MULTIDISCIPLINARY MANAGEMENT OF MULTIDISCIPLINARY MANAGEMENT OF METASTATIC DISEASEMETASTATIC DISEASE

SYSTEMIC THERAPYSYSTEMIC THERAPY

F. Cardoso, MDF. Cardoso, MDJules Bordet Institute, Brussels, BelgiumJules Bordet Institute, Brussels, Belgium

BELGIAN BREAST MEETING 2008

October 4-5, 2008

Breast Cancer

Despite ↑ incidence - ↓ mortality

* Screening & early diagnosis

* Education & advocacy

but also

* Better treatment options

* Better treatment strategies

BUT

The evolution as been quite different between adjuvant and metastatic settings

WHY?

Different diseases?

Different biology?

Different aims

Different attitude of physicians?

Advances in EARLY BC are measured in YEARS (DECADES)

Cohort by year of dxTotal n=2152

1991-92

(1)

1994-55

(2)

1997-98

(3)

1999-01

(4)

Median

survival days

438 450 564 667

p value Cohort 1+2 vs 3 (0.002) Cohort 3 vs 4 (0.04)

Chia et al ASCO 2003 Population Based Study in British Columbia

Advances in METASTATIC BC are measured in DAYS – MONTHS(max: few years; median survival MBC= 2-3 yrs)

Are MBC guidelines needed? definitely YES

RISK OF RECURRENCE REMAINS PRESENT THROUGHOUT ALL PATIENTS’ LIFETIME

Saphner T et al. J Clin Oncol 1996; 14: 2738–2746.

Recurrence rate/year (%)

0 1 2 3 4 5 6 7 8 9 10

0

2

4

6

8

10

12

14

16

Time (years)

Node-negative

Node-positive

Are MBC guidelines needed? definitely YES

EBCC-ESO METASTATIC BREAST CANCER GUIDELINES

First step: 12 Recommendations Statements Published: The Breast 16, 9–10, 2007

1st Session: EBCC-4 (Nice, March 2006):

“Are MBC guidelines possible?” - YES

Preparatory work: Task Force created; meetings; some decisions:

1. MBC guidelines cannot be rigid 2. Should be built on principles and not on specific treatment

regimens3. Need to be in line with latest research findings (biology…)

The management of MBC is complex; therefore involvement of all appropriate specialities in a multi/interdisciplinary team (medical, radiation, surgical and imaging oncologists, palliative care, psycho-social, among others) is crucial.

1ST STATEMENT

12 RECOMMENDATIONS STATEMENTS

2nd STATEMENT

From first diagnosis of MBC, patients should be offered personalised appropriate psychosocial, supportive and symptom-related interventions as a routine part of their care.

MAIN ISSUES IN MBC MANAGEMENTMAIN ISSUES IN MBC MANAGEMENT

• Confirmation of diagnosis Confirmation of diagnosis

• Definition of main goal of treatmentDefinition of main goal of treatment

• Available therapiesAvailable therapies

• Factors determining the choice of treatmentFactors determining the choice of treatment

• Special subgroups (Endocrine-responsive, HER-2+, Special subgroups (Endocrine-responsive, HER-2+, basal-like)basal-like)

• New agentsNew agents

• Individualizing treatmentIndividualizing treatment

PATIENT PREFERENCES

Psychosocial, supportive and

palliative interventions

2nd STATEMENT

3rd STATEMENT

HER-2 seems to be quite consistent between P and M sites:In our series, only 6% discordance by IHC & 7% by FISH (most discordant cases showed greater HER-2 overexpression in M)

However: Conflicting results exist &Interlaboratory variability for both IHC and FISH is a big problem

For all other markers, including Hormonal receptors, the consistency levels are lower

CONFIRMATION OF DIAGNOSIS CONFIRMATION OF DIAGNOSIS

WHENEVER POSSIBLE A BIOPSY OF THE METASTATIC LESION SHOULD BE PERFORMED

DEFINITION OF MAIN GOALS OF TREATMENTDEFINITION OF MAIN GOALS OF TREATMENT

CRUCIAL: Identify the small but very important subset of MBC patients can achieve complete

remission and a long survival – ISOLATED MET

FOR ALL OTHERS

MBC is incurableThe main treatment goal is PALLIATION, transform it

into a chronic diseaseIncrease survival, if possible

Maintain/improve QoLSymptom control

Test new agents/approaches before adjuvant setting

3rd & 4th STATEMENTS

ANY STEM CELL CAN SEED MORE

• Primary cancer must be controlled

• Metastatic foci must be controlled

HOWEVER

We must continue to strive to do better … and keep cure a goal for the future…

Adapted from W Wood, EBCC-6, 2008

• There are few proven standards of care in MBC management

• Well-designed, independent, prospective randomised trials are a priority

• Every proposed option must have a sound scientific rationale, preferably evidence-based

MAIN MESSAGES

AVAILABLE SYSTEMIC THERAPIESAVAILABLE SYSTEMIC THERAPIES

10th STATEMENT

FACTORS to consider in TREATMENT SELECTION

• DISEASE FREE INTERVALDISEASE FREE INTERVAL• PREVIOUS THERAPIES & PREVIOUS THERAPIES &

RESPONSERESPONSE• BIOLOGICAL FACTORS (HR, BIOLOGICAL FACTORS (HR,

HER-2)HER-2)• TUMOR BURDEN (number & TUMOR BURDEN (number &

site of mets)site of mets)• NEED FOR RAPID NEED FOR RAPID

DISEASE/SYMPTOM CONTROLDISEASE/SYMPTOM CONTROL

• BIOLOGICAL AGEBIOLOGICAL AGE• MENOPAUSAL STATUSMENOPAUSAL STATUS• CO-MORBIDITIESCO-MORBIDITIES• P.S.P.S.• SOCIO-ECONOMIC & SOCIO-ECONOMIC &

PSYCHOLOGICAL FACTORSPSYCHOLOGICAL FACTORS• PATIENT’S PREFERENCESPATIENT’S PREFERENCES

From the disease

From the patient

6th STATEMENT

AVAILABLE SYSTEMIC THERAPIESAVAILABLE SYSTEMIC THERAPIES

ADVANCED BREAST CANCERADVANCED BREAST CANCER

Available therapiesAvailable therapies

• ENDOCRINE vs. CHEMOTHERAPY

• COMBINATION vs. SEQUENTIAL SINGLE AGENTS

• WHICH DRUGS? WHICH SCHEDULES?

• MAINTENANCE THERAPY

• WHEN TO STOP

MAIN QUESTIONS / CONTROVERSIES

Endocrine therapy is the preferred option for hormonal receptor positive disease, unless there is concern or proof of endocrine resistance.

The optimal first-line hormonal treatment for postmenopausal patients is an aromatase inhibitor; however tamoxifen remains a viable option.

For pre-menopausal women, tamoxifen combined with ovarian suppression/ablation is the first choice except for tamoxifen resistant tumours.

Optimal post-aromatase inhibitor treatment is uncertain. Maintenance hormonal treatment after chemotherapy is not established but is reasonable.

Concomitant chemo + endocrine therapy should be discouraged.

12 RECOMMENDATIONS7th STATEMENT

LOW RISK GROUPLOW RISK GROUPHR-positiveHR-positive

ENDOCRINE THERAPYENDOCRINE THERAPY+/-+/-

BIOLOGICAL AGENT BIOLOGICAL AGENT

ADVANCED BREAST CANCERADVANCED BREAST CANCER

Available therapiesAvailable therapies

HER-2 negativeHER-2 negative HER-2 positiveHER-2 positiveNo threatening diseaseNo threatening disease

ENDOCRINE THERAPYENDOCRINE THERAPY+/-+/-

HERCEPTIN HERCEPTIN (Tandem trial; others ongoing)(Tandem trial; others ongoing)

ENDOCRINE TREATMENT STRATEGIES IN ADVANCED ENDOCRINE TREATMENT STRATEGIES IN ADVANCED BREAST CANCERBREAST CANCER

19701970 19801980 19901990 20002000

TamoxifenTamoxifen TamoxifenTamoxifen

Megestrol acetateMegestrol acetateAminoglute-Aminoglute-thimidethimide

33rdrd generation AI generation AI

Exemestane/Exemestane/Megestrol acetateMegestrol acetate

33rdrd generation AI generation AI

Faslodex® or SermFaslodex® or Sermor non cross- or non cross- resistant AIresistant AI

Megestrol acetateMegestrol acetate

II

IIII

II

IIII

IIIIII

II

IIII

IIIIII

« Level-1 » evidence-based « Level-1 » evidence-based

EstrogensEstrogensEstrogensEstrogens EstrogensEstrogens

AIAI

Post AIPost AI Much uncertainty persists ! Much uncertainty persists ! Adapted from M. Piccart

Prior AI therapyPrior AI therapy

Fulvestrant LD* + 250 mg / month

+ placebo for exemestane

(n=330)

Fulvestrant LD* + 250 mg / month

+ placebo for exemestane

(n=330)

Exemestane 25 mg po od

+ placebo for

fulvestrant (n=330)

Exemestane 25 mg po od

+ placebo for

fulvestrant (n=330)

*LD, loading dose (500*LD, loading dose (500 mg dmg day ay 1 + 250 mg day 14)1 + 250 mg day 14)

ENDPOINTSENDPOINTS• primaryprimary TTPTTP• secondarysecondary OR rateOR rate duration of duration of

responseresponse CB rateCB rate survivalsurvival quality of lifequality of life

pharmacokineticspharmacokinetics safetysafety

ELIGIBILITYELIGIBILITY• histological histological

confirmationconfirmation• postmenopausal postmenopausal

statusstatus• progression progression

following AIfollowing AI• ER+ and / or PgR+ER+ and / or PgR+• measurable diseasemeasurable disease• performance statusperformance status

0–20–2

ROLE OF FASLODEXROLE OF FASLODEX

ROLE OF FASLODEXROLE OF FASLODEX

EFECT TRIALEFECT TRIAL

TTP (ITT): Kaplan-Meier PlotP

rop

ort

ion

Pat

ien

ts P

rog

ress

ion

-Fre

e

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24 27

3.73.7Median (months)

HR = 0.963, 95% CI(0.819, 1.133), p = 0.6531

Cox analysis, p = 0.7021

ExemestaneFulvestrant

FulvestrantExemestane

MonthsAt Risk:Fulvestrant 351 195 96 50 25 12 4 2 Exemestane 342 190 98 41 21 12 8 6

Pro

po

rtio

n P

atie

nts

Res

po

nd

ing

MonthsAt Risk:Fulvestrant 20 20 16 11 8 3 0 0 Exemestane 18 18 15 10 5 4 3 3

FulvestrantExemestane

9.813.5Median (months)

ExemestaneFulvestrant

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

0 3 6 9 12 15 18 21 24 27

DURATION OF RESPONSE (from randomisation)

p21rasp21ras

Raf

Nucleus

Mek

ERERERER

Histone acetylation

ER-dependent growth

ERERERER

p38 MAPKp38 MAPK

AIB1AIB1 CBPCBP

Membrane

c-jun c-fos

MAPK

PP

P

P

CROSS-TALK BETWEEN THE ER CROSS-TALK BETWEEN THE ER AND THE GF PATHWAYS AND THE GF PATHWAYS

HER2 EGFr

EREREREREE22

ERERERERTamTam

PI3KPTENPTEN

Cell proliferation

AkTAkT

BADBAD FKHRFKHRGSK-3GSK-3 mTORmTOR

SURVIVALSURVIVAL

Cell proliferation

FasLFasL

N-CORN-COR

Failure of mTOR inhibition to improve the activity of Failure of mTOR inhibition to improve the activity of lezotrole in advanced breast cancer lezotrole in advanced breast cancer

Results of a phase III trial in 992 patientsResults of a phase III trial in 992 patients

SABCS 06, abst. 6091

Median PFS (mo) (95% ci)

CR + PR (%)

Stable disease (≥ 24 weeks)

Clinical benefit (%)

PD as best response (%)

Temsirolimus + lezotroleN = 493

Lezotrole + placeboN = 499

9.2 (7.2 – 11.1) 9.2 (7.4 – 11.1)

24 24

16

40

14

19

43

18

HOW TO IMPROVE TREATMENT OF LUMINAL BC???

LOW RISK GROUPLOW RISK GROUPHR-positiveHR-positive

ENDOCRINE THERAPYENDOCRINE THERAPY+/-+/-

BIOLOGICAL AGENT BIOLOGICAL AGENT

ADVANCED BREAST CANCERADVANCED BREAST CANCER

Available therapiesAvailable therapies

HER-2 negativeHER-2 negative HER-2 positiveHER-2 positiveNo threatening diseaseNo threatening disease

ENDOCRINE THERAPYENDOCRINE THERAPY+/-+/-

HERCEPTIN HERCEPTIN (Tandem trial; others ongoing)(Tandem trial; others ongoing)

TANDEM STUDY: Randomized trial of ANASTROZOLE TANDEM STUDY: Randomized trial of ANASTROZOLE ± ± TRASTUZUMAB in advanced HER2+, HR+ breast cancerTRASTUZUMAB in advanced HER2+, HR+ breast cancer

N=207Median age 55 yearsVisceral disease 1/3

Prior chemo 1/2

Anastrozole

Cross-over 70%

6,8% Response rate 20,3%2,4m Median P.F.S. 4,8m p 0.0016

23,9m Median O.S. 28,5m

32,1m Median O.S. 41,9mif no liver mets p 0.03

Mackey et al., SABC 06, abst. 03

Anastrozole+

Trastuzumab

Trastuzumab added to anastrozole RR, PFS (and possibly OS if no liver mets) IMPORTANCE OF STARTING BIOLOGICAL AGENT SOONAdapted from M. Piccart

ADVANCED BREAST CANCERADVANCED BREAST CANCER

Available therapiesAvailable therapies

• ENDOCRINE vs. CHEMOTHERAPY• WHICH DRUGS? WHICH SCHEDULES?• COMBINATION vs. SEQUENTIAL SINGLE AGENTS• MAINTENANCE THERAPY• WHEN TO STOP

MAIN QUESTIONS

12 RECOMMENDATIONS

The choice between sequential use of single cytotoxic drugs and combination chemotherapy should be taken after consideration of the factors mentioned in paragraph 6, with greatest emphasis on the need for a rapid and significant response and quality of life.

For the majority of patients, overall survival outcomes from sequential use of single cytotoxic drugs are equivalent to combination chemotherapy.

Duration of each regimen and number of regimens should be tailored to each individual patient.

9th STATEMENT

Docetaxel vs. Docetaxel vs. Docetaxel + CapecitabineDocetaxel + Capecitabine

PHASE III TRIAL DOCETAXEL VS DOCETAXEL + CAPECITABINE IN MBC PTS FAILING ANTHRACYCLINES

O’Shaughnessy J et al. J Clin Oncol 2002;20:2812–23

DocetaxelCapecitabine +

docetaxel

n 256 255

L1/L2 (%) 31/53 35/48

Anthracyclines (%) 100 100

ORR (%) 30 42

TTP (months) 4.2 6.1

OS (months) 11.5 14.5

Phase III Registration Trial Planned Interim Analysis

Endpoint GT T p-value

Ind ORR 45.5% 25.5% <0.00005(95% C.I.) (38.5, 52.4) (19.2, 31.8)

Median TTP 5.2 2.9 <0.0001(95% C.I.) (4.2, 8.6) (2.6, 3.7)

Median OS, mos 18.5 15.8(95% C.I.) (16.5, 21.2) (14.4, 17.4)

Paclitaxel vs. Paclitaxel vs. Paclitaxel + GemcitabinePaclitaxel + Gemcitabine

COMBINATION vs. SEQUENTIAL SINGLE AGENTSCOMBINATION vs. SEQUENTIAL SINGLE AGENTS

NO OR MINIMAL CROSSOVER

BUTSubsequent Chemotherapy

PG vs. PDocetaxel 10.5% 10.3%Gemcitabine 3.8% 14.1%

T vs. TCCapecitabine 17 % Docetaxel 20 %

BENEFIT OF COMBINATION IS ONLY LEVEL-2 EVIDENCE-BASEDBENEFIT OF COMBINATION IS ONLY LEVEL-2 EVIDENCE-BASED

• Discuss with patients; new treatment option…• Consider combination in « high risk » fit patients

PACLITAXEL VERSUS DOXORUBICIN VERSUS BOTHPACLITAXEL VERSUS DOXORUBICIN VERSUS BOTHCROSSOVER PART OF TRIAL DESIGNCROSSOVER PART OF TRIAL DESIGN

AA TT ATAT

3434

6.26.2

1414

20.120.1

3333

5.95.9

20 20

22.222.2

4646

8.08.0

--

22.422.4

p valuep value

SS

SS

SS

NSNS

RR%-1st lineRR%-1st line

MEDIAN TTF, mosMEDIAN TTF, mos

MEDIAN OS, mosMEDIAN OS, mos

RR% - 2nd lineRR% - 2nd line

QOLQOL Different toxicities, similar tolerabilityDifferent toxicities, similar tolerability

Sledge, ASCO ‘ 97Sledge, ASCO ‘ 97

739 MBC pts

>Toxicity>Impact on daily life

No or very small gain in survivalUses up “all weapons” faster

COMBINATIONCOMBINATION

>RRFaster symptom/disease control

SEQUENTIAL SINGLE AGENTSSEQUENTIAL SINGLE AGENTS

<ToxicitySimilar survival

Better overall QoLBetter management of resources

<RRSlower symptom/disease control

ESO-EBCC MBC RECOMMENDATIONS

Sequential use of single cytotoxic drugs should be the preferred choice except if:

rapidly progressing diseaselife threatening visceral metastasesneed for rapid disease/symptom control

9th STATEMENT –

2008 Proposal

Define the subgroup of pts who need first line combination because we will not be able to rescue the; with 2nd or 3rd line CT

ADVANCED BREAST CANCERADVANCED BREAST CANCER

MAIN ISSUESMAIN ISSUES

• Confirmation of diagnosis Confirmation of diagnosis

• Definition of main goal of treatmentDefinition of main goal of treatment

• Available therapiesAvailable therapies

• Factors determining the choice of treatmentFactors determining the choice of treatment

• SPECIAL SUBGROUPSSPECIAL SUBGROUPS (Endocrine-responsive, (Endocrine-responsive, HER-2+,HER-2+, basal-like) basal-like)

• New agentsNew agents

• Individualizing treatmentIndividualizing treatment

PATIENT PREFERENCES

Psychosocial, supportive and

palliative interventions

12 RECOMMENDATIONS8th STATEMENT

Trastuzumab should be offered EARLY to ALL HER-2-positive MBC patients, after failure of endocrine therapy if this is appropriate.

Trastuzumab in combination with endocrine therapy is under evaluation in clinical trials and can not yet be considered as standard.

Currently, the optimal management of patients progressing on trastuzumab is uncertain and active research is ongoing in this area.

PIVOTAL PHASE III TRASTUZUMAB COMBINATION TRIAL PIVOTAL PHASE III TRASTUZUMAB COMBINATION TRIAL OVERALL SURVIVAL IN HER2 3+ PATIENTSOVERALL SURVIVAL IN HER2 3+ PATIENTS

Smith IE. Anticancer Drugs 2001;12:S3–10

1.0

0.8

0.6

0.4

0.2

00 5 10 15 20 25 30 35 4045 50

18 25

Time (months)

Prob

abili

ty o

f sur

viva

l

40%

H + P

P

Longer OS: 25.1 vs. 20.3 ms Longer OS: 25.1 vs. 20.3 ms (p=0.046)(p=0.046)

Longer TTPLonger TTP: 7.4 vs. 4.6 ms (p: 7.4 vs. 4.6 ms (p0.001)0.001)

Higher RRHigher RR: 50 vs. 32% (p: 50 vs. 32% (p0.001)0.001)

Longer durationLonger duration: 9.1 vs. 6.1 ms (p: 9.1 vs. 6.1 ms (p0.001)0.001)

H + CT KEY MESSAGES

OPTIMAL USE OF OPTIMAL USE OF TRASTUZUMABTRASTUZUMABIMPORTANCE OF EARLY ADMINISTRATIONIMPORTANCE OF EARLY ADMINISTRATION

1.0

0.8

0.6

0.4

0.2

0

Estim

ated

pro

babi

lity

0 3 6 9 12 15 18 21 24 27 30Months

15.3 27.721.9

Herceptin® + docetaxel (n=92)Docetaxel alone/crossover (n=41) Docetaxel alone (n=53)

M77001 trial: estimated M77001 trial: estimated survivalsurvival

OPTIMAL DURATION OF TRASTUZUMAB TREATMENTOPTIMAL DURATION OF TRASTUZUMAB TREATMENT

– Response rate (48.0 vs. 27.0%; p=0.01)– Clinical benefit rate (75.3 vs 54%; p=0.007)– Time to progression (8.2 vs 5.6 mos; p=0.03)– Overall survival (25.5 vs 20.4 mos; non sign. trend)– No increase in toxicity

Study Design of GBG 26

X: X: Capecitabine 2500 mg/m² d 1 – 14 q 22

R

XH: Capecitabine 2500 mg/m² d 1 – 14 q 22

and continuation of Trastuzumab 6 mg/kg q22

156 pts (from 482 pts needed) recruited between 01/04

- 05/07 ; Recruitment stopped after FDA registration of

lapatinib on advice of IDMC

RESULTS OF THE BIG-GBG TBP

&

Bulk of retrospective data

PUTTING INTO PERSPECTIVE

• Adds to the bulk of existing retrospective data (eg Hermine study)

• The only randomised trial that reached reasonable accrual…

• No safety issues

BUT… LANDSCAPE IS CHANGING: New anti-HER2 drugs

• When to continue trastuzumab with another CT regimen vs. changing to another anti-HER-2 therapy (i.e. Lapatinib)?

• Which are the pts that benefit from continuing trastuzumab vs. shifting to another anti-HER-2 drug vs. shifting to a combination strategy

• MAIN MESSAGE: the HER-2 pathway should continue to be blocked in HER-2 + pts even after progression (for how long?)

THE FUTURE THE FUTURE • NEW AGENTS

• “NEW-OLD AGENTS” (i.e. Capecitabine, liposomal anthracyclines, new taxanes…)

• NEW BIOLOGICAL AGENTS (i.e. Lapatinib, Sunitinib, Bevacizumab…)

• COMBINATION OF “STANDARD” + BIOLOGICAL AGENTS

• COMBINATION OF BIOLOGICAL AGENTS

• BIOMARKERS (Treatment tailoring)

MBC – SYSTEMIC THERAPIESMBC – SYSTEMIC THERAPIES

ADVANCED BREAST CANCER TREATMENTADVANCED BREAST CANCER TREATMENTStill an art…but with GUIDENCEStill an art…but with GUIDENCE

STANDARDS STANDARDS OF CAREOF CARE

TREATMENT TREATMENT TAILORING TAILORING

(BIOLOGICAL (BIOLOGICAL MARKERS)MARKERS)

PATIENT’SPATIENT’SPREFERENCESPREFERENCES

MULTI-DISCIPLINARY TEAM (medical, radiation, surgical and imaging oncologists, palliative

care, psycho-social)

Appropriate PSYCHOSOCIAL, SUPPORTIVE and PALLIATIVE

interventions essential part of routine care

QUALITY OF LIFE ASSESSMENTS

PREVIOUS PREVIOUS THERAPIES, THERAPIES,

OTHER OTHER FACTORSFACTORS

NEW AGENTSNEW AGENTS

RATIONAL USE RATIONAL USE OF AVAILABLE OF AVAILABLE

AGENTS & AGENTS & RESOURCESRESOURCES

KNOWING WHEN KNOWING WHEN TO STOP!!TO STOP!!

CLINICAL CLINICAL TRIALSTRIALS

It matters not how long we live, but how.

“Festus”, Philip James Bailey

BACK-UP

TREATMENT OF WOMEN WITH ADVANCED BREAST CANCERTREATMENT OF WOMEN WITH ADVANCED BREAST CANCERTAKE-HOME MESSAGES - 1TAKE-HOME MESSAGES - 1

• Management of MBC is Management of MBC is complexcomplex; ; multi-disciplinary teammulti-disciplinary team essential essential

• From diagnosis, offer pts appropriate psychosocial, supportive From diagnosis, offer pts appropriate psychosocial, supportive and palliative interventions as a routine part of their careand palliative interventions as a routine part of their care

• PatientsPatients should be invited & encouraged to actively should be invited & encouraged to actively participateparticipate in in all decision-makingall decision-making

• Few Standards of care; ENTER PTS IN WELL-DESIGNED TRIALSFew Standards of care; ENTER PTS IN WELL-DESIGNED TRIALS

• Main therapy goal: PALLIATION (except Main therapy goal: PALLIATION (except small subsetsmall subset who can who can achieve achieve CR & long survivalCR & long survival; treat aggressively); treat aggressively)

• Treatment choiceTreatment choice must take into account several pt- & disease- must take into account several pt- & disease-associated associated factorsfactors (i.e. DFI, previous Rx, ps, HER, HER-2, etc…) (i.e. DFI, previous Rx, ps, HER, HER-2, etc…)

• Hormonal therapyHormonal therapy is the preferred option for HR + MBC, unless is the preferred option for HR + MBC, unless there is concern or prove of endocrine resistance there is concern or prove of endocrine resistance

• Maintenance hormonal treatmentMaintenance hormonal treatment after CT is not established but is after CT is not established but is reasonablereasonable

• HER-2 positive MBCHER-2 positive MBC is a separate disease and should be treated is a separate disease and should be treated accordingly; probably the same for accordingly; probably the same for basal-like BCbasal-like BC

• For the majority of patients, OS outcomes from sequential use of For the majority of patients, OS outcomes from sequential use of single agents are equivalent to combination CTsingle agents are equivalent to combination CT

NEED: New agents but also rational use of available agents (TREATMENT TAILORING – Biological markers)

TREATMENT OF WOMEN WITH ADVANCED BREAST CANCERTREATMENT OF WOMEN WITH ADVANCED BREAST CANCERTAKE-HOME MESSAGES - 2TAKE-HOME MESSAGES - 2

CONFIRMATION OF DIAGNOSIS CONFIRMATION OF DIAGNOSIS

• Is the metastatic lesion representative of the primary tumor?

• Does the biology of the cancer changes during the metastasis process?

• Are HR, HER-2 & other markers concordant between primary and metastatic sites?

SHOULD A BIOPSY OF THE METASTATIC LESION BE MANDATORY?

RISK EVALUATION IN MBCRISK EVALUATION IN MBC

YesYes Hormone receptorsHormone receptors NoNo

> 2 years> 2 years Disease-free intervalDisease-free interval < 2 years< 2 years

limitedlimited No. of metastasesNo. of metastases extensiveextensive

soft tissue, bonesoft tissue, bone Sites of metastasesSites of metastases visceraviscera

NoNo Vital organ involvementVital organ involvement YesYes

RISK EVALUATIONRISK EVALUATION

LOWLOW MODERATE, HIGHMODERATE, HIGH