METASTATIC DISEASE IN BREAST CANCER

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METASTATIC DISEASEIN BREAST CANCER

• Mario Alberto Vásquez-Chaves, MD MsC
• Tokyo Womens Medical University
• June 2011

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WHAT IS METASTATIC BRCA?

• Anything more distant than ipsilateral Axillar or
  Internal mammary LNs
• may PRESENT with distant mets
• may RECURR outside of this area

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INCIDENCE

• Between 5-10 metastatic at diagnosis
• Majority women relapsing with metastatic
  disease
• Roughly 40,000 women die each year from
  metastatic BrCa

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SITES OF METASTASES

• Bones
• Liver
• Lungs
• Brain
• Peritoneal
• LAD
• Skin

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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
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MEDIAN OVERALL SURVIVAL

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

Stage 5 yr OS Colon Ca 5 yr OS BrCa 5 yr OS NSCLCa
I 70 88 40
II 60 79 23
III 47 54-55 8-9
IV 6 18-19 2
NCDB, Five Year Survival Table for Cases
Diagnosed in 1998 and 1999
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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.

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SUSPECTED RECURRENCE.

• Establish diagnosis
• ? Need to biopsy
• 13-40 discordance in receptor status between
  primary tumor and metastasis
• Restage
• CBC, LFTs, imaging

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DIAGNOSIS ESTABLISHED.

• Estimate prognosis
• Burden and location of mets
• Estimate likelihood of response to Rx
• Disease free interval
• Tumor factors
• Establish goals of therapy

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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

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GOALS OF SYSTEMIC THERAPY

• Controlling disease
• Palliation
• Prolong survival
• gt 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

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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

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SYSTEMIC THERAPIES

• Bisphosphonates
• Endocrine therapies
• HER2 targeted therapies
• Conventional chemotherapy (cytotoxics)
• Other biologics

Toxicity
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BISPHOSPHONATES

• Reduction of bony complications
• (Thierhault et al, JCO, 1999)
• Which agent? Zolendronate, pamidronate
• When to start? 1st met, 1st bony met.
• Timing? q4wks, q3mos.
• When to stop??

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

• McGuire et al, BCRT, 1987

ER PR Odds Response
- - lt 10
- 25
- 50
75
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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

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ENDOCRINE THERAPY

• Which patients? Low risk pt (HR-?)
• How likely to respond?
• 10-40 RR, SD 20-30
• For how long?
• Response duration variable
• When to use? Used early low toxicity, good
  chance of response

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

• What to use?
• PRE Tam vs ovarian suppression vs ???
• POST AI gt Tam for RR, OS, TTP (11 benefit in
  relative HR, Mauri, JCNI, 2006)
• 2nd line evidence for tam, fulvestrant, another
  AI
• 3rd, 4th.. ???
• Combinations?
• ET combos tamovarian ablation, no study for AI
  Tam in metastatic disease
• ET cytotoxics likely no survival benefit
  (Fossati et al, JCO, 1998 )

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HR AND HER2

• Conflicting evidence..
• TanDem Study
• Median OS
• 28.5 months AH
• 25.1 months A--gtH
• 17.2 months A alone
• Clemens et al, ASCO Breast 2007, 231

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HER2 TARGETED THERAPIES
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PREDICTIVE FACTORS
HER2 status RR Clinical Benefit
IHC 3 35 48
IHC 2 0 7
Vogel et al, JCO, 2002
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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

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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 addl toxicity (Esteva
  et al, JCO, 2002)
• When to stop?

Slamon et al, NEJM, 2001
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LAPATINIB

• Capecitabine/lapatinib vs monotherapy
• RR 22 vs 14, p 0.09
• TTP 8.4 vs 4.3 mos, p lt0.0001
• 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
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CHEMOTHERAPY
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ESTABLISHED AGENTS

• Anthracyclines (doxorubicin, mitoxantrone,
  liposomal doxorubicin)
• Anti-mitotics (taxanes, vinorelbine, ixabepilone)
• Anti-metabolites (5FU, capecitabine,
  methotrexate)
• Alkylators (cis/carboplatin)
• Gemcitabine
• Etoposide

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CHEMOTHERAPY

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

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COMBINATION VS SEQUENTIAL
Trial/Drugs RR OS Toxicity
GP vs P (n 529) Albain et al, JCO, 2008 40 vs 22 plt0.0001 18.6 vs 15.8 mos p 0.0489 G4 neutropenia 47.9 vs 11.5 QoL p NS
ECOG 1193 (n739) AP vs A vs P Sledge et al, JCO, 2003 47 vs 36 vs 34 p NS 22 vs 18.9 vs 22.2 p NS Fact-B, no significant differences
Fossati et al, JCO, 1998 over 31,000 women nearly 200 RCTs n 996 HR 0.82 Not available
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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)

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BEVACIZUMAB MOVING PAST CYTOXIC COMBINATIONS.
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E2100

• Paclitaxel/bev vs paclitaxel wkly (first-line)
• PFS 11.8 vs 5.9 mos
• OS 26.7 vs 25.2 mos (NS)
• RR 36 vs 21
• Grade 3 CVAs 1.9

Miller et al, NEJM 2007
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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)

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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 mets
• Symptomatic
• ERPR HER2-
• Whats the right therapy choice?

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THANKS A LOT