ESMO Breast Cancer Preceptorship

Singapore November 2018

(Neo) Adjuvant Endocrine Therapy and

Special Populations

Prudence Francis MD

Peter MacCallum Cancer Centre

Melbourne, Australia

Dr Prudence Francis

Conflict of Interest

Honoraria: AstraZeneca, Novartis

Overseas Lecture (travel): Pfizer

All our patients are special

but some groups deserve special attention

(Neo) Adjuvant Endocrine Therapy

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 is typically diagnosed at a

5-10 year older age than in women (median

age of diagnosis in men late 60’s)

International Male Breast Cancer Program

Breast Cancer Phenotype

• Male breast cancer typically invasive ductal

grade 2, ER +ve and PR+ve, HER2 negative

(ie. luminal tumours). High Ki67 > 20% in 1/4

• Triple negative breast cancer uncommon (0.3%)

• HER2+ve disease 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 concerning history of thrombosis, concurrent anticoagulation may be an option

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

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

Male Breast Cancer

Genetic Considerations

• Most male breast cancer is sporadic but a significant 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.

Male Breast Cancer

Genomics

• PIK3CA mutations less common in male breast

cancer than in female ER+ve breast cancer

• Genomic analysis of 59 male breast cancers

showed increased frequency of somatic

mutations in genes associated with DNA repair

pathways. ? Future therapeutic implications

for those with metastatic disease.

Piscuoglio et al, Clin Can Res 2016

Male Breast Cancer

Future Directions• Men have often been excluded from randomized trials.

• Men with HR+ breast cancer are eligible to participate in phase 3 adjuvant trials (PALLAS, NATALEE) testing addition of CDK4/6 inhibitors to adjuvant endocrine therapy.

(NB. PALLAS allows tamoxifen, NATALEE requires AI + GnRHa)

• Men with breast cancer and BRCA mutations are eligible to participate in phase 3 OLYMPIA trial testing addition of PARP inhibitor olaparib (concurrent with adjuvant endocrine therapy if HR+), after completion of chemotherapy and loco-regional Rx.

(Neo)Adjuvant Endocrine Therapy

in Elderly (Senior) Patients

Breast Cancer and Age

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

• ~ 40% breast cancer diagnosed > 65 years (in west)

• ~ 20% breast cancer diagnosed > 75 years

• Mean age of population is rising

• Older women under-represented in breast cancer trials

Mean age of global population

is increasing

Figure taken from United Nations World Population P rospectsat 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

age

(yea

rs)

Growing population, with high incidence of disease, are

under-represented in clinical trials

Percentage of trial enrolment of patients ≥65 years old

(Southwest Oncology Group [SWOG] 1993–1996)1

1. Hutchins LF, et al. N Engl J Med 1999;341:2061–72. Droz JP, et al. Crit Rev Oncol Hematol 2008;68:S 1–8

Per

cent

age

patie

nts

70

60

50

40

30

20

10

0

Elderly Patients

Significant Variability in Fitness and Co-morbidities

Physically fit and independent ����

Frail needing substantial functional assistance

Elderly PatientsComprehensive Geriatric Assessment (CGA)

Assess comorbidities and functional status

• Provides extra information beyond ECOG Performance Status

• Assists in prediction of treatment toxicity

• Estimation of life expectancy and prognosis

• Particularly relevant if considering chemotherapy

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

18

1

4.35.8

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

Life

exp

ecta

ncy,

yea

rs

Top 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

Socioeconomicconditions

Health statusgroups

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”

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 cancers (ie. low-intermediate grade, slower growth)

• Adjuvant endocrine therapy particularly relevant in older patients with pT1 N0/Nx ER+ve HER2-negative (luminal) tumours who have de-escalation of loco-regional therapy (ie. no sentinel node biopsy and/or no radiation to conserved breast)

Adjuvant Tamoxifen 5 years vs none: Age > 70 y

EBCTCG, Lancet 2011

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

(Neo) 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)

– Bone health (and dental health) and associated costs

– Pre-existing musculoskeletal complaints (worse on AI)

– Sexual health if remain sexually active (worse on AI)

– Cardiovascular risks (tamoxifen slightly safer)

(Neo)Adjuvant Endocrine Therapy

in Frail Elderly Patients

• Frail elderly patients with operable HR+ breast cancer

may be referred for primary endocrine therapy

because they are “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).

(Neo)Adjuvant 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

(Neo)Adjuvant Endocrine Therapy

in Elderly Patients

• Neoadjuvant endocrine therapy prior to planned surgery is a reasonable option for locally advanced luminal-A like tumours

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

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

• It often takes > 6 months to reach maximum response with neoadjuvant endocrine therapy

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

Invasive Lobular Cancer (ILC)

• 2nd most common histologic subtype after ductal

• Immunhistochemistry (IHC) E-cadherin negative

• Most common is classical lobular which is typically endocrine responsive

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

Lobular Breast Cancer

Adjuvant 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)

Background: Adjuvant Endocrine Therapy

Premenopausal HR+ Breast Cancer

• Ovarian function suppression or ablation (OFS) maybe

recommended in addition to tamoxifen

• OFS (GnRH) frequently started after chemotherapy is

completed, unless fertility preservation is desired

• The value of adding OFS for premenopausal women

who receive tamoxifen (either with or without prior

chemotherapy) was previously considered uncertain

Adjuvant Ovarian Suppression or Ablation

Effect on Breast Cancer Recurrence (no tamoxifen)

EBCTCG Lancet 2005

RANDOMIZE

Tamoxifen x 5y

OFS=ovarian function suppression(GnRH triptorelin, oophorectomy or irradiation)

3047 Patients Randomized in ITT, Dec 2003 - Jan 2011Median follow-up 5.6 years

SOFTPremenopausal ER+ and/or PR+ Breast Cancer

Exemestane+OFS x 5y

Tamoxifen+OFS x 5y

No Chemotherapy

Prior Chemotherapy

Premenopausal, within 12 weeks of surgery(Median time since surgery = 1.8 months )

Premenopausal* after completing chemotherapy; Randomization within 8 months of completion(Median time since surgery = 8.0 months )

(n=1018)

(n=1015)

Primary Analysis (n= 2033)

Two Patient Cohorts (stratified)

(n=1014)

*According to locally-determined E2 level in premenopausal range

(47%)

(53%)

SOFT

Suppression of Ovarian Function Trial

Primary Question:

Does adding ovarian function suppression (OFS)

improve outcomes in premenopausal women

treated with adjuvant tamoxifen?

SOFT DFS8 years median follow-up

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

Tamoxifen

vs ↑ 8 year DFS = 8.7%

Tamoxifen + OFS

vs

Exemestane + OFS ↑ 8 year DFS = 13.1%

SOFT: Disease-Free Survival (DFS)

Very young patients < 35 years

SOFT: Women < 35 years8-year Freedom from invasive breast cancer

SOFT: Women < 35 years

8-year Freedom from distant recurrence

SOFT: Conclusions

• Adding OFS to tamoxifen significantly improves DFS at 8 years median follow-up – HR=0.66 (8.7% absolute benefit) in DFS for women under age 35

– DFS outcomes further improved by use of exemestane plus OFS

• Small (significant) Overall Survival benefit is seen at 8 years– Evident in women with prior chemotherapy

– Consistent with time course of events in ER+ disease

• Population not receiving chemotherapy has a low risk of distant metastases at 8 years with tamoxifen alone

Francis et al, N Engl J Med 2018

SOFT – Young women

Now more likely to recommend ovarian suppression in

women < 35 with HR+ early breast cancer

In young women with chemo-induced amennorhea

if planning to use an AI (exemestane) don’t need to

wait for premenopausal E2 before starting GnRHa, as

cannot guarantee efficacy AI without OFS at young age

In young women, if side effects with exemestane + OFS are

not acceptable, there may still be value in tamoxifen+OFS

over tamoxifen alone.

St Gallen 2017 Early Breast Cancer

International Consensus Panel

• The Panel identified age < 35 and/or involvement of > 4 lymph nodes as factors arguing for inclusion of ovarian function suppression.

• Women with sufficient tumor risk so as to warrant chemotherapy may wish to consider ovarian suppression.

• The Panel believed ovarian suppression could be paired with either tamoxifen or an AI.

Annals Oncology 2017; 28:1700-1712

ASCO 2016 Clinical Practice Guideline Update

on Adjuvant Ovarian Suppression in HR+ve

Burstein et al, J Clin Oncol 2016

ASCO 2016 Guideline Update

Adjuvant Ovarian Suppression in HR+ve

• The Panel recommends that higher-risk patients should receive ovarian suppression in addition to adjuvant endocrine therapy.

• Ovarian suppression may be administered with either tamoxifen or an aromatase inhibitor.

• The Panel particularly encouraged clinicians to consider ovarian suppression in women younger than age 35 years.

Burstein et al, J Clin Oncol 2016

ESO-ESMO 3rd International Consensus Guidelines

for Breast Cancer in Young Women

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