Cancer du sein du Sujet AgéTraitements Systémiques

Dr Etienne Brain

Institut Curie

Saint-Cloud, France

1

www.siog.org

etienne.brain@curie.fr

• Most common shortcut in statistics

“1 in 8 women will develop BC in their lifetime”

instead of

“If everyone lived beyond the age of 70, 1 in 8 of those women

would get or have had BC”

• Since BC risk increases w/ age, lifetime risk changes depending on age

– Age 20-29 1 in 2,000

– Age 30-39 1 in 229

– Age 40-49 1 in 68

– Age 50-59 1 in 37

– Age 60-69 1 in 26

– Ever 1 in 8

2Worldwidebreastcancer.com

Agent Name Approval N Age ≥ 65 N Age ≥ 75

Palbociclib 2/201537 44% 8 10%

86 25% --

Everolimus 7/2012 290 40% 109 15%

Pertuzumab 6/2012 60 15% 5 1%

Eribulin mesylate 11/2010 121 15% 17 2%

Lapatinib 1/201034 17% 2 1%

282 44% 77 12%

Ixabepilone 10/200745 10% 3

Competing Causes for Mortality

4

Kendal Cancer 2008

Competing risks for mortality

5Derks The Oncologist 2019

Dutch & Belgian postmenopausal pts w/ EBC ER+ in the TEAM trial (2001-2006)

exemestane vs sequential tamoxifen exemestane 5 yr

3,159 pts (70%

Competing risks for mortality

6Derks The Oncologist 2019

≥70 yr & no comorbidity (33%)

higher BC mortality

22.2%, 95% CI, 17.5–26.9 vs 15.6%, 95% CI, 13.6–17.7

sHR 1.49, 95% CI, 1.12–1.97, p = .005

Phénotype

Plus de formes hormonosensibles (RH+)

Moins de formes agressives (triple négatif, HER2+++)

BC biology according to age

de Kruijf Mol Oncol 2014, Jenskins Oncologist 2014

Le cancer du sein de la femme âgée se

prête volontiers à l’hormonothérapie

car il est plus souvent RH+

Mais entre anti-aromatase (letrozole/FEMARA, anastrozole/ARIMIDEX,

exemestane/AROMASINE et anti-oestrogène (tamoxifène),

la question de l’observance est majeure (et donc l’ajustement à la tolérance)

En contexte adjuvant/précoce, l’hormonothérapie se donne 5 ans en général

(discussion sur les extensions au delà)

• TAM / 0

15105

60 %

50 %

40 %

30 %

20 %

10 %

rec

hu

te

26,5

38,3

45,0

24,7

15,1

33,2

contrôle

TAM 5A

• IA / TAM

Réduction du

risque de rechute

Bénéfice absolu à 10

ans

RO+ 41 % 13,6 %

Réduction du

risque de rechute

Bénéfice absolu à 10

ans

RO+

Post- MP20 % 5 %

AI 5A

Question centrale

Cancer du sein controlatéral

Ostéoporose

Myalgies

Troubles lipidiques

Tamoxifène Anti-aromatases

Cancer du sein controlatéral

Thromboses veineuses

Cancer de l’endomètre

Bouffées de chaleurCognition

Sexualité

Troubles lipidiques

Cœur et vaisseaux

Bouffées de chaleur

Thromboses veineuses

Cancer de l’endomètre

Troubles génito-urinaires

Arthralgies & myalgies

Ostéoporose

?

Endocrine therapy combinations

• With everolimus (BOLERO)

• With CDK4-6 inhibitors (PALOMA)

• Potential similar efficacy

• But safety profiles are different since trials

populations are highly selected

12

PFS +4.1-6.5 mths (x 2)

But! AEsFatigue, stomatitis, rash, anorexia, diarrhea

Hyperglycemia, non-infectious pneumonitis

20% dose adjustment

Phase III 2:1 > NSAI

13Baselga N Engl J Med 2012

724 patients 265 (40%) 65+ 164 (23%) 70+

70+ vs

• European phase IIIb

• Expanded-access multicenter trial

• 2133 patients, 26% 70+

• Key AEs: stomatitis, fatigue, anemia, NIP

16

1. CDK4/6 inhibitor + AI as 1st line treatment of HR+

MBC in older women similar efficacy benefit as

seen in younger women

2. Incidence and severity of Grade 1-4 AEs similar

between age groups, but greater SAEs and

discontinuations occurred in patients ≥75 (89%

vs 73%)

3. EQ-D5 decline in HRQoL regardless of treatment

4. Need for inclusion of greater numbers of patients ≥70

in clinical trials

17Howie JCO 2019

La chimiothérapie, c’est plus

compliqué…

Car index thérapeutique plus étroit que l’hormonothérapie

Des doses généralement ajustées (inférieures)

Mechanism Consequences

Absorption Gastric dumping and secretionsAbsorption of proteins,

vitamins and drugs

Metabolism

Hepatocytes, blood flow, CYP

P450 activity

Interactions (CYP P450)

Protein synthesis, (de-)

activation of drugs and

carcinogens

Distribution H2O, albumin, Hb Vd hydrosolubles drugs

Vd liposolubles drugs

ExcretionGFR, tubular filtration

Biliary excretion

Renal elimination of drugs

excreted by kidney

Biliary eliminationBalducci Oncologist 2000; Wildiers Clin Pharmacokinet 2003; http://www.ema.europa.eu

Physiological variations x PK & PD

19

Les grands médicaments• Anthracyclines (adriamycine, épirubicine, schémas FEC 100 ou AC)

– Myélotoxicité

– Cardiotoxicité

• Alkylants (cyclophosphamide/Endoxan®, schéma FEC 100 ou AC)

– Myélotoxicité

– Attention à la fonction rénale

• Taxanes (docetaxel/Taxotère®, paclitaxel/Taxol®)

– Myélotoxicité

– Neuropathie

– Onycholyse

– Rétention hydrique

• Antimétabolites (5-flurorouracile, forme orale = capecitabine/Xeloda®)

– Syndrome mains pieds

– Diarrhée

20

• Myelosuppression: greater in older patients

– Lower threshold (

1. Past medical history

Survivors! With long-term toxicity of previous cancer treatments• Cognitive impairment, cardiotoxicity, depression and anxiety, neurotoxicity, ototoxicity, imbalance & lack of

coordination, osteoporosis, metabolic syndrome, second malignancy, sexual and vaginal dysfunction

2. Problems and complications due to comedication/polypharmacy

29% take > 7 drugs, NSAID/MTX, pain medications & cachexia (falls, fractures)

3. Social and psychological aspects

Fear for pain and dependance, frailty and end of life aspects

22

But also other issues difficult to capture!

• CPA & renal function

• Capecitabine

– 750-1000 mg/m² x 2/d 2 wk/3

CMF

23

Chemotherapy Specific Doses!!!

Gelman J Clin Oncol 1984; Crivellari J Clin Oncol 2000; Bajetta J Clin Oncol 2005

0

0.2

0.4

Cumulative proportion with event

0.6

0.8

1.0 Hazard ratio (>65:5) = 2.2595% CI of (>65: 65) = (1.04–4.86)

Log rank p-value = 0.029

Wilcoxon p-value = 0.78

0 200 300 400 700 800 900 1000Cumulative dose of doxorubicin (mg/m2)

600500100

468172

345110

29692

10328

61

41

203

5912

431151

65*>65*

*Patients at risk65

>65

• 630 patients (3 phase III) with 32 CHF

26% >550 mg/m²

>50%: reduction of LVEF 400 mg/m²

24

Doxorubicine, CHF and Age

Swain Cancer 2003

• 2 cornerstones

– Paclitaxel 50% grade 3 RD: 26 mg/m²

– q2w 50 mg/m² GERICO-04

– Grade 3-4 neurosensory/motor toxicity 28%/14% (vs

26

DFS

OS

• CALGB (1975-1999)

• 4 randomized trials

• 6487 pts

> 65 yo 542 (8%)

> 70 yo 159 (2%)

• Results

– Benefit identical

– Toxicity careful!!

• Toxic deaths 1.5%

All

All

≤50

≤50

≥65

≥6551-64

51-64

Adjuvant chemo

Muss JAMA 2005

Giordano* ElkinNo. total 41,390

No. w/ chemo 4,500

No. total 5,081

No. w/ chemo 1,711

Nodal status ER HR (95% IC) HR (95% IC)

pN0 any 1.05 (0.85-1.31) NA

pN+ + 1.05 (0.85-1.31) NA

pN0 & pN+ - NA 0.85 (0.77-0.95)

pN+ - 0.72 (0.54-0.96) 0.76 (0.65-0.88)

pN+ > 70 yo - 0.74 (0.56-0.97) NA

Adjuvant chemo & mortality in 65+ stage I-III BC

Adjuvant chemo is useful FIRST

in ER-, pN0 or pN+, even > 70 yo

*: BC specific mortality

Giordano & Elkin J Clin Oncol 200627

ER-ER+

Muss JCO 201928

CALGB 49907

(AC or CMF vs X)

RFS 56% vs 50%(HR 0.80; P = .03)

BCSS 88% vs 82%(HR 0.62; P = .03)

OS 62% vs 56%(HR 0.84; P = .16)

ER+ (HR 0.89; P = .43)

ER- (HR 0.66; P = .02)

43.9% deaths(13.1% BC vs 16.4% others vs 14.1% ?)

Second non BC 14.1%

1. 58% grade ≥ 3 toxicity

2. Risk increased w/

increasing risk score

3. AUC/ROC 0.65 (95%CI

0.58-0.71) ~ development

cohort 0.72 (95%CI 0.68-

0.77) (P = .09)

4. No association between

PS and chemo toxicity (P

= .25)

A true predictive model for

chemo-related grade 3-5 toxicity

Hurria J Clin Oncol 201629

30Magnuson SABCS 2018

473 pts evaluable/501

- 283 development

- 190 validation

Median age 70 (65-85)

Stage I/II/III 39%/41%/20%

TNBC/ER+/HER2+ER+/HER2+ER- 24%/48%/10%/17%

Grade 3-5 AEs 46% (haematological 25%/non-haematological 36%)

CARG-BC

Copyright © American Society of Clinical Oncology

Jones, S. et al. J Clin Oncol; 27:1177-1183 2009

Fig 1. Disease-free survival (DFS) and overall survival (OS) (A) DFS by treatment; (B) DFS by treatment and age; (C) OS by treatment: 1 day; (D) OS by treatment and age

• 6,600 pts < 70– 02/2007-08/2011

– 112 institutions in 9 European countries

– 11,291 registered patients

– 6,673 enrolled (59.1%)

Primary goal

In patients w/ high-risk clinical & low-risk GEP and no chemotherapy, lower boundary of the 95% CI

for the rate of 5-yr survival w/o distant M+ ≥ 92% (i.e. the noninferiority boundary) at a 1-sided significance level of 0.025

Mammaprint

Risk of distant recurrence

@ 5 years

w/ no treatment

32

High recurrence score > 70 yo

33

• Higher likelihood of death

(HR 1.47, 95% CI 1.15-1.90)

• Chemo lower risk of death in younger but not in older group

Kizy JGO 2019

ASTER 70s (EUDRACT N° 2011-004744-22, PHRC national 2011, NCT01564056)Adjuvant chemotherapy for ER+ HER2- BC in 70+ patients

CGAMicroarray

qRT-PCR

screened

randomized

Chemo = 4 TC or 4 AC or4 MC

4-yr OS 34

• Specifically for 70+ EBC women

• Common question

• Non-exclusive inclusion criteria (40% G8 ≤14 & 20% previous

cancer w/ 50% local or controlateral relapse)

• Question of treatment escalation & de-escalation

• Observational arm for ineligible patients selection bias

• Education of both patients & physicians

• Taking/spending time to explain the relevance of a trial

• Collaboration w/ geriatrician

• QoL and acceptability

• Translational research (biobank)

ASTER 70s 10 key points

35

Adjuvant palbociclib as an alternative tochemotherapy for older patients withhigh risk luminal early breast cancer

EORTC–ETF-BCG Study 1745 (APPALACHES)

Hans Wildiers & Etienne Brain

36

70+, surgery for stage II-III EBC ER pos, HER2 neg

adjuvant chemotherapyrequired according totreating physician and

patient

Adjuvant chemo -> AI

AI + Palbo 2y

Adjuvant chemo choice:

- 4 TC + G-CSF

- 4 EC or AC + G-CSF

- 12 taxol weekly

Stratification for clinical frailty

(G8 >14 vs ≤ 14) and stage

Primary endpoint

3y DRFI (distant metastases or death

from breast cancer) for AI+Palbo arm

- 3-year DRFI of

Thérapies ciblées

• Pertuzumab: 840 mg loading dose 420 mg• Trastuzumab: 8 mg/kg loading dose 6 mg/kg• Docetaxel: 75 mg/m2 100 mg/m2 depending on tolerance• Primary objective: PFS• Secondary objectives: OS, ORR, tolerance• Stratification: geography, (neo)adjuvant treatment

MBC L1

HER2+

(central review)

N = 808

Pertuzumab + trastuzumab + docetaxel

(n = 402)

Placebo + trastuzumab + docetaxel

(n = 406)

R

1:1

Cleopatra double-blinded phase III trial

Baselga N Engl J Med 2012

Cle

op

atr

a

Swain ESMO 2014; Swain NEJM 2015

More frequent in elderly patients

• Any grade: diarrhea, asthenia,

fatigue, anorexia, vomiting and

dysgueusia

• Grade 3: diarrhea, peripheral

neuropathy

• Dose intensity: 12% dose

escalation , 31% dose

reduction, 20-30% G-CSF

CLEOPATRA

808 patients

127 (16%) 65+

19 (2%) 75+

Miles Breast Cancer Res Treat 201341

Pertuzumab

80 pts HER2+ MBC

≥ 70 Years

(≥65/≥60y with co-morbidity)

Pertuzumab

+

Trastuzumab

Pertuzumab + Trastuzumab +

metronomic CT

® 1:1 T-DM1

Primary endpoint

PFS at 6 months of PH or PHM

Pertuzumab 840 mg loading dose, further 420 mg q3w iv

Trastuzumab 8 mg/kg loading dose, further 6 mg/kg q3w iv

Chemotherapy Metronomic chemotherapy: cyclophosphamide 50 mg/d po continuously

On progression Option to have T-DM1 (3.6 mg/kg iv q3w) till progression

PD

Stratification: ER/PgR, previous HER2 treatment, G8Secondary endpoints

OS, BCSS, toxicity, RR (RECIST v1.1),

HRQoL, evolution of GA during treatment

EORTC 75111-10114(Co-PI Hans Wildiers & Etienne Brain)

43

Wildiers Lancet Oncol 2018

44

Wildiers Lancet Oncol 2018

Elderly/frail HER2+ MBC population

Metronomic chemo + TP

• 7-mth longer median PFS vs TP

• Acceptable safety profile

• T-DM1 at progression active

• Alternative to standard taxane + TP?

• SEER database

• 2,028 patients ≥ 66, stage I-III, 2005-2009, trastuzumab

– 71.2% < 76

– 66.8% w/o comorbidities (Charlson)

– 85.2% w/ chemotherapy

– 81.7% w/ complete trastuzumab treatment (> 9 months)

– Factors correlated w/ incomplete treatment• Age 80+ vs 66-70 OR 0.40 (0.30-0.55)

• Comorbidities 2 vs 0 OR 0.65 (0.49-0.88)

Vaz-Luiz. J Clin Oncol 2014

- 2 gr 3 LVSD (0.5%) (95% CI, 0.1%-1.8%)

- 13 significant asymptomatic LVEF decline

(3.2%) (95% CI, 1.9%-5.4%)

Tolaney NEJM 2015

RESPECT (N-SAS BC07)

Accrual of 274 patients from 2009 to 2014

Non-inferiority

HR 1.22-1.69 β 20%

Median FU ~ 3.52 years

(175 patients as parallel cohort)

Sawaki ASCO 201847

RESPECT (N-SAS BC07)

Sawaki ASCO 2018

• 73.5 yo (70-80) 2009-2014

• Small number of events

• @ 3-yr chemo vs no chemo‒ DFS 94.8% (n=131, 12 events) vs 89.2% (n=135, 18 events)

(HR=1.42; 95% CI, 0.68 to 2.95, P=0.35)

‒ RFS 95.6% (9 events, 4 deaths) vs 91.7% (13 events, 5

deaths)

‒ Difference in RMST -0.45 months (95% CI, -1.71 to 0.80)

• RMST: omitting chemo 3-yr survival loss < 1 mth

• Chemo more grade 3-4 AEs (29.8% vs 11.9%,

P=0.0003) & HRQoL deterioration

T monotherapy might be an option as an adjuvant therapy

for elderly HER2+ BC patients

48

IBCSG 55-17 TOUCH

IBCSG 55-17 TOUCH | Investigator meeting 27 September 2019

Phase II open-label, multicenter, randomized trial of neoadjuvant palbociclib in combination

with hormonal therapy and HER2 blockade versus paclitaxel in combination with HER2

blockade for elderly patients with hormone receptor positive/HER2 positive early breast

cancer

Early BC, ER+, HER2+,≥65 years,Neo-adj. treatment planned

R

A: paclitaxel

trastuzumab

pertuzumab

B: palbociclib

letrozole

trastuzumab

pertuzumab

surgery

surgery

Week 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

+

+

staging

FFPE sample FFPE sample

Pertuzumab: loading dose

• Generally feasible to administer

• Benefit is variable

• Toxicity often (slightly) increased; but often lower than

chemotherapy toxicity

• Beware of a high-selection bias

Most data only in “fit” elderly!

• Balance efficacy vs toxicity (+ cost) in every individual

• Challenging choice of right partner (endocrine therapy)

and multi-blockade (e.g. EORTC 75111 trial)51

Targeted Therapy for MBC in Elderly

Tumour

extentTNM

Patient

preference

& acceptability

Tumour

biologyLuminal A/B

HER2 & TNBC

Gene expression profile

General

health

statusGeriatric assessment

Life expectancy

Treatment toxicity

52

Biganzoli Lancet Oncol 2012; Cancer Treat rev 2016; Brain J Ger Oncol 2019

53

General recommendations for adjuvant

chemo & trastuzumab in older BC patients

• Focus on ER- and HER2+ (if > 5 mm)

• Regimen

– Validated 4 AC, 6 CMF

– Options 4 TC; paclitaxel qw x 12?; liposomal doxorubicin?

– No! capecitabine, docetaxel qw

– No data! Sequential regimen

• Primary prophylaxis of febrile neutropenia w/ G-CSF

• No restriction on trastuzumab if chemo indicated

– 4 TC + trastuzumab

– Paclitaxel qw x 12 + trastuzumab (Tolaney)

– TCH x 6?? (but very unlikely in older patients since carboplatin AUC 6!)

– Trastuzumab alone: can be considered, especially for unfit patients (+ ET if ER+)

– Shorter duration for trastuzumab (6 months?)

Cheung, Livi, Brain in Geriatric Oncology/Elsevier, Editors Extermann, Fulop, Dale, Klepin & Brain 2019

Brain J Ger Oncol 201954

HER2+ metastatic breast cancer

55

FIRST LINE

1) DTX q3w + G-CSF or PTX qw w/ TZT + PTZ is 1st line SOC in fit older patients

only

1B

2) In frail older patients, metronomic CPA, VNR or capecitabine w/ TZT + PTZ can

be considered

2C

3) TZT monotherapy, or dual anti-HER2 combinations (TZT + PTZ, lapatinib +

TZT) w/o chemo should be reserved for frail older patients at high risk of side

effects and used in combination with endocrine therapy for ER+ tumours

2C

SECOND LINE

1) T-DM1 is recommended for ≥ 2nd line in fit older patients, w/ further

investigations warranted in frail patients

2C

FURTHER LINES, OTHERS

1) Lapatinib side effects are increased in older patients making early and close

monitoring crucial

1B

Brain J Ger Oncol 2019

HER2+ early-stage breast cancer

56Brain J Ger Oncol 2019

REGIMEN

1) Only very fit older patients can receive classical adjuvant sequential chemo (anthracylines

taxanes) + G-CSF + TZT 1 year

2B

2) TZT can be combined with the TC regimen, which is the best documented regimen in older

patients, but G-CSF is required to avoid febrile neutropenia

2A

3) In frail older patients and/or those with low-risk tumours, qw PTX is the preferred regimen to

combine with TZT

2C

4) TZT w/o chemo or w/ endocrine therapy (if ER+) can be considered, especially for unfit patients 2C

5) TZT + PTZ combined with sequential anthracycline- and taxane-based chemo, or extended anti-

HER2 treatment after TZT with neratinib, can only be considered in very fit and high-risk

patients, being aware of the higher risk of side effects

2C

DURATION

1) Standard duration of TZT is 1 year, but the threshold for shorter duration can be low in cases of

side effects, increased cardiovascular risk, or lower risk tumours

2B

NEOADJUVANT STRATEGY

1) Neoadjuvant therapy can help in the individualizing of treatment (before or after surgery), from

which older patients should derive great benefit

2C

• Young patient

– Social and family obligations (children)

– Quantity of life +++

• Elderly patient

– QoL+++

– Independence

– Staying at home

• Oncology

– Therapies and innovation

– Toxicity, response, survival

• RECIST

• NCI CTC v4.0

• Survival (DFS, PFS, DDFS, OS)

• Translational research

– Fast-moving world

– "Molecular portrait" of tumour & GEP

• Geriatrics

– Symptoms, diagnosis

– Quality of survival, i.e. amount of

life with good QoL

• Cognition

• Functional status

• Nutrition, etc.

– Requiring time

– "Global portrait" of patient & GA

GAversus

or+?

Genomicdefects

targetedtherapy

GAdefects

targetedgeriatric

intervention

2 worlds confronting one another?

57

FEC, AACR, FAC, ASCO, anti-PDL1, anti-PD1, CMF, SABCS, PD-1, PDL1, DXR, PK/PD, CEX, 5FU CDDP, CalvertAUC, ESMO, Chatelut AUC, CTC, TILs,

population PK, EORTC, FOLFIRI, ctDNA, FOLFOX 7, CPA, DFS, CALGB, DDFS, OS, TTP, NCI, CYP P450, JCO, JNCI, HER2, PI3K, mTOR, Phase 0,

ECCO, ib and ab, Unicancer, EORTC, SWOG, CALGB, etc.

Charlson, CIRSG, CGA, AD, MCI, MNA, GDS, MMS, ADL,

IADL, GFI, CMR2, JAGS, EUGMS, G8, CARG,

Oncodage, VES-13, TRFs, JGO, NIA, SoFOG, Walter’sscore, Lee’s score, CRASH,

etc.

58

FEC, FAC, SoFOG, ADL, IADL, CMF, SABCS, DXR, PK/PD, CEX, G8, EORTC, 5FU CDDP, MCI, Calvert and ChatelutAUC, CARG, GDS, population PK, AD, FOLFIRI, MMS, FOLFOX, CPA, CRASH,

SWOG, DFS, OS, TTP, NCI, GERICO, TILs, CARG, anti-PDL1, anti-PD1, EORTC TFE, JCO, JNCI, Charlson, JGO, CIRSG, PD-1, PDL-1, ctDNA, EGS, EGA, MNA, GFI,

Unicancer, Lee’s score, JAGS, etc.

To be practice changing,let us be practice sharing!

59

"Geriatric Oncology: the Past, Present and Future"

Optimising treatment in older cancer patients

is precision medicine too!

60