Current Therapy of Metastatic Current Therapy of Metastatic Breast CancerBreast Cancer

Julie R. Gralow, M.DJulie R. Gralow, M.D

Assistant Professor, Medicine/OncologyAssistant Professor, Medicine/Oncology

University of Washington School of MedicineUniversity of Washington School of Medicine

Fred Hutchinson Cancer Research CenterFred Hutchinson Cancer Research Center

Metastatic Breast CancerMetastatic Breast Cancer

• Metastatic breast cancer is generally incurable with Metastatic breast cancer is generally incurable with current conventional therapycurrent conventional therapy

• Median survival after development of metastatic Median survival after development of metastatic breast cancer is 3 yearsbreast cancer is 3 years

• Goals in the treatment of metastatic breast cancer:Goals in the treatment of metastatic breast cancer:

–Control and regression of diseaseControl and regression of disease

– Improvement in quality of lifeImprovement in quality of life

–Prolongation of lifeProlongation of life

–??Cure??Cure

Metastatic Breast CancerMetastatic Breast Cancer• Choice of treatment is based on several factors:Choice of treatment is based on several factors:

–age, menopausal status, performance statusage, menopausal status, performance status

–HR status, HER-2 statusHR status, HER-2 status

–disease-free interval from diagnosis or disease-free interval from diagnosis or previous treatmentprevious treatment

–response to previous treatmentresponse to previous treatment

–presence of life-threatening diseasepresence of life-threatening disease

–extent and sites of metastatic diseaseextent and sites of metastatic disease

Hormonal TherapyHormonal Therapy

Hormone Therapy for Hormone Therapy for Metastatic Breast CancerMetastatic Breast Cancer

• A reasonable first-line approach for patients A reasonable first-line approach for patients with ER/PR positive tumors who do not have with ER/PR positive tumors who do not have lymphangitic lung disease, liver metastasis, or lymphangitic lung disease, liver metastasis, or life-threatening, rapidly-progressive disease.life-threatening, rapidly-progressive disease.

• There is little clinical evidence that one form There is little clinical evidence that one form of hormone therapy is more effective than of hormone therapy is more effective than another.another.

• Selection is generally based on the relative Selection is generally based on the relative toxicities.toxicities.

Hormone Therapy for Metastatic Hormone Therapy for Metastatic Breast CancerBreast Cancer

• Anti-estrogens: tamoxifen (Nolvadex), toremifene Anti-estrogens: tamoxifen (Nolvadex), toremifene (Fareston)(Fareston)

• Aromatase inhibitors: ananstrazole (Arimidex), letrozole Aromatase inhibitors: ananstrazole (Arimidex), letrozole (Femara), exemestane (Aromasin), aminoglutethamide(Femara), exemestane (Aromasin), aminoglutethamide

• Progestins: megestrol acetate (Megace), Progestins: megestrol acetate (Megace), medroxyprogesteronemedroxyprogesterone

• Estrogens: DESEstrogens: DES• Androgens: HalotestinAndrogens: Halotestin• Medical or surgical oophorectomy: goserelin (Zoladex), Medical or surgical oophorectomy: goserelin (Zoladex),

leuprolide (Lupron)leuprolide (Lupron)

Aromatase InhibitorsAromatase Inhibitors

Adrenal HormonesAdrenal Hormones

CortisolCortisol AndrostenedioneAndrostenedione AldosteroneAldosterone

EstradiolEstradiol

TestosteroneTestosteroneEstroneEstrone

Letrozole (Femara) vs. Tamoxifen Letrozole (Femara) vs. Tamoxifen (Nolvadex) as First-line Treatment of (Nolvadex) as First-line Treatment of

Advanced Breast CancerAdvanced Breast CancerR Smith et al, San Antonio 2000R Smith et al, San Antonio 2000

• 907 907 postmenopausal breast cancer patients with locally postmenopausal breast cancer patients with locally advanced or metastatic breast canceradvanced or metastatic breast cancer– 65% ER/PR positive 65% ER/PR positive – 20% prior anti-estrogen treatment20% prior anti-estrogen treatment

• TreatmentTreatment: Randomized to letrozole 2.5 mg/day vs. tamoxifen : Randomized to letrozole 2.5 mg/day vs. tamoxifen 20 mg qd20 mg qd

• ResultsResults: : TTPTTP OROR Clinical BenefitClinical BenefitLetrozoleLetrozole 41 wks41 wks 30%30% 49%49%TamoxifenTamoxifen 26 wks26 wks 20%20% 38%38%

(p=0.0001)(p=0.0001) (p=0.001)(p=0.001) (p=0.001)(p=0.001)

Pre-Operative Letrozole Pre-Operative Letrozole (Femara) vs. Tamoxifen(Femara) vs. Tamoxifen

Ellis et al, San Antonio 2000Ellis et al, San Antonio 2000

• 337 337 postmenopausal ER/PR positive breast cancer postmenopausal ER/PR positive breast cancer patients with primary tumors > 2 cm (not a candidate for patients with primary tumors > 2 cm (not a candidate for breast conserving surgery - BCS)breast conserving surgery - BCS)

• TreatmentTreatment: Letrozole 2.5 mg qd vs. tamoxifen 20 mg qd x : Letrozole 2.5 mg qd vs. tamoxifen 20 mg qd x 4 months4 months

• ToxicityToxicity: well tolerated: well tolerated

• ResponseResponse:: OROR RR HER2+RR HER2+ RR HER2-RR HER2- BCS BCS

LetrozoleLetrozole 55%55% 69% 69% 53% 45% 53% 45%

TamoxifenTamoxifen 36%36% 17% 40% 17% 40% 36% 36%

(p<0.001)(p<0.001) (p=0.022)(p=0.022)

ChemotherapyChemotherapy

Chemotherapy for Metastatic Chemotherapy for Metastatic Breast CancerBreast Cancer

• Optimal agentsOptimal agents

• Dose intensity, dose densityDose intensity, dose density

• Treatment schedulesTreatment schedules

• Monotherapy vs. combination regimensMonotherapy vs. combination regimens

• Duration of therapyDuration of therapy

• Addition of biologicsAddition of biologics

Chemotherapy for Metastatic Breast Chemotherapy for Metastatic Breast CancerCancer

• Anthracyclines: doxorubicin (Adriamycin), epirubicin Anthracyclines: doxorubicin (Adriamycin), epirubicin (Ellence), mitoxantrone, liposomal formulations (Doxil)(Ellence), mitoxantrone, liposomal formulations (Doxil)

• Taxanes: paclitaxel (Taxol), docetaxel (Taxotere)Taxanes: paclitaxel (Taxol), docetaxel (Taxotere)• Vinca alkaloids: vinblastine (Velban), vinorelbine Vinca alkaloids: vinblastine (Velban), vinorelbine

(Navelbine)(Navelbine)• Alkylating agents: cyclophosphamide, melphalan, Alkylating agents: cyclophosphamide, melphalan,

thiotepa, cisplatin, carboplatinthiotepa, cisplatin, carboplatin• Antimetabolites: 5-FU, methotrexate, gemcitabine Antimetabolites: 5-FU, methotrexate, gemcitabine

(Gemzar), capecitabine (Xeloda)(Gemzar), capecitabine (Xeloda)• Topoisomerase inhibitors: etoposide (VP-16)Topoisomerase inhibitors: etoposide (VP-16)

Capecitabine (Xeloda)Capecitabine (Xeloda)

• Selective tumor-activated fluoropyrimidine Selective tumor-activated fluoropyrimidine

• FDA-approved in U.S. 1998FDA-approved in U.S. 1998

• Oral agentOral agent

• Activity observed in breast and colon cancers Activity observed in breast and colon cancers

• No alopecia, minimal myelosuppressionNo alopecia, minimal myelosuppression

A Multicenter Phase II Trial of Capecitabine A Multicenter Phase II Trial of Capecitabine (Xeloda) in Paclitaxel (Taxol)-Refractory (Xeloda) in Paclitaxel (Taxol)-Refractory

Metastatic Breast CancerMetastatic Breast CancerBlum, ASCO 1998Blum, ASCO 1998

• PatientsPatients: 163 paclitaxel-resistant breast cancer : 163 paclitaxel-resistant breast cancer patients, 2-3 prior regimenspatients, 2-3 prior regimens

• TreatmentTreatment: Capecitabine 2510 mg/m2/day : Capecitabine 2510 mg/m2/day divided bid given for 2 out of 3 weeksdivided bid given for 2 out of 3 weeks

• ToxicityToxicity: Grade 3/4 diarrhea (14%), hand-foot : Grade 3/4 diarrhea (14%), hand-foot syndrome (10%)syndrome (10%)

• ResponseResponse: 20% response rate (3 CRs), median : 20% response rate (3 CRs), median duration of response 8.1 months, TTP 93 daysduration of response 8.1 months, TTP 93 days

A Randomized Phase II Trial of Capecitabine A Randomized Phase II Trial of Capecitabine (Xeloda) vs. CMF as First Line Chemotherapy (Xeloda) vs. CMF as First Line Chemotherapy of Breast Cancer in Women Aged of Breast Cancer in Women Aged >> 55 Years 55 Years

O’Shaughnessy, ASCO 1998O’Shaughnessy, ASCO 1998

• PatientsPatients: 95 untreated stage IV breast : 95 untreated stage IV breast cancer patients cancer patients >> 55 55

• TreatmentTreatment: Capecitabine 2510 mg/m2/day : Capecitabine 2510 mg/m2/day divided bid 2 out of 3 weeks vs. CMFdivided bid 2 out of 3 weeks vs. CMF

A Randomized Phase II Trial of Capecitabine A Randomized Phase II Trial of Capecitabine (Xeloda) vs. CMF as First Line Chemotherapy (Xeloda) vs. CMF as First Line Chemotherapy of Breast Cancer in Women Aged of Breast Cancer in Women Aged >> 55 Years 55 Years

O’Shaughnessy, ASCO 1998O’Shaughnessy, ASCO 1998

• Grade 3/4 toxicityGrade 3/4 toxicity::

– Hand-foot syndrome: Capecitabine 16%, CMF 0%Hand-foot syndrome: Capecitabine 16%, CMF 0%

–Diarrhea: Capecitabine 8%, CMF 3%Diarrhea: Capecitabine 8%, CMF 3%

–Myelosuppression: Capecitabine 20%, CMF 47%Myelosuppression: Capecitabine 20%, CMF 47%

• ResultsResults::

–Response rate: Capecitabine 25%, CMF 16%Response rate: Capecitabine 25%, CMF 16%

–Median TTP: Capecitabine 132 days, CMF 94 daysMedian TTP: Capecitabine 132 days, CMF 94 days

Docetaxel (Taxotere) +/- Capecitabine Docetaxel (Taxotere) +/- Capecitabine (Xeloda) in Stage IV Breast Cancer(Xeloda) in Stage IV Breast Cancer

O’Shaughnessy et al, San Antonio 12/00O’Shaughnessy et al, San Antonio 12/00

• PatientsPatients: 511 stage IV breast cancer patients, : 511 stage IV breast cancer patients, s/p anthracyclines/p anthracycline

• TreatmentTreatment: Docetaxel 100 mg/m2 q3 wks vs. : Docetaxel 100 mg/m2 q3 wks vs. docetaxel 75 mg/m2 q3 wks plus capecitabine docetaxel 75 mg/m2 q3 wks plus capecitabine 2500 mg/m2 days 1-142500 mg/m2 days 1-14

Docetaxel (Taxotere) +/- Capecitabine Docetaxel (Taxotere) +/- Capecitabine (Xeloda) in Stage IV Breast Cancer(Xeloda) in Stage IV Breast Cancer

O’Shaughnessy et al, San Antonio 12/00O’Shaughnessy et al, San Antonio 12/00

• ToxicityToxicity: T alone: more neutropenia, myalgia, : T alone: more neutropenia, myalgia, arthralgia. T/X: more diarrhea, stomatitis, nausea, arthralgia. T/X: more diarrhea, stomatitis, nausea, vomiting, hand/foot syndromevomiting, hand/foot syndrome

• ResultsResults:: T/XT/X TT

Overall survival Overall survival 14.4 mo14.4 mo 11.2 mo11.2 mo p=0.0159p=0.0159

1 year survival1 year survival 56.7%56.7% 46.2%46.2% n.s.n.s.

OROR 41.6%41.6% 29.729.7 p=0.06p=0.06

TTPTTP 6.1 mo6.1 mo 4.2 mo4.2 mo p=0.0001p=0.0001

Paclitaxel (Taxol) Plus Carboplatin Paclitaxel (Taxol) Plus Carboplatin First-line Therapy in Metastatic First-line Therapy in Metastatic Breast Cancer (NCCTG 953252) Breast Cancer (NCCTG 953252)

Perez et al, Cancer 2000Perez et al, Cancer 2000

• PatientsPatients: 50 evaluable patients: 50 evaluable patients

–No prior therapy for metastatic diseaseNo prior therapy for metastatic disease

• TreatmentTreatment: Paclitaxel 200 mg/m2 over 3-hrs : Paclitaxel 200 mg/m2 over 3-hrs and carboplatin AUC 6 q3 wksand carboplatin AUC 6 q3 wks

Paclitaxel (Taxol) Plus Carboplatin Paclitaxel (Taxol) Plus Carboplatin as First-line Therapy in Metastatic as First-line Therapy in Metastatic

Breast Cancer (NCCTG) Breast Cancer (NCCTG) Perez et al, Cancer 2000Perez et al, Cancer 2000

• Toxicity:Toxicity:–grade 3-4 neutropenia: 82%grade 3-4 neutropenia: 82%– febrile neutropenia: 0febrile neutropenia: 0–grade 3 neuropathy: 16%grade 3 neuropathy: 16%

• ResultsResults::–OR: 62%; CR: 16%; PR: 46%OR: 62%; CR: 16%; PR: 46%–Median TTP: 7.3 moMedian TTP: 7.3 mo–12 mo survival estimate: 72%12 mo survival estimate: 72%

UW Docetaxel (Taxotere)/Vinorelbine UW Docetaxel (Taxotere)/Vinorelbine (Navelbine) Regimen(Navelbine) Regimen

Gralow et al, ASCO 2000Gralow et al, ASCO 2000

• PatientsPatients: Stage IV breast cancer, s/p : Stage IV breast cancer, s/p anthracyclineanthracycline–Prior taxane 45%Prior taxane 45%–Concurrent trastuzumab (Herceptin) 31%Concurrent trastuzumab (Herceptin) 31%

• TreatmentTreatment::–Docetaxel 60 mg/m2 day 1Docetaxel 60 mg/m2 day 1–Vinorelbine 27.5 mg/m2 days 8+15Vinorelbine 27.5 mg/m2 days 8+15–G-CSF days 2-21G-CSF days 2-21

UW Docetaxel (Taxotere)/Vinorelbine UW Docetaxel (Taxotere)/Vinorelbine (Navelbine) Regimen(Navelbine) Regimen

Gralow et al, ASCO 2000Gralow et al, ASCO 2000

• ToxicityToxicity–6/39 grade 4 neutropenia, 3/39 febrile 6/39 grade 4 neutropenia, 3/39 febrile

neutropenia, 5/39 treated for infection, 1/39 neutropenia, 5/39 treated for infection, 1/39 grade 4 thrombocytopeniagrade 4 thrombocytopenia–Grade 3/4 non-hematologic toxicities: 1 case Grade 3/4 non-hematologic toxicities: 1 case

each of grade 3 stomatitis, diarrhea, each of grade 3 stomatitis, diarrhea, neuropathyneuropathy

• ResponseResponse–OR 59.4% (22/37)OR 59.4% (22/37)–CR 29.7% (11/37)CR 29.7% (11/37)

Biological TherapyBiological Therapy

HER-2 in Breast CancerHER-2 in Breast Cancer

HER-2growth factor receptor

nucleus

cell division

ligand

cancer cell

Trastuzumab (Herceptin) Trastuzumab (Herceptin) Anti-HER-2 AntibodyAnti-HER-2 Antibody

BREAST CANCER CELLBREAST CANCER CELL

HER-2HER-2

Trastuzumab (Herceptin)Trastuzumab (Herceptin)

• Derived from murine 4D5 antibodyDerived from murine 4D5 antibody

• 95% humanized recombinant molecule95% humanized recombinant molecule

• Targets ECD of HER2 growth factor Targets ECD of HER2 growth factor receptorreceptor

• Anti-proliferative to HER2+ cell linesAnti-proliferative to HER2+ cell lines

• Enhances antibody dependent cellular Enhances antibody dependent cellular toxicitytoxicity

• Not immunogenicNot immunogenic

Trastuzumab (Herceptin) Plus Trastuzumab (Herceptin) Plus Chemotherapy in Metastatic Breast Chemotherapy in Metastatic Breast

CancerCancerSlamon et al, NEJM 2001Slamon et al, NEJM 2001

• 31 31 month follow-upmonth follow-up

AC+HAC+H ACAC T+HT+H TT

CRCR 8%8% 4%4% 8%8% 2%2%

PRPR 48%48% 38%38% 34%34% 15%15%

OROR 56%56% 42%42% 41%41% 17%17%

DurationDuration 9.1 mo9.1 mo 6.76.7 10.510.5 4.5 p<0.0014.5 p<0.001

TTPTTP 7.8 mo7.8 mo 6.16.1 6.96.9 3.0 p<0.0013.0 p<0.001

Survival Survival 26.8 mo26.8 mo 21.4 21.4 22.122.1 18.4 p=0.1618.4 p=0.16

Trastuzumab (Herceptin) Trastuzumab (Herceptin) CardiotoxicityCardiotoxicity

HH AC+HAC+H ACAC T+HT+H TT

Any DysfunctionAny Dysfunction 7% 7% 28% 28% 7%7% 11% 11% 1%1%

Class III-IVClass III-IV 5% 5% 19% 19% 3%3% 4% 4% 1%1%

Class III-IV Class III-IV 6%6% 0% 0%after rxafter rx

94% of pts in H-only trial had received an anthracycline94% of pts in H-only trial had received an anthracycline

Only correlated risk factor: age (not corrleated with Only correlated risk factor: age (not corrleated with anthracycline dose, prior XRT, HER-2 expression level)anthracycline dose, prior XRT, HER-2 expression level)

Future Applications of Trastuzumab Future Applications of Trastuzumab (Herceptin): Proposed and Ongoing (Herceptin): Proposed and Ongoing

StudiesStudies

• New treatment combinationsNew treatment combinations

• Earlier stage breast cancerEarlier stage breast cancer

• Easier routes and schedules of Easier routes and schedules of administrationadministration

• Lower levels of HER-2 expressionLower levels of HER-2 expression

• Other tumor typesOther tumor types

Anti-Cancer Treatment StrategiesAnti-Cancer Treatment Strategies

• Cytotoxic drugsCytotoxic drugs

–new analogs, classes, moleculesnew analogs, classes, molecules

• Hormonal AgentsHormonal Agents

• Drug resistance modulatorsDrug resistance modulators

• Immunologic approachesImmunologic approaches

–Antibodies, immunoconjugates, fusion proteins, Antibodies, immunoconjugates, fusion proteins, vaccinesvaccines

• Growth factor directedGrowth factor directed

–HER-2, EGFR, hormonal receptors, mammastatin, HER-2, EGFR, hormonal receptors, mammastatin, osteoclastosteoclast

Anti-Cancer Treatment StrategiesAnti-Cancer Treatment Strategies

• Signal transduction inhibitorsSignal transduction inhibitors–Tyrosine kinase, farnesyl transferaseTyrosine kinase, farnesyl transferase

• Angiogenesis inhibitorsAngiogenesis inhibitors• Apoptosis inducers (SAANDS)Apoptosis inducers (SAANDS)• Inhibition of the metastatic cascadeInhibition of the metastatic cascade–Adhesion molecules, matrix metalloprotease Adhesion molecules, matrix metalloprotease

inhibitorsinhibitors• Gene therapyGene therapy