cancer du sein du sujet agé traitements systémiques · cancer du sein du sujet agé traitements...
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Cancer du sein du Sujet AgéTraitements Systémiques
Dr Etienne Brain
Institut Curie
Saint-Cloud, France
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www.siog.org
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• 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
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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
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Competing Causes for Mortality
4
Kendal Cancer 2008
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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%
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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
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Phénotype
Plus de formes hormonosensibles (RH+)
Moins de formes agressives (triple négatif, HER2+++)
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BC biology according to age
de Kruijf Mol Oncol 2014, Jenskins Oncologist 2014
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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)
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• 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
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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
?
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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
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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
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724 patients 265 (40%) 65+ 164 (23%) 70+
70+ vs
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• European phase IIIb
• Expanded-access multicenter trial
• 2133 patients, 26% 70+
• Key AEs: stomatitis, fatigue, anemia, NIP
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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
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La chimiothérapie, c’est plus
compliqué…
Car index thérapeutique plus étroit que l’hormonothérapie
Des doses généralement ajustées (inférieures)
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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
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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
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• Myelosuppression: greater in older patients
– Lower threshold (
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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
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But also other issues difficult to capture!
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• CPA & renal function
• Capecitabine
– 750-1000 mg/m² x 2/d 2 wk/3
CMF
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Chemotherapy Specific Doses!!!
Gelman J Clin Oncol 1984; Crivellari J Clin Oncol 2000; Bajetta J Clin Oncol 2005
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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
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Doxorubicine, CHF and Age
Swain Cancer 2003
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• 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
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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
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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
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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%
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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
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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
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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
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• 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
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High recurrence score > 70 yo
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• 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
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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
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• 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
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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
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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
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Thérapies ciblées
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• 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
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Cle
op
atr
a
Swain ESMO 2014; Swain NEJM 2015
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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
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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)
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Wildiers Lancet Oncol 2018
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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?
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• 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
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- 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
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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
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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
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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
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• 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
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Tumour
extentTNM
Patient
preference
& acceptability
Tumour
biologyLuminal A/B
HER2 & TNBC
Gene expression profile
General
health
statusGeriatric assessment
Life expectancy
Treatment toxicity
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Biganzoli Lancet Oncol 2012; Cancer Treat rev 2016; Brain J Ger Oncol 2019
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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
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HER2+ metastatic breast cancer
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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
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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
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• 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?
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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
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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!
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"Geriatric Oncology: the Past, Present and Future"
Optimising treatment in older cancer patients
is precision medicine too!
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