METASTATIC DISEASEIN BREAST CANCER

Mario Alberto Vásquez-Chaves, MD MsC

Tokyo Women´s Medical University

June 2011

WHAT IS METASTATIC BRCA?

Anything more distant than ipsilateral Axillar or Internal mammary LNsmay PRESENT with

distant metsmay RECURR

outside of this area

INCIDENCE

Between 5-10% metastatic at diagnosis

Majority = women relapsing with metastatic disease

Roughly 40,000 women die each year from metastatic BrCa

SITES OF METASTASES

Bones Liver Lungs Brain Peritoneal LAD Skin

SURVIVAL WITH MBRCA Can be few months to years (Vogel et al, Cancer, 1992)

15 - 90+ months Depends on sites involved and rate of tumor progression

Volume of disease Nonvisceral vs visceral Receptor status (?HER2) Response to Rx

Yamamoto et al, JCO, 1998

MEDIAN OVERALL SURVIVAL

~ 2 years (26 months, Vogel JCO, 1992)

StageStage 5 yr OS

Colon Ca

5 yr OS5 yr OS

BrCaBrCa

5 yr OS

NSCLCa

II 70% 88%88% 40%

IIII 60% 79%79% 23%

IIIIII 47% 54-55%54-55% 8-9%

IVIV 6% 18-19%18-19% 2%

NCDB, Five Year Survival Table for Cases Diagnosed in 1998 and 1999

CLINICAL VIGNETTE

64 yo F presents with new dry cough, progressive over last several weeks Stage IIB infiltrating ductal, HR+,HER2-

diagnosed in 2002 S/p lumpectomy, AC x4, XRT and 5 yrs of AI 40 pack-yr history

Work up reveals….

SUSPECTED RECURRENCE….

Establish diagnosis ? Need to biopsy 13-40% discordance in receptor status between

primary tumor and metastasis

Restage CBC, LFTs, imaging

DIAGNOSIS ESTABLISHED….

Estimate prognosis Burden and location of mets

Estimate likelihood of response to Rx Disease free interval Tumor factors

Establish goals of therapy

CURRENT TREATMENT PHILOSOPHY MACROmetastasis = expression of systemic

disease

Locoregional therapy Appropriate if impending local complication Palliative benefit Generally, no improvement in survival

Systemic medical therapy backbone of Rx

GOALS OF SYSTEMIC THERAPY

Controlling disease Palliation Prolong survival==> no prospective

randomized clinical trials showing therapy extends survival over BSC

“Cure”Greenberg et al, JCO,

1996 1581 pts with met BrCa CR with therapy = 16% Alive and still in CR at 5

yrs = 1.6%

“TREATABLE BUT NOT CURABLE”

Prolong survival with as few symptoms and side effects as possible….

Data where available, often no head-to-head trials of the multiple therapies….

OS remains gold standard

SYSTEMIC THERAPIES Bisphosphonates

Endocrine therapies

HER2 targeted therapies

Conventional chemotherapy (cytotoxics)

Other biologics

Toxicity

BISPHOSPHONATES

Reduction of bony complications(Thierhault et al, JCO, 1999)

1) Which agent? Zolendronate, pamidronate2) When to start? 1st met, 1st bony met….3) Timing? q4wks, q3mos….4) When to stop??

ENDOCRINE THERAPY

PREDICTIVE FACTORS, RESPONSE TO HORMONAL THERAPY (TAMOXIFEN, ARIMIDEX)

McGuire et al, BCRT, 1987

ERER PRPR Odds ResponseOdds Response

-- -- < 10%< 10%

++ -- 25%25%

-- ++ 50%50%

++ ++ 75%75%

AGENTS Ovarian ablation/suppression Hormone withdrawal SERMs

Tamoxifen Toremifene

Aromatase inhibitors Steroidal: exemestane Non-steroidals: anastrozole, letrozole

Estrogen receptor down-regulators Androgens/estrogens/progestins

Megesterol acetate

ENDOCRINE THERAPY

1) Which patients? Low risk pt (HR-?) How likely to respond? 10-40% RR, SD 20-30% For how long? Response duration variable

2) When to use? Used early: low toxicity, good chance of response

Wilcken N, Hornbuckle J, Ghersi D. Cochrane Database of Systematic Reviews 2003

ENDOCRINE THERAPY

3) What to use? PRE: Tam vs ovarian suppression vs ??? POST: AI > Tam for RR, OS, TTP (11%

benefit in relative HR, Mauri, JCNI, 2006) 2nd line: evidence for tam, fulvestrant,

another AI 3rd, 4th….. ???

4) Combinations? ET combos: tam+ovarian ablation, no

study for AI + Tam in metastatic disease ET + cytotoxics: likely no survival

benefit (Fossati et al, JCO, 1998 )

HR+ AND HER2+ Conflicting evidence…..

TanDem Study Median OS

28.5 months A+H25.1 months A-->H17.2 months A aloneClemens et al, ASCO Breast 2007, #231

HER2 TARGETED THERAPIES

PREDICTIVE FACTORS

HER2 HER2 statusstatus

RRRR Clinical Clinical BenefitBenefit

IHC IHC 3+3+

35%35% 48%48%

IHC IHC 2+2+

0%0% 7%7%

Vogel et al, JCO, 2002

HER2 TARGETED AGENTS

Trastuzumab (humanized, monoclonal Ab)

Lapatinib (small molecule, tyrosine kinase inhibitor [TKI] of EGFR and HER2)

Pertuzumab (monoclonal Ab, blocks dimerization of HER2/3)

CI-1033, pan-HER TKI

TRASTUZUMAB Can use with or without chemo

Monotherapy: RR close to 30%, clinical benefit rate close to 50% (Vogel et al, JCO, 2002)

Combination: up to 63% RR, TTP 9 mos for docetaxel + tras, minimal add’l toxicity (Esteva et al, JCO, 2002)

When to stop?

Slamon et al, NEJM, 2001

LAPATINIB Capecitabine/lapatinib vs

monotherapy RR 22% vs 14%, p = 0.09 TTP 8.4 vs 4.3 mos, p

<0.0001 OS not sig

Pts progressing on trastuzumab combined with capecitabine Other combinations? Monotherapy 1st line: RR

24%, TTF 16.1 wks (Gomez et al, JCO, 2007)

Geyer et al, NEJM, 2006

CHEMOTHERAPY

ESTABLISHED AGENTS Anthracyclines (doxorubicin, mitoxantrone,

liposomal doxorubicin) Anti-mitotics (taxanes, vinorelbine,

ixabepilone) Anti-metabolites (5FU, capecitabine,

methotrexate) Alkylators (cis/carboplatin) Gemcitabine Etoposide

CHEMOTHERAPY

1) Which patients?2) When?

Consider if (NCCN consensus-based): Visceral disease with symptoms Patients failing ET Hormone receptor negative Rapidly progressing?

COMBINATION VS SEQUENTIALTrial/DrugsTrial/Drugs RRRR OSOS ToxicityToxicity

GP vs P (n = 529)GP vs P (n = 529)

Albain et al, JCO, 2008Albain et al, JCO, 2008

40 vs 22%40 vs 22%

p<0.0001p<0.0001

18.6 vs 18.6 vs 15.8 mos15.8 mos

p = p = 0.04890.0489

G4 neutropenia G4 neutropenia 47.9 vs 11.5%; 47.9 vs 11.5%; QoL p = NSQoL p = NS

ECOG 1193 (n=739)ECOG 1193 (n=739)

AP vs A vs PAP vs A vs P

Sledge et al, JCO, 2003Sledge et al, JCO, 2003

47% vs 47% vs 36% vs 36% vs 34%34%

p = NSp = NS

22 vs 22 vs 18.9 vs 18.9 vs 22.222.2

p = NSp = NS

Fact-B, no Fact-B, no significant significant differencesdifferences

Fossati et al, JCO, 1998 over 31,000 women nearly 200 RCTsn = 996

HR 0.82HR 0.82 Not availableNot available

SINGLE AGENTS What to use first? No studies to suggest optimal

sequence What dose? No advantage to higher dose Schedule? Weekly vs q3Wks, esp for taxanes

(CALGB 9840) How likely to respond? First line, RR 30-50% Continuous vs intermittent? PFS prolonged, but

probably not OS (Muss et al, NEJM 1991)

BEVACIZUMAB: MOVING PAST CYTOXIC COMBINATIONS….

E2100 Paclitaxel/bev vs paclitaxel wkly (first-line)

PFS 11.8 vs 5.9 mosOS 26.7 vs 25.2 mos (NS)RR 36% vs 21%Grade 3+ CVAs 1.9% Miller et al, NEJM 2007

BEVACIZUMAB AVADO study (ASCO 2008)

Doce/bev 15 or 7.5 vs docetaxel q3wk alone

RR 63.1% vs 55.2% vs 44.4%PFS: 8.8 vs 8.7 vs 8.0 mos

HER2+ patients? (phase II, Pegram SABCS 2006)

Dose? When to stop? 2nd line? (Miller et al, JCO, 2005) Combinations? (Xcalibur trial, RIBBON-

1 and 2)

SUMMARY

Choose therapy MOST likely to work with LEAST toxicity

Monitor pt for response and toxicity

When to stop actively treating the cancer in mBrCa???

Return to our patient:Visceral metsSymptomaticER+PR+ HER2-

What’s the right therapy choice?

THANKS A LOT