METASTATIC DISEASEIN BREAST CANCER

Mario Alberto Vsquez-Chaves, MD MsCTokyo Womens Medical UniversityJune 2011

WHAT IS METASTATIC BRCA?Anything more distant than ipsilateral Axillar or Internal mammary LNsmay PRESENT with distant metsmay RECURR outside of this area

INCIDENCEBetween 5-10% metastatic at diagnosis

Majority = women relapsing with metastatic disease

Roughly 40,000 women die each year from metastatic BrCa

SITES OF METASTASESBonesLiverLungs BrainPeritonealLADSkin

SURVIVAL WITH MBRCACan be few months to years (Vogel et al, Cancer, 1992)15 - 90+ monthsDepends on sites involved and rate of tumor progression Volume of disease Nonvisceral vs visceral Receptor status (?HER2) Response to RxYamamoto et al, JCO, 1998

MEDIAN OVERALL SURVIVAL~ 2 years (26 months, Vogel JCO, 1992)NCDB, Five Year Survival Table for Cases Diagnosed in 1998 and 1999

Stage5 yr OSColon Ca5 yr OSBrCa5 yr OSNSCLCaI70%88%40%II60%79%23%III47%54-55%8-9%IV6%18-19%2%

CLINICAL VIGNETTE64 yo F presents with new dry cough, progressive over last several weeksStage IIB infiltrating ductal, HR+,HER2- diagnosed in 2002S/p lumpectomy, AC x4, XRT and 5 yrs of AI40 pack-yr history

Work up reveals.

SUSPECTED RECURRENCE.Establish diagnosis? Need to biopsy13-40% discordance in receptor status between primary tumor and metastasis

RestageCBC, LFTs, imaging

DIAGNOSIS ESTABLISHED.Estimate prognosisBurden and location of mets

Estimate likelihood of response to RxDisease free intervalTumor factors

Establish goals of therapy

CURRENT TREATMENT PHILOSOPHYMACROmetastasis = expression of systemic disease

Locoregional therapyAppropriate if impending local complicationPalliative benefitGenerally, no improvement in survival

Systemic medical therapy backbone of Rx

GOALS OF SYSTEMIC THERAPYControlling diseasePalliationProlong survival==> no prospective randomized clinical trials showing therapy extends survival over BSCCureGreenberg et al, JCO, 19961581 pts with met BrCaCR with therapy = 16%Alive and still in CR at 5 yrs = 1.6%

TREATABLE BUT NOT CURABLEProlong 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 THERAPIESBisphosphonates

Endocrine therapies

HER2 targeted therapies

Conventional chemotherapy (cytotoxics)

Other biologicsToxicity

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

Which agent? Zolendronate, pamidronateWhen to start? 1st met, 1st bony met.Timing? q4wks, q3mos.When to stop??

ENDOCRINE THERAPY

PREDICTIVE FACTORS, RESPONSE TO HORMONAL THERAPY (TAMOXIFEN, ARIMIDEX)McGuire et al, BCRT, 1987

ERPROdds Response--< 10%+-25%-+50%++75%

AGENTSOvarian ablation/suppressionHormone withdrawalSERMsTamoxifenToremifeneAromatase inhibitorsSteroidal: exemestaneNon-steroidals: anastrozole, letrozoleEstrogen receptor down-regulatorsAndrogens/estrogens/progestinsMegesterol acetate

ENDOCRINE THERAPYWhich 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 responseWilcken N, Hornbuckle J, Ghersi D. Cochrane Database of Systematic Reviews 2003

ENDOCRINE THERAPYWhat 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 AI3rd, 4th.. ???

Combinations?ET combos: tam+ovarian ablation, no study for AI + Tam in metastatic diseaseET + cytotoxics: likely no survival benefit (Fossati et al, JCO, 1998 )

HR+ AND HER2+Conflicting evidence..

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

HER2 TARGETED THERAPIES

PREDICTIVE FACTORSVogel et al, JCO, 2002

HER2 statusRRClinical BenefitIHC 3+35%48%IHC 2+0%7%

HER2 TARGETED AGENTSTrastuzumab (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

TRASTUZUMABCan use with or without chemoMonotherapy: 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

LAPATINIBCapecitabine/lapatinib vs monotherapyRR 22% vs 14%, p = 0.09TTP 8.4 vs 4.3 mos, p

CHEMOTHERAPY

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

CHEMOTHERAPYWhich patients?When?

Consider if (NCCN consensus-based): Visceral disease with symptomsPatients failing ETHormone receptor negativeRapidly progressing?

COMBINATION VS SEQUENTIAL

Trial/DrugsRROSToxicityGP vs P (n = 529)Albain et al, JCO, 200840 vs 22%p

SINGLE AGENTSWhat to use first? No studies to suggest optimal sequenceWhat dose? No advantage to higher doseSchedule? 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.

E2100Paclitaxel/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

BEVACIZUMABAVADO study (ASCO 2008)Doce/bev 15 or 7.5 vs docetaxel q3wk aloneRR 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)

SUMMARYChoose 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-

Whats the right therapy choice?

THANKS A LOT

*****************1st line letrozole 9.4 months1st line anastrozole 11.1 months, RR 21%, clinical benefit 59%*Fulvestrant:

Third line exemestane, clinical benefit 30%, Jones et al JCO 1999***************