mdmdi il lmedical …hormonal therapyhormonal therapy effect of steroid hormones and inhibitors on...

M di lM di lMedical Medical M fM fManagement of Management of Breast CancerBreast Cancer

Morbidity and MortalityMorbidity and MortalityAug 13, 2009Aug 13, 2009

Irina Kovatch, PGY3Irina Kovatch, PGY3

www.downstatesurgery.org

IntroductionIntroductionIntroductionIntroduction

Metastatic disease is the principal cause of death fromMetastatic disease is the principal cause of death fromMetastatic disease is the principal cause of death from Metastatic disease is the principal cause of death from breast cancerbreast cancerMetastatic events often occur prior to initial clinical Metastatic events often occur prior to initial clinical ppevaluationevaluationSystemic approach is needed in concert with local Systemic approach is needed in concert with local y ppy pptreatmenttreatmentBenefit from chemo and/or hormonal therapy is due to Benefit from chemo and/or hormonal therapy is due to metastasis being prevented, cured, or delayedmetastasis being prevented, cured, or delayed


Molecular MarkersMolecular MarkersERERPRPRHERHER--2 (erb2 (erb--B2/neu protein) B2/neu protein) –– has 3 binding partners: has 3 binding partners: HERHER--1 (EGFR), HER1 (EGFR), HER--3, and HER3, and HER--44TripleTriple––negative cancers (basalnegative cancers (basal--like cancers)like cancers)Oncotype DX (21 gene RTOncotype DX (21 gene RT--PCR Assay) PCR Assay) –– genomic test genomic test which quantifies expression of specific mRNA for 16which quantifies expression of specific mRNA for 16which quantifies expression of specific mRNA for 16 which quantifies expression of specific mRNA for 16 cancer genes and 5 reference genes in breast cancer cancer genes and 5 reference genes in breast cancer biopsy tissue, combining the expression results into a biopsy tissue, combining the expression results into a p y g pp y g psingle Recurrence Score (0single Recurrence Score (0--100) which predicts a 100) which predicts a chance of the breast cancer recurrence within 10 years. chance of the breast cancer recurrence within 10 years. Risk categories: low <=18 intermediate 19Risk categories: low <=18 intermediate 19 31 high31 highRisk categories: low <=18, intermediate 19Risk categories: low <=18, intermediate 19--31, high 31, high >31>31


St r id H rm n R pt rSt r id H rm n R pt rSteroid Hormone ReceptorsSteroid Hormone Receptors

If >10% of tumor cells stain positive for the nuclearIf >10% of tumor cells stain positive for the nuclearIf 10% of tumor cells stain positive for the nuclear If 10% of tumor cells stain positive for the nuclear receptor, response to hormonal treatment is likelyreceptor, response to hormonal treatment is likely60% of breast tumors contain either ER or PR60% of breast tumors contain either ER or PRMale breast cancer is almost always ERMale breast cancer is almost always ER--positivepositiveClinically the most important protein induced by ER isClinically the most important protein induced by ER isClinically the most important protein induced by ER is Clinically the most important protein induced by ER is the receptor for progesteronethe receptor for progesteronePR may serve as an indicator for the presence of a PR may serve as an indicator for the presence of a y py pfunctional ER (PRfunctional ER (PR--positive breast cancers display positive breast cancers display intermediate responsiveness to hormonal treatments, intermediate responsiveness to hormonal treatments, even if measured value of ER is very low or zero)even if measured value of ER is very low or zero)


Distribution of Steroid ReceptorsDistribution of Steroid ReceptorsDistribution of Steroid ReceptorsDistribution of Steroid Receptors


Response Based on Steroid ReceptorsResponse Based on Steroid ReceptorsResponse Based on Steroid ReceptorsResponse Based on Steroid Receptors

Presence of ER predicts clinical response to all types of Presence of ER predicts clinical response to all types of endocrine therapy, both additive and ablativeendocrine therapy, both additive and ablativePresence of PR correlates with response to endocrine Presence of PR correlates with response to endocrine therapytherapyPresence of both receptors is associated with 80% Presence of both receptors is associated with 80% chance of favorably responding to hormone addition or chance of favorably responding to hormone addition or blockadeblockadeblockade blockade


Relationship Between Steroid Receptor Relationship Between Steroid Receptor Status and Objective Response toStatus and Objective Response toStatus and Objective Response to Status and Objective Response to

Endocrine TherapyEndocrine Therapy


Hormonal TherapyHormonal TherapyHormonal TherapyHormonal Therapy

Effect of steroid hormones and inhibitors on sensitiveEffect of steroid hormones and inhibitors on sensitiveEffect of steroid hormones and inhibitors on sensitive Effect of steroid hormones and inhibitors on sensitive tissues is the basis for effective treatment of breast tissues is the basis for effective treatment of breast cancercancerSurgically induced menopause (bilateral oophorectomy) Surgically induced menopause (bilateral oophorectomy) produced a beneficial regression in 25produced a beneficial regression in 25--40% of pre40% of pre--menopausal patientsmenopausal patientsEndocrine organ ablation has been replaced by Endocrine organ ablation has been replaced by antiestrogen therapy in most patientsantiestrogen therapy in most patientsTamoxifen (estrogen agonistTamoxifen (estrogen agonist--antagonist) is currently the antagonist) is currently the fifi li fli f i i bi i bfirstfirst--line treatment of estrogenline treatment of estrogen--sensitive breast cancersensitive breast cancer


Hormonal AgentsHormonal Agentsggwww.downstatesurgery.org

Selective Estrogen Receptor ModulatorsSelective Estrogen Receptor Modulators/ f/ fEstrogen receptor agonists/antagonists (e.g. tamoxifen, Estrogen receptor agonists/antagonists (e.g. tamoxifen,

raloxifene, toremifene) raloxifene, toremifene) T if i i i fT if i i i fTamoxifen acts as a competitive antagonists of estrogen Tamoxifen acts as a competitive antagonists of estrogen in breastin breastC pl ph t i p p lC pl ph t i p p lCan replace oophorectomy in premenopausal women Can replace oophorectomy in premenopausal women with ERwith ER--positive metastatic cancerpositive metastatic cancerConsidered the drug of first choice in bothConsidered the drug of first choice in bothConsidered the drug of first choice in both Considered the drug of first choice in both premenopausal and postmenopausal patients with ERpremenopausal and postmenopausal patients with ER--positive breast cancerpositive breast cancerppIdeal SERM blocks ER in breast cancer tissue, is Ideal SERM blocks ER in breast cancer tissue, is neutral or inhibitory in the endometrium, lacks neutral or inhibitory in the endometrium, lacks y ,y ,procoagulant activity, and acts like estrogen in skeletal, procoagulant activity, and acts like estrogen in skeletal, cardiovascular, and central nervous systemcardiovascular, and central nervous system


Selective Aromatase InhibitorsSelective Aromatase Inhibitors

SAI inhibit the last enzymatic step in the formation of SAI inhibit the last enzymatic step in the formation of estroneestroneSAI include nonsteroidal compounds (reversible SAI include nonsteroidal compounds (reversible inhibitors inhibitors –– e.g anastrozole, letrozole) and steroide.g anastrozole, letrozole) and steroid--based based compounds (irreversible inhibitors compounds (irreversible inhibitors –– e.g. exemestane)e.g. exemestane)SAI used in postmenopausal women to completely SAI used in postmenopausal women to completely suppress production of estrogen from extragonadalsuppress production of estrogen from extragonadalsuppress production of estrogen from extragonadal suppress production of estrogen from extragonadal sites (adipose tissue)sites (adipose tissue)In premenopausal women SAI cause reflex pituitary In premenopausal women SAI cause reflex pituitary p p p yp p p yrelease of gonadotropins, development of polycystic release of gonadotropins, development of polycystic ovaries, and excessive androgen production [may be ovaries, and excessive androgen production [may be

d i bi ti ith l t i i i hd i bi ti ith l t i i i h l il iused in combination with luteinizing hormoneused in combination with luteinizing hormone--releasing releasing hormone agonists (LHRH)] hormone agonists (LHRH)]


Luteinizing HormoneLuteinizing Hormone--Releasing Releasing H A iH A iHormone AgonistsHormone Agonists

LHRHLHRH--As are superagonists that cause early, massive As are superagonists that cause early, massive release of pituitary gonadotropins, followed by paralysis release of pituitary gonadotropins, followed by paralysis of pituitary and resistance to normal LHRHof pituitary and resistance to normal LHRHof pituitary and resistance to normal LHRHof pituitary and resistance to normal LHRHLHRHLHRH--As are peptide analogs of normal releasing As are peptide analogs of normal releasing hormone which are 50hormone which are 50--100 times more potent100 times more potenthormone which are 50hormone which are 50--100 times more potent100 times more potentTwo are in clinical use for treatment of breast cancer Two are in clinical use for treatment of breast cancer (goserelin and leuprolide)(goserelin and leuprolide)(goserelin and leuprolide)(goserelin and leuprolide)


Adjuvant Tamoxifen TrialsAdjuvant Tamoxifen TrialsAdjuvant Tamoxifen TrialsAdjuvant Tamoxifen Trials

Scottish trial 1978 randomized women after surgery for Scottish trial 1978 randomized women after surgery for g yg ybreast cancer regardless of ER statusbreast cancer regardless of ER statusResults in tamoxifen treated arm: Results in tamoxifen treated arm:

R d ti i f 38 t 24%R d ti i f 38 t 24%Reduction in recurrence from 38 to 24%Reduction in recurrence from 38 to 24%Increase in survival rates from 18 to 23% Increase in survival rates from 18 to 23%

Twenty more trials combined into large metaTwenty more trials combined into large meta--analysisanalysisTwenty more trials combined into large metaTwenty more trials combined into large meta analysis analysis confirmed the above resultsconfirmed the above resultsLater trials showed that all benefit from endocrine Later trials showed that all benefit from endocrine t t t i ith ERt t t i ith ER iti di diti di dtreatment was in women with ERtreatment was in women with ER--positive disease and positive disease and PRPR--positive but ERpositive but ER--poor tumorspoor tumors


MetaMeta--Analysis of Adjuvant Tamoxifen for Analysis of Adjuvant Tamoxifen for B CB CBreast CancerBreast Cancer

M th 60 d i d t i lM th 60 d i d t i lMore than 60 randomized trialsMore than 60 randomized trialsCompared 1 to 2 years or 5 years with no treatment Compared 1 to 2 years or 5 years with no treatment (control) in women with ER(control) in women with ER positive breast cancerpositive breast cancer(control) in women with ER(control) in women with ER--positive breast cancerpositive breast cancerResult: 5 years of treatment was better than 1 to 2 yearsResult: 5 years of treatment was better than 1 to 2 yearsP ti l d ti ff t d b lP ti l d ti ff t d b lProportional reductions unaffected by age, menopausal Proportional reductions unaffected by age, menopausal status, nodal status or concomitant treatmentstatus, nodal status or concomitant treatment5 years of tamoxifen halved recurrence rate and5 years of tamoxifen halved recurrence rate and5 years of tamoxifen halved recurrence rate and 5 years of tamoxifen halved recurrence rate and reduced breast cancer mortality by a thirdreduced breast cancer mortality by a third


Results of MetaResults of Meta--AnalysisAnalysiswww.downstatesurgery.org

Tamoxifen vs. AnastrozoleTamoxifen vs. Anastrozole

ATAC trial ATAC trial ––large, multinational, prospective, double large, multinational, prospective, double g , , p p ,g , , p p ,blinded (9366 women)blinded (9366 women)Compared 5 years of tamoxifen with 5 years of Compared 5 years of tamoxifen with 5 years of anastozole and combination of the twoanastozole and combination of the twoanastozole and combination of the twoanastozole and combination of the twoResults at 4 years favor use of anastrozole as a single Results at 4 years favor use of anastrozole as a single agent with a 14% reduction in the risk for recurrence agent with a 14% reduction in the risk for recurrence

d b l b fi f 2 4%d b l b fi f 2 4%and absolute benefit of 2.4%and absolute benefit of 2.4%Benefits are in women with ERBenefits are in women with ER--positive breast cancer positive breast cancer (no difference in ER(no difference in ER--negative)negative)(( g v )g v )Drugs in SAI group are not appropriate as single agents Drugs in SAI group are not appropriate as single agents in premenopausal womenin premenopausal women


TrastuzumabTrastuzumab

Trastuzumab (Herceptin) Trastuzumab (Herceptin) –– humanized murine humanized murine ( p )( p )monoclonal antibody raised against erbmonoclonal antibody raised against erb--B2/HERB2/HER--2 2 surface receptorsurface receptor

d d dd bd d dd bRecent studies evaluated addition of trastuzumab to Recent studies evaluated addition of trastuzumab to conventional chemotherapy in women with operable conventional chemotherapy in women with operable breast cancer (surgical adjuvant) and women withbreast cancer (surgical adjuvant) and women withbreast cancer (surgical adjuvant) and women with breast cancer (surgical adjuvant) and women with metastatic disease that is HERmetastatic disease that is HER--2 positive2 positiveOutcomes: 50% reduction in either recurrence (for Outcomes: 50% reduction in either recurrence (for adjuvant treatment) or time to progression (for adjuvant treatment) or time to progression (for metastatic disease)metastatic disease)


MetaMeta--analysis of Adjuvant analysis of Adjuvant ChemotherapyChemotherapy

Adjuvant chemotherapy Adjuvant chemotherapy –– administration of cytotoxic administration of cytotoxic drugs after surgerydrugs after surgery33 000 i i d i 100 li i l i l33 000 i i d i 100 li i l i l33,000 women participated in >100 clinical trial 33,000 women participated in >100 clinical trial worldwideworldwideT i l d b f 1995 d d i d b f 2000T i l d b f 1995 d d i d b f 2000Trials opened before 1995 and randomized before 2000Trials opened before 1995 and randomized before 2000Results published on a 5Results published on a 5--year cycle, last summarized in year cycle, last summarized in 2005200520052005Substantial improvements in recurrence and survival Substantial improvements in recurrence and survival for invasive cancerfor invasive cancerfor invasive cancerfor invasive cancer


S i T dS i T dStrategies TestedStrategies Tested

No chemotherapy (control)No chemotherapy (control)Single agent chemotherapySingle agent chemotherapyPolychemotherapyPolychemotherapyPolychemotherapyPolychemotherapyPolychemotherapy containing an anthracycline Polychemotherapy containing an anthracycline (doxorubicin or epirubicin)(doxorubicin or epirubicin)ppMore recent studies include More recent studies include

use of taxanes (docetaxel, paclitaxel) use of taxanes (docetaxel, paclitaxel) –– mitotic mitotic inhibitors radiosensitizing agentsinhibitors radiosensitizing agentsinhibitors, radiosensitizing agentsinhibitors, radiosensitizing agentsuse of trastuzumab for patients with HERuse of trastuzumab for patients with HER--22


ResultsResults

AnthracyclineAnthracycline--based chemotherapy combination based chemotherapy combination reduces estimated breast cancer death rate by 38% in reduces estimated breast cancer death rate by 38% in women <50 and 31% in women 50women <50 and 31% in women 50 69 years of age69 years of agewomen <50, and 31% in women 50women <50, and 31% in women 50--69 years of age69 years of ageSeen in virtually all subtypes of breast cancer based on Seen in virtually all subtypes of breast cancer based on node status ER status and characteristics of the tumornode status ER status and characteristics of the tumornode status, ER status, and characteristics of the tumornode status, ER status, and characteristics of the tumor


Adjuvant ChemotherapyAdjuvant Chemotherapywww.downstatesurgery.org

NCCN Clinical Practice GuidelinesNCCN Clinical Practice Guidelineswww.downstatesurgery.org

NCCN Clinical Practice GuidelinesNCCN Clinical Practice GuidelinesNCCN Clinical Practice GuidelinesNCCN Clinical Practice Guidelines


Adjuvant Endocrine TherapyAdjuvant Endocrine Therapywww.downstatesurgery.org

NCCN Clinical Practice GuidelinesNCCN Clinical Practice Guidelineswww.downstatesurgery.org

SummarySummaryyy

Adjuvant chemotherapy, endocrine therapy, or both, Adjuvant chemotherapy, endocrine therapy, or both, lik l b fi l ll i i h i i blik l b fi l ll i i h i i blikely to benefit nearly all patients with invasive breast likely to benefit nearly all patients with invasive breast cancercancerAdjuvant hormonal therapies benefit only breast cancerAdjuvant hormonal therapies benefit only breast cancerAdjuvant hormonal therapies benefit only breast cancer Adjuvant hormonal therapies benefit only breast cancer patients with ERpatients with ER--positive cancerspositive cancersRiskRisk--benefit ratio of adjuvant therapy must be benefit ratio of adjuvant therapy must be j pyj pyestimated for each patient estimated for each patient Patients with very favorable tumors (e.g. <1cm in size Patients with very favorable tumors (e.g. <1cm in size

i h d hi l 2i h d hi l 2 3 )3 )or tumors with good histology up to 2or tumors with good histology up to 2--3cm) are 3cm) are candidates for no treatment besides local surgery plus candidates for no treatment besides local surgery plus irradiationirradiationirradiationirradiation


ReferencesReferencesReferencesReferences

Willett WC, Rockhill B, Hankinson SE, et al: Willett WC, Rockhill B, Hankinson SE, et al: Nongenetic factors in the causation of Nongenetic factors in the causation of b tb t I H i JR Li ME M M O b CK dI H i JR Li ME M M O b CK dbreast cancerbreast cancer. In: Harris JR, Lippman ME, Morrow M, Osborne CK, ed. . In: Harris JR, Lippman ME, Morrow M, Osborne CK, ed. Diseases of the BreastDiseases of the Breast, 3, 3rdrd ed. Philadelphia: Lippincott Williams Wilkins; ed. Philadelphia: Lippincott Williams Wilkins; 2004:2232004:223--276. 276. Early Breast Cancer Trialists' Collaborative Group:Early Breast Cancer Trialists' Collaborative Group: Effects of chemotherapy Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15and hormonal therapy for early breast cancer on recurrence and 15--year year survival: An overview of the randomised trials. survival: An overview of the randomised trials. LancetLancet 2005;2005; 365:1687365:1687--1717. 1717. Citron ML,Citron ML, Berry DA,Berry DA, Cirrincione C,Cirrincione C, et al:et al: Randomized trial of doseRandomized trial of dose--dense dense versus conventionally scheduled and sequential versus concurrent versus conventionally scheduled and sequential versus concurrent y qy qcombination chemotherapy as postcombination chemotherapy as post--operative adjuvant treatment of nodeoperative adjuvant treatment of node--positive primary breast cancer: First report of Intergroup Trial C9741/Cancer positive primary breast cancer: First report of Intergroup Trial C9741/Cancer and Leukemia Group B Trial 9741. and Leukemia Group B Trial 9741. J Clin OncolJ Clin Oncol 2003;2003; 21:143121:1431--1439. 1439. Goldhirsch AGoldhirsch A Glick JHGlick JH Gelber RDGelber RD et al:et al: Meeting highlights: InternationalMeeting highlights: InternationalGoldhirsch A,Goldhirsch A, Glick JH,Glick JH, Gelber RD,Gelber RD, et al:et al: Meeting highlights: International Meeting highlights: International expert consensus on the primary therapy of early breast cancer 2005. expert consensus on the primary therapy of early breast cancer 2005. Ann Ann OncolOncol 2005;2005; 16:156916:1569--1583. 1583. National Comprehensive Cancer Network Clinical Practice Guidelines in National Comprehensive Cancer Network Clinical Practice Guidelines in Oncolog Breast Cancer V 1 2009Oncolog Breast Cancer V 1 2009Oncology. Breast Cancer. V.1.2009Oncology. Breast Cancer. V.1.2009


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