Hormonal and targeted therapy dr sandip

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gives in a nut shell about the hormonal therapies in breast carcinoma and current practice in oncology

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  • Limitations of the data: Timing of randomization, longest median follow up data is 8 years, different definitions of study end points.
  • Core slide kit: pivotal trial, combination therapy Pivotal trial Phase III Breast cancer, metastatic, first line Breast cancer, metastatic Herceptin combination Trial design Anthracyclines Paclitaxel
  • Core slide kit: pivotal trial, combination therapy Pivotal trial Phase III Herceptin combination Efficacy Survival TTP Conclusions Breast cancer, metastatic, first line
  • Hormonal and targeted therapy dr sandip

    1. 1. Dr.Sandip Kumar Barik
    2. 2.  GONADAL EXTRAGONADALAdipose tissuebrain, skin, boneBlood vessels, placentaEndometrium
    3. 3. It is intra-nuclear type of receptor2 forms - ER-alphaER-betaER-alpha – Gene found on chromosome 6endometrium, breast cell,ovarian stromal cell,hypothalamus.ER-beta – gene found on chromosome 14kidney, bone, brain, heart,lungs, intestinal cells,prostate, endothelial cells.
    4. 4.  Intranuclear steroid receptor. Encoded by single gene PGR on ch.11q22. Exits in 2 forms 1.PR-A – It oppose estrogen inducedproliferation 2.PR-B – It cause epithelial cell proliferationin synchronous with estrogen orestrogen alone can stimulate it
    5. 5.  LIGAND BINDING ASSAYEstrogen – I-125 estradiolProgesteron – H3-R5020considered to be positive if ER>3fmol/mg of protein
    6. 6.  IHC – Antibodies against receptor are used Receptor +ve if score >2NO OF +VE CELLS INTENSITY OF STAININGNone o O no staining< 1/100 1 1 weak1/100 – 1/10 2 2 Intermediate1/10 - 1/3 3 3 strong1/3 - 2/3 4> 2/3 5
    7. 7. Receptor status Pre menopausal Post menopausalER/PR + 45% 63%ER/PR - 28% 17%ER+ only 12% 15%witteff jl.steroid harmone receptors in breast cancer. cancer 53:630,1984ER+PR+ (25%)ER+PR- (7.4%)ER-PR+ (21.1%)ER-PR- (46.5%)Receptor status in Indian populationTata Memorial Hospital Breast. 2000 Oct;9(5):267-70
    8. 8.  Gene located on chromosome 15 Member of cytP450 enzyme Present in ER It has two transcript variant
    9. 9.  Selective Estrogen Receptor Modulator(SERM)1. Tamoxifen2. Tormemifene3. Raloxifen Non Steroidal Inhibitors of Aromatase1. Anastrazole2. Letrozole3. Fadrazole Steroidal Irreversible Inhibitors of Aromatase1. Exemestane Pure Estrogen Receptor Antagonists1. Fulvestrant
    10. 10. EstrogenOvaries Peripheral Sites: adrenal gland,liver, muscle, fatAromataseInhibitorsTamoxifenXPostmenopausalOvarian SuppressionGnRH inhibitors orOvarian removalPremenopausalCancer CellERERFulvestrantTamoxifen
    11. 11. Tamoxifen(10 – 20 mg BD)Raloxifene( 60 mg OD) S/E :-- hot flushes,- fluid retention- vaginal discharge- Irregular menses- Skin rashes- DiarrhoeaPotential risk of developing-- thrombosis- ocular toxicities- endometrial cancer,endometrialhyperplasia,endometrial polyp
    12. 12. NonsteroidalAnastrazole(1 mg OD)Letrazole(2.5 mg OD)SteroidalExemestane(25 mg OD)S/E- skin reactions, jaundice hot flashes, back pain insomnia.
    13. 13. Fulvestrant(250 mg IM monthly ) Side/effects gastrointestinal symptoms headache, back pain, vasodilatation (hot flushes), pharyngitis.
    14. 14. 1 Surgical2 Radiation3 HormonalLHRH agonistsLeuprolideGoserlin
    15. 15.  The upper border - inferior sacroiliac joint. The lower border – mid-obturator foramen. Lateral borders - 1 cm laterally to the pelvicsidewall Dose – 14 - 20 Gy /7 -10 #
    16. 16. • Leuprolide(11.25 mg I.M every3 month)• Goserlin(6.6 mg s/c every2 month)S/E:- Nausea vomiting Sweating , Breast atropphy, Severe polydipsia Polyurea, Ammenorhea.
    17. 17.  Cells in LCIS are usually Estrogen receptorpositive Hence Tamoxifen is indicated in high riskpatients DCIS – estrogen receptor +ve in 70% of DCISTrial group No of pt Follow up No tam WithtamLOCALRECURRENCE (%)P valueNSABP B -241798 7 YR 11.1 7.7 .02UKCCCR 1576 4.38 YR 15 13 .42
    18. 18. In this trial, ovarian ablation or suppression did not add to the benefits of 5 years oftamoxifen treatment or to those of tamoxifen plus chemotherapy in terms of relapse-free survival or overall survival ratesEven in the subgroup of women younger than 40 years who received chemotherapy,the majority of whom would have retained ovarian function, there appears to be nogain from ovarian ablation or suppression in combination with 5 years of tamoxifentreatment.
    19. 19. What to do ???????
    20. 20.  Three scenarios are currently considered:1. Monotherapy with AI for 5yrs vs Tamoxifen.2. Switching or sequencing from tamoxifen to AI orreverse halfway through 5 yrs of treatment.3. Extended adjuvant therapy randomising to AI orplacebo/no furthur therapy after completion of about 5yrs of Tamoxifen.
    21. 21. PRIMARY ADJUVANTTRIALEXTENDED ADJUVANTTRIALAnastrozole is a reasonable choice asinitial therapy because of Improved DFS Decreased incidence ofThromboembolic events Decreased Ca Endometrium Letrozole therapy after 5 years ofadjuvant tamoxifen is tolerable andeffective Letrozole improved DFS and distantDFS across all age groups Significant improvements vsplacebo among patients≤ 60 yrs of age OS improved in those with nodepositive disease(MA17 trial)
    22. 22.  The superiority of AI in reducing recurrence is manifested early in thetreatment and a strategy of randomization after 2-3 yrs of tamoxifenwill exclude women with the most endocrine resistant tumors. Compared with 5 yrs of tamoxifen a switch from tamoxifen to AI after 2-3 yrs improved DFS in all studies. Thus the data so far suggests that initiation of adjuvant endocrinetherapy in post menopausal women should be with an AI and thatcontinuing to 5 years with same therapy or switching to tamoxifen after2-3 yrs appear equally efficacious.
    23. 23.  Member of EGFR family Also k/a CD340 & p185 Her2 is a cell membrane surface bound receptortyrosine kinase Her2 gene is a proto-oncogene located at long arm ofch.17. Neu terminology is used, as it was derived from arodent glioblastoma cell line, a type of neural tumor . 15-20% of breast cancers have an amplification ofHer2neu gene. Over-expression of this receptor in breast cancer isassociated with increased disease recurrence and worseprognosis.
    24. 24.  IHC FISH – Probe tagged with fluorescent label if>2 fluorescent light come out cellconsidered to be overexpressing HER - 2SCORING GRADING0 Absence of staining or < 10% cells are +ve1 Weak & incomplete staining in > 10% cells2 Weak & moderate staining in > 10 % cells3 Strong & complete staining in >10 % cells
    25. 25. Bilous M, et al. Mod Pathol 2003;16:173–82FISHPatient Tumour SampleTranstuzumabtherapy+–2+ 3+1+0+–FISHIHCTranstuzumabtherapyTranstuzumabtherapy
    26. 26.  TRANSTUZUMAB(herceptin)-- Monoclonal antibody.- Acts on cell membrane bound her 2 receptor.- Duration- 1 yr.- Initial trastuzumab dose of 4 mg/kg i.v. over 90 minutes,followed by a weekly maintenance dose of 2 mg/kg i.v.administered over 30 minutes if the initial dose is well tolerated- Toxicity- cardiac dysfunctioning.
    27. 27.  chest pain or heavy feeling, pain spreading to the arm or shoulder,nausea, sweating, general ill feeling; fast or pounding heartbeats; feeling short of breath, even with mild exertion; swelling, rapid weight gain; cough or wheezing; white patches or sores inside your mouth or on your lips; or fever, chills, body aches, flu symptoms. Less serious side effects are more likely to occur, such as: nausea, vomiting, diarrhea; sore throat, sinus pain; joint or muscle pain, back pain; headache; tired feeling.
    28. 28. No prior anthracyclines Prior anthracyclinesPaclitaxel(n=96)Herceptin®+ paclitaxel(n=92)AC(n=138)Herceptin®+ AC(n=143) MBC HER2 IHC 2+/3+ (CTA) No prior CT for MBC Measurable disease KPS ≥60%Patients (n=469)Slamon DJ, et al. N Engl J Med 2001;334:783–92
    29. 29.  Adding Transtuzumab to paclitaxel improves allclinical outcome parameters ORR (from 17 to 49%*) TTP (from 3 to 7 months*) OS (from 18 to 25 months*) Transtuzumab adds little to the toxicity profileof paclitaxel Transtuzumab plus paclitaxel should beconsidered as first-line therapy in HER2-positiveMBC*IHC 3+ patients
    30. 30.  Large adjuvant trials have recently established its role inthe adjuvant setting in 5 RCTs:- HERA- NSABP B31- NCCTG N9831- BCIRG 006- FinHerAdjuvant Transtuzumab Therapy
    31. 31. Women with HER-2 POSITIVE invasiveWomen with HER-2 POSITIVE invasivebreast cancer IHC3+ or FISH+breast cancer IHC3+ or FISH+centrally confirmedcentrally confirmedSurgery + (neo)adjuvant chemotherapy (CT)Surgery + (neo)adjuvant chemotherapy (CT) ±± radiotherapyradiotherapyStratificationStratificationNodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age,Nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age,regionregionRandomizationRandomizationTrastuzumabTrastuzumab8 mg/kg8 mg/kg  6 mg/kg6 mg/kg3 weekly x 2 years3 weekly x 2 yearsTrastuzumabTrastuzumab8 mg/kg8 mg/kg  6 mg/kg6 mg/kg3 weekly x 1 year3 weekly x 1 yearObservationObservation
    32. 32. CONCLUSIONSCONCLUSIONSAt one year median follow-up:At one year median follow-up:• Trastuzumab given every 3 weeks for one year followingTrastuzumab given every 3 weeks for one year followingadjuvant chemotherapy significantly prolongs DFS and RFSadjuvant chemotherapy significantly prolongs DFS and RFSfor women with HER-2 positive early breast cancerfor women with HER-2 positive early breast cancer• Trastuzumab significantly reduces the risk of distantTrastuzumab significantly reduces the risk of distantmetastasesmetastases• Trastuzumab’s clinical benefits are independent ofTrastuzumab’s clinical benefits are independent ofpatients’ baseline characteristics (nodal status, hormonepatients’ baseline characteristics (nodal status, hormonereceptor status, ...) and of type of adjuvant chemotherapyreceptor status, ...) and of type of adjuvant chemotherapyreceivedreceived
    33. 33.  Lapatinib(Tykerb):-Dose 1250 mg daily• Inhibits the Tyrosine kinase activity associated with twooncogenes EGFR1 & EGFR2.• Approved in combination with capecitabine for treatment ofpatients with:• Advanced or metastatic breast cancer whose tumor overexpress HER2 neu.• Who have received prior therapies with Anthracyclins,Taxanes andTrastuzumab.
    34. 34.  Everolimus:(5 mg OD)• Its acts by selectively inhibiting mTOR(mammalian target ofRapamycin),an intracellular protein kinase .• Useful for endocrine resistant,hormone receptor positive,Her2neu negative advanced breast cancer.• Potentially overcome resistance to endocrine therapy.• Phase II studies have reported that combination ofmTORinhibitors with endocrine therapy shows efficacy in pts withadvanced disease that progressed after treatment with aromataseinhibitors
    35. 35. The addition of everolimus to exemestane for women with HR positive metastaticBreast cancer is now considered a new therapeutic strategy.
    36. 36.  Bevacizumab(binds to VEGF) Aflibercept(Fusion protein targeting VEGF) Pertuzumab(blocks HER2 with EGFR,HER3,HER4) Sorafenib
    37. 37.  THANK YOU

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