42 DATA IDEAL

DFS – hazard ratio 0.66 0.85 0.79 0.96

DFS – Δ absolute % 4% 3.5% 3.7% (0.5%)

Contral – hazard ratio 0.42 0.37

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 17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

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

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

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?

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

Premenopausal women

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

San Gallen recommendations Premenopausal women

Ann Oncol. 2017;28(8):1700-1712

High receptor, low tumor burden (pT1a, pT1b), no nodal involvement (pN0), low proliferation, low grade or low “genomic risk”

Tamoxifen for 5 years No role for extended adjuvant tamoxifen beyond 5 years No OFS

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”

OFS + Tam or OFS + Exemestane Extended Tam in some cases

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

SOFT DFS 8 years median follow-up

T+OFS significantly improves DFS

vs T-alone in the overall population 17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

SOFT Secondary Endpoints: No Chemo

No Chemo cohort remains at low risk of distant recurrence with T alone;

12 of 24 deaths were in setting of no distant recurrence

Distant Recurrence-Free Interval Overall Survival

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

Prior Chemo cohort has small absolute OS improvements in OFS arms at 8 yrs

SOFT Secondary Endpoints: Prior Chemo

Distant Recurrence-Free Interval Overall Survival

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

TEXT Sustained Improvement in DFS

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

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

TEXT Overall Survival

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

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

TEXT HER2-negative Patients (N=4035) DFS

• Consistent treatment effects in cohorts

• Different absolute

benefits of E+OFS at 8 years DRFI

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

Very young women

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

385 HER2- pts < 35 93% received CT

All women < 35 years of age in SOFT and TEXT

Saha P e al JCO 35, June 27, 2017 17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

Timing of OFS

Regan MM, Ann Oncol. 2017;28(9):2225 17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

Outline

• Early breast cancer

• Advanced breast cancer

• Open questions

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

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)

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

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.

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

Combining Targeted Agents and Endocrine Therapy

SOS RAS

RAF

Basal Transcription

Machinery p160

ERE ER Target Gene Transcription

ER CBP P

P P P

ER

P p90RSK

Akt P

MAPK P

Cell Survival Tam

Cytoplasm

Nucleus

ER

AI

P13-K P

P

P P P

P

Cell

Growth

MEK P

Plasma Membrane

EGFR/HER2

IGFR Growth Factor

Estrogen

Tamoxifen

EGF30008

mTOR

Cell

Cycle

CDK 4/6 Inhibitor PD 0332991

HDAC Inhibitor Entinostat

Transcription Silencing

BOLERO

TAMRAD

HORIZON

TANDEM

eLEcTRA

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

PRIMARY: - Relapse while on the first 2 years of adjuvant ET - PD within first 6 ms of initiating 1st 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):1871-88 17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

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

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

PFS Benefit in 1st Line AI + CDK 4/6 inhibitor Phase III Trials

mPFS (months)

Palbociclib–letrozole:

24.8

Placebo–letrozole: 14.5

PALOMA-2 MONALEESA-2 MONARCH-3

Finn R, et al. NEJM. 2016;375(20):1925–1936 Hortobagyi G, et al. NEJM 2016; 375(18):1738-1748 Goetz MP, et al. J Clin Oncol 2017.

Courtesy Dr Johnston 17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

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%)

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

PALOMA-3

PFS Benefit in 2nd Line Fulvestrant + CDK 4/6 inhibitor Phase III Trials

MONARCH-2

Turner N, et al. SABCS 2016 (Abstract P4-22-06); Sledge GW, et al JCO 2017;35:2875-84

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

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%)

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

Neither everolimus nor CDK4/6 inhibitors should be used post-progression. (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%)

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

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.

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology

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 17th ESO-E

SMO Maste

rclass

in C

linica

l Onco

logy

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 17th ESO-E

SMO Maste

rclass

in C

linica

l Onco

logy

17th ESO-ESMO M

astercl

ass in

Clin

ical O

ncology