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Cancer du Sein
du Sujet Agé
Docteur Etienne Brain
Hôpital René Huguenin / Institut Curie
Saint-Cloud, France
• 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+++)
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
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
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
?
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
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
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
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%
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!)
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
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
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!