(Neo)Adjuvant Endocrine Therapy and Special Populations...Neoadjuvant Endocrine Therapy in Postmenopausal Women •Neoadjuvant endocrine therapy prior to surgery is an option for large

ESMO PRECEPTORSHIP ON BREAST CANCER

(Neo)Adjuvant Endocrine Therapy

and Special Populations

Prudence Francis MD

Peter MacCallum Cancer Centre, Melbourne

November 2019

DISCLOSURES

Dr Prudence Francis

Honoraria: AstraZeneca, Novartis

Overseas Lectures (travel): Pfizer, Ipsen

ESMO Early Breast Cancer Clinical Practice Guidelines 2019

Cardoso et al, Ann Oncol August 2019

ESMO Pocket Guidelines: Breast Cancer 2019

St. Gallen International Consensus

Guidelines for Early Breast Cancer 2019

Burstein et al, Ann Oncol October 2019

Collaboration was sought between the co-ordinators of all randomized trials of the treatment of early breast cancer and in 1985 the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) was initiated.

EBCTCG conduct individual patient-level meta-analyseson questions studied in randomized trials based on submitted data of thousands of patients (often published in The Lancet or NEJM)

Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) “Oxford Overviews”

Adjuvant Endocrine Therapy

Recommended for ER+ or PR+ tumours

( > 1% cells staining +ve on IHC )

Postmenopausal ER+ Adjuvant Tamoxifen 5 years

EBCTCG, Lancet 2011

Adjuvant Tamoxifen 5 years: Age 55-69 (postmenopausal) Uterine Cancer

EBCTCG, Lancet 2011

Adjuvant Tamoxifen 5 yrs: No Increase Overall Vascular Mortality(cerebrovascular + pulmonary embolism + cardiovascular)

EBCTCG, Lancet 2011

Adjuvant Aromatase Inhibitor (AI) vs Tamoxifen 5 yrsMeta-analysis ER+ Postmenopausal

EBCTCG, Lancet 2015

AI vs Tamoxifen: Absolute Benefit at 5 y by Nodal statusRecurrence

EBCTCG, Lancet 2015

AI vs Tamoxifen: Absolute Benefit at 5 yrs by Tumor GradeRecurrence

EBCTCG, Lancet 2015

AI vs Tamoxifen: Absolute Benefit at 5 years Recurrence by PR status

EBCTCG, Lancet 2015

Choosing between adjuvant AI and Tamoxifen in Postmenopausal Women

• The greater the absolute risk of recurrence based on pathologic features, the larger the absolute benefit from adjuvant AI vs. tamoxifen → with higher risk features prefer AI over tamoxifen

• With a small (screen detected) cancer with favourable pathologic features, unlikely to derive relevant difference in recurrence between AI vs. tamoxifen – choose either according to patient preference (considering side effect profiles, costs)

ATAC Trial: Anastrozole vs Tamoxifen QoLSexual Side Effects worse on Adjuvant AI

Fallowfield et al, J Clin Oncol 2004

Randomized Trials of Adjuvant AI vs another AI

FACE Trial MA.27 TrialLetrozole vs Anastrozole Exemestane vs Anastrozole

Smith et al, J Clin Oncol 2017 Goss et al, J Clin Oncol 2013

Postmenopausal Adjuvant Endocrine Therapy: Strategies for clinic

• Aromatase Inhibitor 5 y

• Aromatase Inhibitor 10 y (discuss if very high risk recurrence)

• Aromatase Inhibitor → Tamoxifen (if AI tolerance problematic)

Best outcomes obtained with choice that supports adherence

• Tamoxifen 5-10 y (reasons not to prefer AI)

– Patient preference

– Sexual problems (vaginal dryness/ dyspareunia/ libido)

– Musculoskeletal symptom problems at baseline

– Low bone density (BMD) plus BMD treatment problematic

– Cost differential (AI plus bone health) relevant factor for patient

Neoadjuvant Endocrine Therapy

Postmenopausal Women

Neoadjuvant Endocrine Therapy in Postmenopausal Women

• Neoadjuvant endocrine therapy prior to surgery is an option for large luminal-A like tumours

• Aromatase Inhibitors (AI) superior to tamoxifen in neoadjuvant trials (P024 and IMPACT trials) and increased likelihood of breast conservation

• Comparison of 3 different aromatase inhibitors in neoadjuvant setting did not show clear differences (ACOSOG Z1031 trial)

• Often takes > 6 months to reach maximum response

Smith et al, J Clin Oncol 2005Eiermann et al, Ann Oncol 2001 Ellis et al, J Clin Oncol 2011

POETIC Trial: 2 weeks Neoadjuvant ETBaseline→ 2 week Ki67 dynamic and Time To Recurrence

Robertson et al, SABCS 2017

Special Populations

• Male Breast Cancer

• Elderly - Senior

• Lobular histology

• Very Young Women

Male Breast Cancer: Pink Ribbon Blues

Francis P, Ann Oncol 2018

Male Breast Cancer

• Men in general population have ~ 0.1% chance of developing breast cancer

• Slightly < 1% of all breast cancers occur in men

• Male breast cancer typically diagnosed at 5-10 years older age than in women (median age of diagnosis in men is late 60’s)

International Male Breast Cancer ProgramBreast Cancer Phenotype

• Male breast cancer typically invasive ductal grade 2, ER +ve and PR+ve, HER2 negative (ie. luminal).

• High Ki67 > 20% in 1/4

• Lobular breast cancer uncommon in men (1%)

• Triple negative breast cancer uncommon (0.3%)

• HER2+ve less common (8.7%) than in women

Cardoso et al, Ann Oncol 2018; 29:405-417

International Male Breast Cancer Program

• Central pathology review of early stage cancers: 99% ER+ve, 82% PR+ve, 97% AR+ve

• Adjuvant endocrine therapy should be standard but approximately one in four men did not receive

• Breast cancer-specific mortality was higher in men aged < 50 years

Cardoso et al, Ann Oncol 2018; 29:405-417

Adjuvant Endocrine Therapy for Male Breast Cancer

• Tamoxifen is the recommended adjuvant endocrine therapy for men with breast cancer

• If men have history of thrombosis, concurrent anticoagulation may be an option

• Adjuvant hormonal therapy with aromatase inhibitor (AI) monotherapy should not be recommended

• If adjuvant AI is chosen over tamoxifen, it should be combined with GnRH agonist

Male Breast CancerGenetic Considerations

• Most male breast cancer is sporadic but a relevant minority will have a germline BRCA mutation →men should be offered genetic counselling/assessment.

• Men with BRCA2 mutation have ~ 7% lifetime risk of breast cancer and also ↑ risk of prostate cancer.

• Men with BRCA1 mutation have ~ 1% lifetime risk of breast cancer.

(Neo)Adjuvant Endocrine Therapyin Elderly (Senior) Patients

Breast Cancer and Age

• In Geriatric Oncology, age of 70 years is the most common cut-off for defining elderly

• Mean age of population is rising

Mean age of global population is increasing

Figure taken from United Nations World Population Prospects

at http://esa.un.org/unpp/index.asp?panel=2

55

50

45

40

35

30

25

20

15

Year

United States

South Korea

JapanChina

India

Mexico

Pakistan

1950 1960 1970 1980 1990 2000 2010 2020 2030 2040 2050

Med

ian

ag

e (

years

)

Elderly Patients

Significant Variability in Fitness and Co-morbidities

Physically fit and independent →→→→

Frail needing substantial functional assistance

Life expectancy in senior adults: a large variability reflecting health status variability

18

1

4.3

5.8

7.9

10.8

14.2

2.33.2

4.7

6.7

12.4

9.3

1.52.2

3.3

6.7

4.9

0

5

10

15

20

25

70 years 75 years 80 years 85 years 90 years 95 years

Lif

e e

xp

ec

tan

cy

, y

ea

rsTop 25th percentile (FIT seniors)

Lowest 25th percentile (FRAIL seniors)

50th percentile (MEDIAN life expectancy)

Walter LC et al. JAMA 2001, 285, 2750-2756

Domains

Cognition

Comorbidity

Emotional conditions

Function

Geriatric syndromes

Nutrition

Pharmacy

Socioeconomic

conditions

Health status

groups

Breast Cancer in Elderly

• Elderly have higher proportion of ER+ve tumours and so can benefit from adjuvant endocrine therapy.

• Elderly on average (but not all) have more indolent endocrine responsive tumours

• Adjuvant endocrine therapy relevant in older pts with pT1 ER+ve HER2-negative tumours who have de-escalation of loco-regional therapy (no sentinel node biopsy and/or no radiation to breast)

Adjuvant Tamoxifen 5 years vs none: Age > 70 y

EBCTCG, Lancet 2011

Adjuvant Endocrine Therapy in Elderly Patients

• Unless a high-risk breast cancer, it is reasonable to choose between tamoxifen and AI based on toxicities/comorbidities/patient preferences

• Consider– Risk for thrombo-embolism (tamoxifen worse)– endometrial cancer (tamoxifen worse)– Ocular toxicity (tamoxifen worse)– Bone (and dental) health and costs (AI worse)– Pre-existing musculoskeletal complaints (AI worse)– Sexual health if remain sexually active (AI worse)– Cardiovascular risks (tamoxifen slightly safer)

ESMO Resource

“before recommending hormonal therapy to elderly patients,

the benefits of treatment should be balanced against potential harms and competing risks of morbidity and mortality”

Neoadjuvant Endocrine Therapy in “unfit” Elderly Patients

• Elderly patients with operable HR+ breast cancer may be referred for primary endocrine therapy because they are considered “unfit” for surgery

• Oral endocrine therapy can control unresected luminal breast cancer for a limited time, so this is only appropriate if life expectancy is short (< 2-3yrs) or in case of surgery refusal. Resection under local anaesthetic is also an option (without axillary surgery).

Neoadjuvant Endocrine Therapy in Elderly Patients

• Cochrane Review of 7 trials comparing surgery vs. primary endocrine therapy (tamoxifen) for elderly women with operable breast cancer

• Primary endocrine therapy was significantly inferior to surgery (+/- endocrine therapy) for local control of breast cancer ie. worse PFS (progression-free survival)

http://www.cochrane.org/reviews/en/ab004272.html

Lobular Breast Cancer

Invasive Lobular Cancer (ILC)

• 2nd most common histologic subtype after ductal –accounts for 10-15% of breast cancer

• Immunhistochemistry (IHC) negative for E-cadherin (a cell to cell adhesion protein)

• Most common is classical lobular which is typically endocrine responsive

• Pleomorphic lobular is more aggressive and chemotherapy often recommended prior to ET

Invasive Lobular Cancer (ILC)

• Increased risk with combined HRT

• More frequently occult on mammography

• Primary more frequently larger, more spread out, multifocal, bilateral

• Distant metastasis sites include bones, ovaries, gastro-intestinal tract, renal tract

Lobular Breast CancerAdjuvant Endocrine Therapy

Metzger-Filho et al, J Clin Oncol 2015

BIG 1-98 Trial Postmenopausal HR+Advantage of AI over Tamoxifen in Invasive Duct (NST)

BIG 1-98 Trial Postmenopausal HR+Advantage of AI over Tamoxifen in Lobular

BIG 1-98 Trial Postmenopausal HR+

BIG 1-98 Trial Postmenopausal HR+Magnitude of benefit for Letrozole

greater with lobular than ductal

Metzger-Filho et al, J Clin Oncol 2015

Adjuvant Endocrine Therapy in Very Young Patients

Role of Ovarian Function Suppression (OFS)

SOFTSuppression of Ovarian Function Trial

Primary Question:

Does adding ovarian function suppression (OFS) improve outcomes in premenopausal women

treated with adjuvant tamoxifen?

SOFT: Suppression of Ovarian Function Trial

R

A

N

D

O

M

I

Z

E

Stratification

Receipt of (neo)adjuvant chemo

-No chemotherapy (47%)

-Prior chemotherapy (53%)premenopausal E2 level within 8 months

Lymph Node status-Positive (34.5%)

OFS method planned

-Triptorelin (91%)

Tamoxifen x 5y (n=1018)

Tamoxifen+OFS x 5y (n=1015)

Exemestane+OFS x 5y (n=1014)

Enrolled: Dec 2003-Jan 2011 Median follow-up 8 years

OFS =Ovarian Function Suppression(GnRH triptorelin, oophorectomy or irradiation)

SOFT Patient Characteristics

• Prior Chemotherapy Cohort at higher risk of recurrence with young median age (40 years) due to requirement for premenopausal E2 after chemotherapy, more lymph node positive cancers, more frequent high grade cancers, more HER2+ve cancers

• No Chemotherapy Cohort at lower risk of recurrence with older median age (46 years - may go into natural menopause in 5 years), mainly pT1N0 cancers of low or intermediate grade

SOFT DFS 8 years median follow-up

T+OFS significantly improves DFS vs T-alone in the overall population

Francis et al, N Engl J Med 2018

SOFT: Disease-Free Survival (DFS)No Chemotherapy Cohort

Tamoxifen

vs No Chemo patients ↑ 8 year DFS = 3.2%

Tamoxifen + OFS

vs

Exemestane + OFS No Chemo patients ↑ 8 year DFS = 5.1%

SOFT Secondary EndpointsNo Chemotherapy Cohort

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

12 of 24 deaths had no distant recurrence

Distant Recurrence-Free Interval Overall Survival

SOFT: Disease-Free Survival (DFS)Chemotherapy Cohort

Tamoxifen

vs Chemo patients ↑8 year DFS = 5.3%

Tamoxifen + OFS

vs

Exemestane + OFS Chemo patients ↑ 8 year DFS = 9.0%

Prior Chemotherapy cohort: Overall survival improvement in OFS arms at 8 years

SOFT Secondary EndpointsPrior Chemotherapy Cohort

Distant Recurrence-Free Interval Overall Survival

SOFT: Disease-Free Survival (DFS)Very young patients < 35 years

Tamoxifen

vs ↑ 8 year DFS = 8.7%

Tamoxifen + OFS

vs

Exemestane + OFS ↑ 8 year DFS = 13.1%

SOFT: 8-year outcomes in Women < 35 years

Francis et al, N Engl J Med 2018

Adjuvant Endocrine Therapy in Very Young Patients

• Guidelines now recommend consideration of ovarian function suppression (OFS) as part of adjuvant endocrine therapy for very young patients < 35 years

ESO-ESMO 3rd International Consensus Guidelines for Breast Cancer in Young Women

Paluch-Shimon et al, The Breast 2017;35: 2013-217

BCY4 publication expected soon