St. Gallen 2007St. Gallen 2007

Consensusmeeting Consensusmeeting

P. BertelootP. Berteloot

First select the target : better First select the target : better choice of adjuvant treatments for choice of adjuvant treatments for

breast cancer patientsbreast cancer patientsSt Gallen 2005St Gallen 2005

1 Target = endocrine sensivity1 Target = endocrine sensivity

(low – intermediate -high)(low – intermediate -high)

2 defining the riskgroups2 defining the riskgroups

(low – intermediate- high)(low – intermediate- high)

Break-throughs since 2005Break-throughs since 2005

Herceptin!Herceptin!

Confirmation A.I.Confirmation A.I.

Lower threshold for TaxanesLower threshold for Taxanes

Present ProblemsPresent Problems

Past trials : large but not selectivePast trials : large but not selective

General conclusionsGeneral conclusions

Possibly not suitable for all subgroupsPossibly not suitable for all subgroups

Not pre-planned subgroup analysis are Not pre-planned subgroup analysis are statistically not reliablestatistically not reliable

Need forNeed for Inclusion criteria for future trials should Inclusion criteria for future trials should

be selective for important targetsbe selective for important targets Individualised therapy should be based on Individualised therapy should be based on

reliable and selective tumor informationreliable and selective tumor information Pitfalls of diagnostic proceduresPitfalls of diagnostic procedures

DCIS ~ micro-invasionDCIS ~ micro-invasion Passive transportation of malignant cells -> Passive transportation of malignant cells ->

axillaaxilla Error rate in HR assessementError rate in HR assessement

Depending on different kitsDepending on different kits FixationFixation

Eroor rate in HEREroor rate in HER22 status status Viale G.Viale G.

Importance of local control by Importance of local control by surgery and Radiotherapysurgery and Radiotherapy

Improved local control at 5 years of Improved local control at 5 years of follow-upfollow-up

Proportional survival benefit at 15 Proportional survival benefit at 15 years of follow-up years of follow-up

Ratio 4:1Ratio 4:1

Important highlights of St Important highlights of St Gallen 2007Gallen 2007

MRI staging in breastcancerMRI staging in breastcancer Ipsilateral Ipsilateral : 15-20 %: 15-20 %

Contralateral Contralateral : 3-5 %: 3-5 %

Independent of :Independent of : AgeAge PathologyPathology Mammographic densityMammographic density

C. Kuhl NEJMC. Kuhl NEJM

Breast surgery in advanced Breast surgery in advanced breast cancerbreast cancer

Regained importance due to :Regained importance due to :

Better and longer control of distant diseaseBetter and longer control of distant disease

Ability of detecting small metastatic fociAbility of detecting small metastatic foci

Large retrospective reviews of patients Large retrospective reviews of patients treated by surgical resection of the treated by surgical resection of the

primary tumor to clear borders have primary tumor to clear borders have demonstrated longer survivaldemonstrated longer survival

Predictive factors for Predictive factors for chemosensitivitychemosensitivity

TOPO IITOPO II Sensitivity for anthracyclinesSensitivity for anthracyclines Gene level Gene level ~~ protein level protein level

if proliferation index ( KI67) is elevatedif proliferation index ( KI67) is elevated TaxanesTaxanes

Tau-proteinTau-protein HERHER22 pos ? pos ? P-53 mutationsP-53 mutations

Predictive factors for Predictive factors for chemosensitivitychemosensitivity

AlkylantiaAlkylantia

PlatinumPlatinum

ER positiveER positive

< 35 years< 35 years

HERHER22 signaling signaling

worse prognosisworse prognosis

DNA Damaging Agents in BRCA1 patientsDNA Damaging Agents in BRCA1 patients

Association HERAssociation HER22 – ER- – ER-pospos

Chances of finding HERChances of finding HER22 positivity positivity associated with ER-positivity is associated with ER-positivity is higher in young than in older womenhigher in young than in older women

HerceptinHerceptin

Update Hera-trialUpdate Hera-trial 2 years of follow-up2 years of follow-up 1 year of Herceptin1 year of Herceptin

DFS : 6,3 % DFS : 6,3 % OS : 2,7 % OS : 2,7 %

Compairable gain for all subgroups Compairable gain for all subgroups

2 important questions2 important questions Sequencing ?Sequencing ? Duration of therapy ?Duration of therapy ?

absolute gainabsolute gain

Consensus issues Consensus issues concerning Herceptinconcerning Herceptin

Chemo in HerChemo in Her22 positive patients positive patients

Dependent on receptor statusDependent on receptor status : 60 % yes: 60 % yes

Anthracyclines to allAnthracyclines to all : 73 % : 73 % yesyes

Taxanes to allTaxanes to all : 43 % yes: 43 % yes

6 to 8 cycles6 to 8 cycles : 63 % yes: 63 % yes

Chemotherapy schedules in Chemotherapy schedules in HERHER22 + +

CAF CAF ~ CEF~ CEF : 62 % yes: 62 % yes

AC-TAC-T : 32 % yes: 32 % yes

FECFEC : 32 % yes: 32 % yes

TACTAC : 30 % yes: 30 % yes

FEC-TAXFEC-TAX : 32 % yes: 32 % yes

TAX + carboTAX + carbo : 51 % yes: 51 % yes

The opinions are very devidedThe opinions are very devided

Sequencing Herceptin-Sequencing Herceptin-ChemotherapyChemotherapy

Sequential Sequential : 38 %: 38 %

ConcommittantConcommittant : 40 %: 40 %

No preferenceNo preference : 22 %: 22 %

Duration of Herceptin Duration of Herceptin administrationadministration

Shorter in elderlyShorter in elderly : 51 % yes: 51 % yes Shorter for node negShorter for node neg : 38 % yes: 38 % yes Is duration riskdependentIs duration riskdependent : 40 % yes: 40 % yes Importance of early onsetImportance of early onset : 60 % yes: 60 % yes 12 months12 months : 91 % yes: 91 % yes 9 weeks + Docetaxel9 weeks + Docetaxel : 14 % yes: 14 % yes 2 years2 years : ?: ?

Herceptin indicationsHerceptin indications IHC +++IHC +++ : 92 %: 92 %

FISH requestedFISH requested : 15 % yes: 15 % yes

T<1 cmT<1 cm

Node negNode neg : 56 % yes: 56 % yes

Receptor negReceptor neg

Tx node negTx node neg : 58 % yes: 58 % yes

Receptor posReceptor pos

independent of node and receptorstatusindependent of node and receptorstatus

Safety of HerceptinSafety of Herceptin

Avoid low LVEF (Avoid low LVEF ( 50-55) 50-55) : 74 % : 74 % yesyes

> 70 years> 70 years : 30 % yes: 30 % yes

Preventive use of ace inhibitorsPreventive use of ace inhibitors: 7 % yes : 7 % yes

Hormonal therapyHormonal therapy

Postmenopausal consensus topicsPostmenopausal consensus topics

Tam aloneTam alone Node negNode neg : 50 %: 50 % Node posNode pos : /: / High ER-PRHigh ER-PR : 54 %: 54 % HERHER22 neg neg : 52 %: 52 %

Hormonal therapyHormonal therapy

Postmenopausal consensus topicsPostmenopausal consensus topics

AI upfrontAI upfront In all patientsIn all patients : 19 % yes: 19 % yes High riskHigh risk : 65 % yes: 65 % yes HERHER22 pos pos : 66 % yes: 66 % yes

HERHER22 neg neg : 33 % yes: 33 % yes

Hormonal therapyHormonal therapy

Postmenopausal consensus topicsPostmenopausal consensus topics

If started with TAMIf started with TAMSwitch Switch

allall : 50 % yes: 50 % yes

After 2 to 3 yearsAfter 2 to 3 years : 89 % yes: 89 % yes

After 5 yearsAfter 5 years : 60 % yes: 60 % yes

Only for TAM-intoleranceOnly for TAM-intolerance : 65 % : 65 % yesyes

PreferencePreference

1.1. AI upfrontAI upfront : 31 %: 31 %

2.2. TAM TAM AI AI : 63 %: 63 %

3.3. TAM x 5 TAM x 5 : 5,7 : 5,7 %%

After 5 years of TAM After 5 years of TAM AIAI

AllAll : 84 % yes: 84 % yes

Node posNode pos : 92 % yes: 92 % yes

HERHER22 neg neg : 40 % yes: 40 % yes

HERHER22 pos pos : 74 % yes: 74 % yes

Total duration of hormonal Total duration of hormonal therapytherapy

5 years5 years : 58 %: 58 %

5 to 10 years5 to 10 years : 75 %: 75 %

> 10 years > 10 years : ?: ?

Life-time for high-risk patientsLife-time for high-risk patients :37 %:37 %

Evaluation ovarian function Evaluation ovarian function at the start of AIat the start of AI

By onsetBy onset : 55 % yes: 55 % yes

After 6 to 12 weeksAfter 6 to 12 weeks : 48 % yes: 48 % yes

Supportive care + AISupportive care + AI

Ca + Vit DCa + Vit D : 61 % yes: 61 % yes

Bifosfanates for allBifosfanates for all : 3 %: 3 %

Fysical exerciseFysical exercise : 100 %: 100 %

BMCBMC : 88 %: 88 %

Pre-menopausal : Pre-menopausal : consensus topicsconsensus topics

TAM alone is an optionTAM alone is an option : 92 % yes: 92 % yes

OFS + TAM is an optionOFS + TAM is an option : 83 % yes: 83 % yes

OFS aloneOFS alone For everyoneFor everyone : 7 % yes: 7 % yes

For low riskFor low risk : 32 % yes: 32 % yes

Modality of ovarian Modality of ovarian suppressionsuppression

LHRH analogueLHRH analogue : 100 %: 100 %

SurgerySurgery : 76 %: 76 %

RadiotherapyRadiotherapy : 19 %: 19 %

Depending on age andDepending on age and : 75 % : 75 % histological subtype histological subtype

Duration of ovarian Duration of ovarian suppressionsuppression

2 years for all2 years for all : 29 %: 29 % 2 years node negative 2 years node negative : 43 %: 43 % node positivenode positive 5 years node positive 5 years node positive : 66 %: 66 %

HERHER22 positive positive 5 years for all5 years for all : 25 %: 25 % IndividualisationIndividualisation : 79 %: 79 %

Chemo + OFSChemo + OFS

ConcurrentlyConcurrently : 30 %: 30 %

SequentiallySequentially : 82 %: 82 %

Concurrently to preserve Concurrently to preserve : 65 % : 65 %

fertilityfertility

OFS + AIOFS + AI

AllAll : 6 %: 6 %

Contra-indication for TamContra-indication for Tam : 68 %: 68 %

TrialsTrials : 54 %: 54 %

AI : timing AI : timing attempt to conclusionsattempt to conclusions

Upfront : patients with high risk for early Upfront : patients with high risk for early relapserelapse

High tumorload : High tumorload : T2 ; T2 ; N2 N2

Biological agressivenessBiological agressiveness gr IIIgr III HERHER22 pos pos vascular invasionvascular invasion Negative hormone receptor statusNegative hormone receptor status

Mauriac, Ann OncolMauriac, Ann Oncol

AI : timingAI : timing

Switch after 2-3 years : intermediate Switch after 2-3 years : intermediate riskrisk

Adjuvant hormonal therapy ≥ 5 yearsAdjuvant hormonal therapy ≥ 5 years

Relapse curve receptor positive patientsRelapse curve receptor positive patients

Increased benefit ~ duration extended Increased benefit ~ duration extended adjuvant therapyadjuvant therapy

Saphner et al. J Clin Oncol. 1996;14:2738.

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0.2

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Years

ER– (n=1305)

ER+ (n=2257)

Long-Term Risk of Breast Long-Term Risk of Breast Cancer Recurrence Cancer Recurrence

Remains High in ER+ Remains High in ER+ PatientsPatients

Annual Risk of Annual Risk of Recurrence by Nodal Recurrence by Nodal

StatusStatus

The risk of late recurrence remains substantial even The risk of late recurrence remains substantial even in patientsin patientswith node-negative tumorswith node-negative tumors

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0 1 2 3 4 5 6 7 8 9 10 11 12

Saphner et al. J Clin Oncol. 1996;14:2738.

Years

Benefit of TAM +/- OSBenefit of TAM +/- OS

No clear evidence found !No clear evidence found !N. DavidsonN. Davidson

No large prospective randomised trials No large prospective randomised trials availableavailable Actual SOFT trial and TEXT trialActual SOFT trial and TEXT trial

Meta-analysis by Jack CuzickMeta-analysis by Jack Cuzick Limited benefit likelyLimited benefit likely Age dependent ?Age dependent ?

ChemotherapyChemotherapy

Hormone sensitivityHormone sensitivity

indicateindicate : the additional gain of chemotherapy

eg postmenopausal patients : hormone receptor positive 3 % and hormone receptor negative 8%

Preference of schedule No consensus at all Tendency to be more aggressive in HR neg en HER2 pos

patients

HERHER22 Status Status

Incorporation of taxanesIncorporation of taxanes

Only trials in node pos patientsOnly trials in node pos patients3 – 7 % gain3 – 7 % gain

Level 1 evidence ?Level 1 evidence ? Only PACS 01 has an optimal control armOnly PACS 01 has an optimal control arm PACS 01: imbalance of ER status and PACS 01: imbalance of ER status and

unexplained age differenceunexplained age difference Dependent on:Dependent on:

Hormone receptor statusHormone receptor status HERHER22 positivity ? positivity ?

Conclusion St. Gallen Conclusion St. Gallen 20072007

No consensus yetNo consensus yet

We don’t expect large changes in We don’t expect large changes in our home strategyour home strategy

Guidelines: UZ leuven Guidelines: UZ leuven Adjuvant therapyAdjuvant therapy??