New

Paradigm in The Management

of
Post Menopausal Breast Cancer

dr. Septiman

Divisi Bedah Onkologi Departemen Bedah

FK UNHAS – RS Wahidin Sudirohusodo
Makassar
Introduction

• Breast cancer (BC) is the most commonly diagnosed cancer

worldwide
• The second most common cause of cancer-related deaths
among females
• Estrogen is known as a key regulator of breast tissue growth
and differentiation
• About 75% off all breast cancers are estrogen receptor (ER)
positive
• The cellular effect works through binding and activating the
nuclear ER

Tremont A et al. Endocrine Therapy for Early Breast Cancer: Updated Review. 2017
K Krauss, et al. Endocrine Therapy in Early Breast Cancer. 2020
Postmenopausal women

• Estrogen is no longer produced by ovarian tissue and is

predominantly synthesized from nonglandular sources via
aromatase
• This enzyme can be found in a number of tissues including
subcutaneous fat, liver, and muscle and has also been isolated
from breast cancer cells
• Have a lower risk of breast cancer than premenopausal women
of the same age and childbearing pattern

K Krauss, et al. Endocrine Therapy in Early Breast Cancer. 2020

A Surakasula, et al. A comparative study of pre- and post-menopausal breast cancer: Risk factors, presentation, characteristics and management. 2014
Stages of Breast Cancer

F Cardoso, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). 2020
NCCN. 2020
 TN
10-15%

HER2+
15-20%

HR+, HER2+
10% HR+ 60-70%

F Cardoso, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). 2020
X Dai, et al. Breast cancer intrinsic subtype classification, clinical use and future trends. 2015
Therapy modalities of breast cancer

• Local modalities [surgery, radiotherapy (RT)]

• Systemic anticancer treatments (Chemotherapy, Endocrine
therapy, molecularly targeted therapies)
• Supportive and palliative care

F Cardoso, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2019
Early Breast Cancer Treatment
The choice of treatment strategy

• Tumour burden/location (size and location of primary tumour,

number of lesions, extent of lymph node involvement)
• Biology (pathology, including biomarkers and gene expression)
• Age
• Menopausal status à for endocrine therapy
• General health status
• Preferences of the patient

F Cardoso, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2019
F Cardoso, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2019
Early breast
cancer
algorithm

F Cardoso, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2019
(Neo)-adjuvant systemic treatment choice by marker expression and intrinsic
phenotype

F Cardoso, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2019
Primary (neoadjuvant) endocrine therapy in postmenopausal

• Usually given for 4–8 months before surgery or until maximum

response and continued postoperatively
• AIs are more effective than tamoxifen in decreasing the tumour
size and facilitating less extensive surgery

F Cardoso, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2019
Endocrine therapy for postmenopausal

• AIs (both non-steroidal and steroidal) & tamoxifen are

considered standard treatments [I, A]
• AIs can be used upfront (non-steroidal AI & exemestane), after
2–3 years of tamoxifen (non-steroidal AI & exemestane) or as
extended adjuvant therapy, after 5 years of tamoxifen (letrozole
& anastrozole) [I, A]
• Extended adjuvant therapy should be discussed with all
patients, except those with a very low risk of relapse [I, A]
• Patients undergoing OFS and those taking AIs should be
advised to have adequate calcium + vitamin D3 intake &
undergo periodic assessment of bone mineral density [I, A]

F Cardoso, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2019
Advanced Breast Cancer Treatment
Locoregional treatment general guidelines

• Removal of the primary tumour in patients with de novo stage

IV breast cancer
• If controlled systemic disease à improve QoL
• Valuable : complete removal of the disease
• Oligometastatic disease or low-volume metastatic disease that is
highly sensitive to systemic therapy, can achieve complete remission
and a long survival

F Cardoso, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). 2020
Systemic treatment general guidelines
• Treatment choice should take at least these factors into account:
• HR and HER2 status and germline BRCA status, PIK3CA in HR-positive
& PD-L1 in TNBC, if targeted therapies are accessible
• Previous therapies and their toxicities
• Disease free interval (DFI)
• Tumour burden (defined as number and site of metastases)
• Biological age
• Performance Status (PS)
• Comorbidities (including organ dysfunctions)
• Menopausal status (for endocrine therapy)
• The need for rapid disease/symptom control
• Socio-economic and psychological factors
• Available therapies in the patient’s country
• Patient’s preference

F Cardoso, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). 2020
Endocrine therapy for postmenopausal
• The preferred first-line agent: AI, tamoxifen or fulvestrant
• CDK4/6 inhibitor combined with ET is the standard of care for
patients with ER+/HER2- ABC
• CDK4/6 inhibitor can be combined with an AI or with
fulvestrant à first or second line
• The addition of everolimus to an AI / tamoxifen / fulvestrant is
a valid option for some patients previously exposed to or naive
of (in case CDK4/6 inhibitors are not available) ET
• Alpelisib with fulvestrant is a treatment option for patients with
PIK3CA-mutated tumours

F Cardoso, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). 2020
Treatment algorithm for patients with hormone receptor–positive, HER2
(human epidermal growth factor receptor 2)–negative metastatic breast cancer

A Matutino, et al. Hormone receptor–positive, HER2-negative metastatic breast cancer: redrawing the lines. 2018
ASCO 2016:
Hormone
Therapy for
Postmenopausal
Women with
HR+ mBC

HS Rugo, et al. Endocrine Therapy for Hormone Receptor–Positive Metastatic Breast Cancer: American Society of Clinical Oncology Guideline. 2016
ESMO guidelines
2018:
Postmenopausal
ER+/HER2- aBC

F Cardoso, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). 2020
NCCN. Version 6. 2020
NCCN. Version 6. 2020
FULVESTRANT for ER+ Advanced Post
Menopausal Breast Cancer
 Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive
advanced breast cancer (FALCON): An international, randomised, double-blind,
phase 3 trial

• Robertson JFR et al. Fulvestrant 500 mg versus anastrozole 1 mg for hormone receptor-positive advanced breast
cancer (FALCON): An international, randomised, double-blind, phase 3 trial. Lancet. 2016;388:2997-3005
 The FALCON study design
As FALCON is a phase III trial, the size and duration of the study made including PFS and OS endpoints feasible and also
builds on the data generated by the multiple analyses of the FIRST study

Fulvestrant Primary analysis Survival follow up

500 mg im on phase phase
Postmenopausal
days 0, 14, 28 then
women with ER+
Randomise monthly thereafter
ABC
1:1 OS
PFS
ET-naïve N = 450 Two analyses are
Evaluated once,
Up to 1 line of planned: alongside
Stratification by: when 306
chemotherapy for PFS and when
progression rates
ABC • Locally advanced or 50% of patients
metastatic breast Anastrozole have occurred
have died
cancer 1 mg/day
• Prior chemotherapy for
ABC or not
• Measurable or non-
measurable disease

Patients treated until disease progression or death

Ref. Robertson JFR et al. Lancet. 2016;388:2997-3005

1st line Faslodex in Advanced Breast Cancer is associated with a 41% risk reduction in disease progression or
death in patients without visceral disease

Faslodex demonstrated significantly

increased PFS in patients without
visceral disease

Ref. Robertson JFR et al. Lancet. 2016;388:2997-3005

 CONFIRM demonstrated fulvestrant 500mg is
superior in efficacy to fulvestrant 250mg dosing

CONFIRM was a phase III study investigating the efficacy of fulvestrant

500mg given at optimal dosing (500mg via intramuscular injection (im) on
Days 0, 14, and 28 and every 28 days thereafter), compared with fulvestrant
250mg (250mg im every 28 days) in women with ABC who have progressed
on prior endocrine treatment.1

CONFIRM demonstrated that fulvestrant 500mg given at optimal dosing

was superior to fulvestrant 250mg in terms of progression free survival
(PFS) and overall survival (OS).1

1. Di Leo A et al. JCO 2010; 28(30), 4594-

4600.
SWOG Study (S0226)
Overall Survival with Fulvestrant plus Anastrozole in Metastatic Breast Cancer

• Mehta, R. S., et al, 2019, N Engl J Med, 2019; 380:1226-34

 SWOG Study (S0226) study design

Primary endpoint:
• PFS
Anastrozole Secondary endpoint:
Inclusion Criteria • OS
n = 345 • safety
• Post-menopausal women (ER+, PgR+, or R
both) mBC 1:1
• PS 0-2
N = 694 Anastrozole

Exclusion criteria: Fulvestrant (250 mg)

- No previous chemotherapy, hormonal therapy, or n = 349
immunotherapy*
Fulvestrant à 500mg on day 1 (loading
dose) à 250mg on days 14, 28 and as
maintenance therapy every 28 days
J 500 mg dose /month were
permitted if patients had disease
progression

*Previous treatment with adjuvant tamoxifen was allowed and was a stratification factor
*Neoadjuvant or adjuvant chemotherapy or aromatase inhibitor therapy had to be completed >12 month before enrollment

Ref. Mehta, R. S., et al, 2019, N Engl J Med, 2019; 380:1226-34

Combination Anastrozole + Faslodex in Advanced Breast Cancer is associated with a has increased Overall Survival until 12 months
(52.2 mo vs 40.3 mo) for patients with no previous hormonal adjuvant therapy

Who get most of the benefit from

combination Fulvestrant-anastrozole:
• Bone metastases
• Slow disease progression
• Not received ET previously

Ref. Mehta, R. S., et al, 2019, N Engl J Med, 2019; 380:1226-34

FIRST: Fulvestrant First-Line Study Comparing Endocrine Treatments

• Ellis MJ et al. Fulvestrant 500 mg versus anastrozole 1 mg for the first-line treatment of
advanced breast cancer: Overall survival analysis from the phase II FIRST study. J Clin Oncol
2015;33:3781-3787
 FIRST: study design

Fulvestrant
500 mg im
Postmenopausal women on days 0, 14, 28
with ER+ and/or PgR+ then monthly thereafter
ABC
Primary endpoint
Clinical benefit rate (CBR)
Endocrine therapy-naïve Randomise 1:1
OR N = 205
Secondary endpoints
Prior endocrine therapy >
ORR; TTP; DoR; DoCB
12 months before
randomisation, for early
breast cancer Anastrozole
1 mg/day

ORR: Objective response rate; TTP: Time to progression; DoR: Duration of response; DoCB: Duration of clinical benefit

Ellis MJ et al. J Clin Oncol. 2015;33:3781-3787

 Faslodex improved Overall Survival compared to anastrozole in women
receiving their 1st treatment for Advanced Breast Cancer

Ellis MJ et al. J Clin Oncol. 2015;33:3781-3787

Bone-targeted agents (Biphosphonates, denosumab)

• Bisphosphonates for early breast cancer are recommended in

women with low-oestrogen status (undergoing OFS or
postmenopausal), especially if at high risk of relapse [I, A]
• Bisphosphonates are also recommended in patients with
treatment-related bone loss [I, A]
• Bone metastases

F Cardoso, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2019
Conclusions

• Treatment paradigms must focus on precise and personalized

approaches for patients à long-term remissions
• Administer the most effective first-line treatment for as long as it is
tolerable and effective, because PFS diminishes with each
subsequent line of therapy
• Maximize the benefits of ET with sequential lines of therapy until
endocrine resistance manifests and/or there is a need for
chemotherapy
• Translate findings regarding the biology, genomics, and biomarkers
of BC into individualized/personalized therapy include the patient,
and their specific needs, in treatment decisions
• Conduct clinical trials to identify and define new agents,
combinations, and optimal treatment sequences focusing on
improvement of overall survival and QoL
Case Sharing 1

• Ny. RS 52 years Metastatic Breast Cancer

• 1L endocrine therapy (metastatic to Bone & Lung): CDK4/6 +
Letrozole)
• On 2nd month, has progressed to head bone and brain. 2L:
Fulvestrant + CDK4/6
• On 3rd month: No mass at the head and can continue routine
activities

F Cardoso, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2019
ESMO guidelines
2018:
Postmenopausal
ER+/HER2- aBC

F Cardoso, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). 2020
Case Sharing 2

• Ny. J 65 years
• 5 years disease free survival
• Recurrence metastatic at Lung à Receive Fulvestrant
• At 4th month using Faslodex, The Lung is clean

F Cardoso, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2019
ESMO guidelines
2018:
Postmenopausal
ER+/HER2- aBC

F Cardoso, et al. 5th ESO-ESMO international consensus guidelines for advanced breast cancer (ABC 5). 2020
 THANK YOU
FOR YOUR ATTENTION
HER2-positive breast cancer treatment

F Cardoso, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2019
AGO 2020: Endocrine treatment of early breast cancer

K Krauss, et al. Endocrine Therapy in Early Breast Cancer. 2020

Combination therapy for breast cancer

• ChT should not be used concomitantly with ET [II, D], with the
exception of gonadotropin-releasing hormone (GnRH)
analogues used for ovarian protection [I, A]
• Anti-HER2 therapy may routinely be combined with
nonanthracycline-based ChT, ET and RT [I, A]
• RT may be delivered safely during anti-HER2 therapy, ET and
non-anthracycline, non-taxane-based ChT [III, B]
• If ChT and RT are to be used, ChT should usually precede RT

F Cardoso, et al. Early breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. 2019
N Ditsch, et al. AGO Recommendations for the Diagnosis and Treatment of Patients with Locally Advanced and Metastatic Breast Cancer: Update 2020. 2020
 Breast cancer treatment timeline (FDA approval)
SL Tarruella. Fenotype RH+ / HER2- Breast Cancer. 2019 available at: www.forodebateoncologia.net
Phase II and III trials of everolimus in patients with hormone receptor-positive,
HER2-negative breast cancer

E Paplomata, et al. New and emerging treatments for estrogen receptor-positive breast cancer: focus on everolimus. 2013
A Matutino, et al. Hormone receptor–positive, HER2-negative metastatic breast cancer: redrawing the lines. 2018
Summary of randomised phase 3 clinical trials evaluating CDK4/6 inhibitors in hormone receptor-positive and HER2-
negative metastatic breast cancer

LM Spring, et al. Cyclin-dependent kinase 4 and 6 inhibitors for hormone receptor-positive breast cancer: past, present, and future. 2020
PIK3CA Mutation Status on PI3K Inhibitors in HR+ Breast Cancer Therapy Studies

• SOLAR I: alpelisib provided PFS benefit of 11.0 months versus

5.7 months

M wang, et al. The Predictive Role of PIK3CA Mutation Status on PI3K Inhibitors in HR+ Breast Cancer Therapy: A Systematic Review and Meta-Analysis. 2020