Cancer du Sein

du Sujet Agé

Docteur Etienne Brain

Hôpital René Huguenin / Institut Curie

Saint-Cloud, France

etienne.brain@curie.fr

Binder-Foucard INCa report 2013

• 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

Worldwidebreastcancer.com

Current dilemna and extreme positions

1. Therapeutic nihilism – Elderly patients do not receive any treatment

2. The intermediate position? – Elderly patients may benefit from treatments

3. Blind therapeutic enthusiasm – Elderly patients receive futile/non beneficial

treatments

Place and role of geriatrician and oncologist Pelike from Attica 480–470 BC

Musée du Louvre

Breast cancer mortality

Other cause mortality

• Univariate HR 1.66

(95% CI 1.34-2.06), p<0.001

• Multivariable HR 1.63

(95% CI 1.23-2.16), p<0.001

Ca

use

sp

ecific

de

ath

Substudy from TEAM trial (adjuvant exemestane)

Age <65y Age ±75y Age 65 – 74y

Schonberg JCO 2010, Van de Water JAMA 2012

Under & overtreatment

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

Dépistage

Pas d’indication d’extension du dépistage de masse > 74A (stades plus précoces dépistés mais aucun bénéfice démontré sur survie)

Mais dépistage individuel à poursuivre selon état de santé

Aucune étude conduite spécifiquement sur cette population

Breast-cancer screening > 70?

9

Warner NEJM 2011; Royce JAMA 2014; Gross JAMA 2014

Age

(yr)

Nb of trial(s) Relative risk

of death (95%CI)

60-69 Malmö &

Ostergöland

0.68 (0.54-0.87)

70-79 Ostergöland 1.12 (0.73- 1.72)

75+: YES YOU CAN, but

– No mass screening

– Depends on life expectancy

Radiothérapie

Hughes J Clin Oncol 2013

After BCS: TAM vs XRT + TAM (CALGB 9343)

334/636 deaths

(21 i.e 6.3% due to BC)

Radiotherapy

• Omission if pT1 ER+? (NCCN)

– According to life expectancy

– > 80 yo, multi-morbidities, good compliance to endocrine treatment?

• Low risk patients

– Once-per-week fraction schedule (Whelan regimen)

– Accelerated partial breast irradiation (APBI)

• Larger radiation doses given to the localized tumour bed (instead of to the

entire breast)

Spare extensive and burdensome transportations

But don’t neglect the psychological burden of recurrence!

Khan Semin Radiat Oncol 2012

Les traitements

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)

En contexte métastatique, l’hormonothérapie est le traitement

généralement de première intention (phénotype RH+ fréquent)

• TAM / 0

15 10 5

60 %

50 %

40 %

30 %

20 %

10 %

rech

ute

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-

MP

20 % 5 %

AI 5A

COMPLIANCE

is the issue!!!

TAM AI

Neurocognition

Sexuality

Hot flushes

Thrombosis & embolism

Uterus cancer

Gynecological tractus

Vaginal discharge

Cataract

Arthralgias & myalgias

Osteoporosis

Fractures

Dryness

Cardiovascular

Lipid profile

?

Hormonothérapie

Mais attention aux combinaisons nouvelles

(+ everolimus/CDK4/6 inhibiteurs)

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

Baselga. N Engl J Med 2012

Pritchard. Clin Breast Cancer 2013

70+ vs <70

Similar efficacy & incidences of AEs

More on-treatment deaths

But

Prior chemo x 2 if <70

• European phase IIIb

• Expanded-access multicenter trial

• 2133 patients, 26% 70+

• Key AEs: stomatitis, fatigue, anemia, NIP

Jerusalem. Ann Oncol 2016

<70 70+

AE-related treatment discontinuations (%) 13 24

Median duration of exposure (months) 5 4

Dose reduction/interruption (%) 27/54 38/61

Stomatitis any grade/3-4 (%) 52/8 56/12

Asthenia any grade/grade 3-4 (%) 21/3 29/6

Decreased appetite (%) 14 22

Hyperglycemia grade 3-4 (%) 2 5

NIP (%) 9 11

20

This exploratory analysis suggests the use of a CDK4/6 inhibitor in

combination with an aromatase inhibitor for the first line treatment

of HR+ MBC in older women results in similar efficacy benefit as

seen in younger women. Although incidence and severity of Grade

1-4 adverse reactions appeared similar between age groups,

greater serious adverse events and discontinuations occurred

in patients ≥65. The inclusion of greater numbers of patients ≥70,

in clinical trials will further inform clinicians about the safety and

efficacy of CDK4/6 inhibitors in older adults.

A U.S. food and drug administration pooled analysis of outcomes of older

women with hormone-receptor positive metastatic breast cancer treated

with a CDK4/6 inhibitor as initial endocrine based therapy

Singh H, Howie LJ, Bloomquist E, Wedam S, Amiri-Kordestani L, Tang S,

Sridhara R, Ibrahim A, Goldberg K, McKee A, Beaver JA, Pazdur R US Food

and Drug Administration, Silver Spring, MD

La chimiothérapie, c’est plus

compliqué…

Car index thérapeutique plus étroit que l’hormonothérapie

Des doses généralement ajustées (inférieures)

Physiological variations x PK & PD

Mechanis

m Consequences

Absorptio

n

Gastric dumping and

secretions

Absorption of proteins,

vitamins and drugs

Metabolis

m

Hepatocytes, blood flow,

CYP P450 activity

Interactions (CYP P450)

Protein synthesis, (de-)

activation of drugs and

carcinogens

Distributio

n H2O, albumin, Hb

Vd hydrosolubles drugs

Vd liposolubles drugs

Excretion GFR, tubular filtration

Biliary excretion

Renal elimination of drugs

excreted by kidney

Biliary elimination

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

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

23

• Myelosuppression: greater in older patients

– Lower threshold (<20%) for primary prophylaxis of febrile neutropenia w/ G-CSF

• Cardiomyopathy: more common in older patients

– Certainly if underlying cardiac disease

• Mucositis, delayed nausea and vomiting

• Peripheral or central neurotoxicity

– Debilitating and interfering w/ functionality and independence

– !Concomitant problems that affect mobility and function (e.g. arthritis)

• Renal function: declines with age! ~ 1 mL/min/year

– Creatinineserum = insufficient! Cockcroft-Gault CLcreatinine = better but not as

accurate as in younger patients MDRD/CDK-EPI = best in elderly?

Benefit/risk balance of chemotherapy is narrower

than other treatments, especially in elderly

• CPA & renal function

• Capecitabine

– 750-1000 mg/m² x 2/d 2 wk/3

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

CMF

Chemotherapy Specific doses!!!

0

0.2

0.4

Cumulative proportion with event

0.6

0.8

1.0 Hazard ratio (>65:£65) = 2.25

95% 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 1000

Cumulative dose of doxorubicin (mg/m2)

600 500 100

468 172

345 110

296 92

103 28

6 1

4 1

20 3

59 12

431 151

£65* >65*

*Patients at risk

£65

>65

• 630 patients (3 phase III) with 32 CHF

26% >550 mg/m²

>50%: reduction of LVEF <30% w/ chemo

Doxorubicine, CHF and age

• HRage

2.25 (1.04–4.86) vs 3.28 (1.4–7.65)

if >400 mg/m²

Swain. Cancer 2003

• 2 cornerstones

– Paclitaxel <80 mg/m²qw

– Docetaxel q3w but not standard @ 100 mg/m²! • Same pharmacokinetics, but increased risk of neutropenia ± febrile if 65+

– q3w 75 mg/m² grade 3-4 ANC/FN: 63%/16% vs 30%/0%

– qw 35 mg/m² > 50% grade 3 RD: 26 mg/m²

– q2w 50 mg/m² GERICO-04

– Grade 3-4 neurosensory/motor toxicity 28%/14% (vs <18%/<8% if <65)

• Nab-paclitaxel – Efficacy comparable with solvent-based taxanes

– No need for steroid premedication

Taxanes

Del Mastro. Ann Oncol 2005;

ten Tije. J Clin Oncol 2005; Girre. Ann Oncol 2008; Biganzoli. Cancer Treat Rev 2016

La chimiothérapie adjuvante

« marche » si on est attentif aux

effets secondaires…

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%

Adjuvant chemo for breast cancer All

All

≤50

≤50

≥65

≥65 51-64

51-64

Muss JAMA 2005

La chimiothérapie adjuvante

« marche » surtout si RH-

Giordano* Elkin

No. total

No. w/CT

I-III, ER , 65+

41,390

4,500

I-III, ER-, 66+

5,081

1,711

pN ER HR (95% IC) HR (95% IC)

pN0 1.05 (0.85-1.31) NA

pN+ + 1.05 (0.85-1.31) NA

both - 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)

Adjuvant chemotherapy and mortality

Adjuvant chemo is useful FIRST

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

*: BC specific mortality

Giordano & Elkin J Clin Oncol 2006

All

ER-

ER+

DFS OS CALGB/CTSU 49907

(AC or CMF vs X)

Muss NEJM 2009

Eviter les anthracyclines ?

liposomes

taxanes

GERICO 06 (EUDRACT N° 2005-000069-20, PHRC national 2005)

MC MC MC MC XRT

ADL

Tolerance CGA

ADL + MNA +

MMS + GDS +

CIRSG

QLQ-C30

Willingness

CGA ADL + MNA +

MMS + GDS +

CIRSG

QLQ-C30

Willingness

Tolerance

CGA ADL + MNA +

MMS + GDS +

CIRSG

QLQ-C30

Willingness

Tolerance

1 & 2 year

DFS & OS

ADL

Tolerance

ADL

Tolerance

± trastuzumab

if HER2+++

trastuzumab

if HER2+

q3w q3w q3w

4 cycles of “AC-like” chemo In MC, M stands for liposomal non pegylated doxorubicin

1. Febrile neutropenia 15%

2. Risk of denutrition 15% vs 38%

3. Impact on QoL (social & role functioning)

4. Cardiac tolerance of trastuzumab

5. No palmar plantar erythrodysesthesia

6. DFS3A 85%

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

General recommendations for adjuvant

chemo in elderly

• Focus on ER-

• Regimen

– Validated 4 AC, 6 CMF

– Option 4 TC

paclitaxel qw x 12?

Liposomal doxorubicin?

– Capecitabine no

– Docetaxel qw no

– Sequential regimen no data

• Primary prophylaxis of febrile neutropenia w/ G-CSF

Chimiothérapie adjuvante

Il faut essayer de mieux faire pour les

RH+ en sélectionnant les vrais hauts

risques signatures génomiques ?

Protocol ASTER 70s

GERICO 11 / PACS10

Adjuvant systemic treatment for oestrogen-receptor (ER)-positive HER2-negative breast carcinoma in women over 70

according to Genomic Grade (GG): chemotherapy + endocrine treatment versus endocrine treatment. A French UNICANCER

Geriatric Oncology Group (GERICO) and Breast Group (UCBG) multicentre phase III trial

Microarray

qRT-PCR CGA

EUDRACT N° 2011-004744-22, PHRC national 2011, NCT01564056

R** 1:1

All patients Lee Score

G8, CCI

Polymedications

Genomic Grade

(GG)

evaluation

CCI

Polymedications Events

Group II

Low GG

NO CHEMOTHERAPY IS RECOMMENDED - Follow up

Cy1 + GCSF

Cy2 + GCSF

Cy3 + GCSF

Cy4 + GCSF

q3w q3w q3w

HT 5 yr

Group I**

High GG

Arm B = CT + HT

Arm A = HT HT 5 yr XRT

XRT

baseline 16 weeks 1, 2, 3 & 4 year

1, 2, 3 & 4 year

MMSE, IADL

QLQ C30 & ELD15

LVEF

Socioeconomic

Standard Lab

1 blood + serum

Polymedications

MMSE, IADL

QLQ C30 & ELD15

LVEF

Socioeconomic

Willingness

Standard Lab

1 blood + serum

G8, CCI

Polymedications

MMSE, IADL

QLQ C30 & ELD15

LVEF

Socioeconomic

Willingness

Standard Lab every year

1 blood + serum (M12 & M48)

Events

Chemo tolerance

Standard Lab

Complete

curative

surgery

Sc

ree

nin

g

** Group I include both high and equivocal GG cases

*Randomization stratified on pN, G8 and centre

time

GERICO 11 (EUDRACT N° 2011-004744-22, PHRC national 2011, NCT01564056)

2,000

1,100

900

Hypothesis B > A +7.5% (A 80% vs B 87.5%) HR 0.60 5% 10%

Targeted treatments

Lack of specific data!

But clinical evidence for benefit

The incidence of CHF from the Finnish Herceptin Study (FINHER), Herceptin Adjuvant trial (HERA), Breast

Cancer International Collaborative Group trial 006 (006) with TCH and AC-TH analyzed separately, the North Central Cancer Treatment Group trial 9831 (N9831), and NSABP B-31 (B-31).

Bird B R H , Swain S M Clin Cancer Res 2008;14:14-24

©2008 by American Association for Cancer Research

• NSABP B31

– Age

– 2% < 50 yo vs 5.4% > 60 yo

– LVEF > 4 AC

– 12% if LVEF < 55%

– Concomitant > sequential

– Hypertension comedications

• B31/N9831

– 6.7% pts who had completed AC had a lower LVEF or

developed cardiac symptoms preventing the initiation of

TZT

– 1/3 pts who started TZT discontinued it: 4.7% with

symptomatic CHF, 14.2% with confirmed asymptomatic

decline in LVEF, and the rest for noncardiac reasons

• 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

General recommendations for adjuvant

chemo & tratsuzumab in elderly

• Focus on ER-

• Regimen

– Validated 4 AC, 6 CMF

– Option 4 TC

paclitaxel qw x 12?

Liposomal doxorubicin?

– Capecitabine no

– Docetaxel qw no

– Sequential regimen no data

• Primary prophylaxis of febrile neutropenia w/ G-CSF

• No restriction on trastuzumab if chemo indicated

– 4 TC + trastuzumab

– Paclitaxel qw x 12 + trastuzumab

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

Traitements ciblés

Et en métastatique ?

Miles Breast Cancer Res Treat 2013

Pertuzumab

Verma N Engl J Med 2013

Dieras J Clin Oncol 2014

Barrios ASCO 2015

T-DM1

Kamilla 194 pts 65-69, 78 pts 70-74, 120 pts 75+

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, G8 Secondary endpoints

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

evolution of GA during treatment

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

50

TPM showed 7 months longer median PFS than TP alone in an elderly/frail HER2+ MBC population,

with an acceptable safety profile

TPM T-DM1 at progression may delay or supersede taxane chemotherapy in this population.

The benefit of avoiding chemotherapy side-effects with the use of dual anti-HER2 blockade only,

does not compensate for a significant loss of activity in the metastatic setting

Antitumor activity seems to remain much higher when a gentle chemotherapy like oral

cyclophosphamide is added to TP

Biganzoli, Lancet Oncol 2012

Definition of “old” x ageing heterogeneity

Age

Top 25th%

Fit

50th%

Intermediate

Lowest 25th%

Sick

50 40 33 24.5

70 21.3 15.7 9.5

75 17 11.9 6.8

80 13 8.6 4.6

85 9.6 5.9 2.9

90 6.8 3.9 1.8

95 4.8 2.7 1.1

Women life expectancy

Walter JAMA 2001

Kendal Cancer 2008

Competing causes for mortality

Comprehensive Geriatric

Assessment Assessment Instrument Administration Prognosis

Dependency,

functional

status

PS, Activity of Daily Living (ADL),

Instrumental ADL Self administered +

Comorbidity

Charlson Comorbidity Index (CCI),

Cumulative Illness rating Scale-

Geriatric (CIRS-G)

Self- or interviewer-

administered or

chart-based

+

Economic /

social support Life conditions, relatives, care-givers ?

Cognition Folstein Mini-mental State

Examination (MMSE)

Interviewer-

administered

+

functional status

Depression Geriatric Depression Scale (GDS) Self administered +

Polypharmacy List ?

Nutrition Mini Nutritional Assessment (MNA),

BMI

Interviewer-

administered +

Geriatric

syndromes Dementia, delirium, falls

+

functional status

Mobility/falls Timed-up-and-go-test, Tinetti Performance-tests ?

≥ 75 yo 1st visit

New cancer or relapse

G8

Physician

± nurse

≤ 14/17 > 14/17

Primary focus on*: systemic treatment?

Decision 1

YES NO

Standard health cares vigilance and geriatrician

sought according to needs

GA

* But not exclusively

Adjusted health cares ± MDTB 2 and decision 2

Geriatric interventions

1. Streamlining geriatrician time

2. Involvement of oncologists

3. Impact

- Decisions 1 and 2

- Geriatric interventions

- Day hospital in geriatric oncology

MDTB 1 + geriatrician

Adapted recommendations for patient’s referral for GA at Institut Curie

MDTB: multi disciplinary tumor board

1. Social environment: Q1 “do you live alone?” + Q2 “do you have a person or caregiver able to provide care and support?”

2. Autonomy: Activities of Daily Living (ADL) (abnormal if <6/6) and 4-Instrumental ADL (IADL) (abnormal if <4/4)

3. Mobility: Time Get Up and Go test (TGUG) (abnormal if >20 sec)

4. Nutrition: unintentional weight loss (>10% in 6 months) and BMI (< 21)

5. Cognitive status: Mini-Cog (abnormal if <4/5)

6. Mood: Mini-Geriatric Depression Scale (Mini-GDS) (abnormal if ≥ 1/4)

7. Comorbidities: updated Charlson index score

National & International validation

Geriatric COre DatasEt (G-CODE) (Delphi/RAND + Consensus Methods)

DIALOG = GERICO + UCOG = intergroup of clinical research in GO labeled by INCa in 2014 & 2017

Paillaud. Eur J Cancer 2017 Volume 72, Supplement 1, Page S114

• 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)

– 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

• QoL

• Nutrition, etc.

– Requiring time

– "Global portrait" of patient & CGA

CGA versus

or + ?

Two worlds confronting one another?

Genomic defect

targeted therapy

CGA defect

targeted geriatric

intervention

FEC, AACR, FAC, ASCO, anti-PDL1, anti-PD1, CMF, SABCS, PD-1, PDL1, DXR, PK/PD, CEX, 5FU CDDP, Calvert AUC, 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’s score,

Lee’s score, CRASH, etc.

FEC, FAC, SoFOG, ADL, IADL, CMF, SABCS, DXR, PK/PD, CEX, G8, EORTC, 5FU CDDP, MCI, Calvert and Chatelut AUC, 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!