Breast cancer 2014 by sd moodley

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<p>Milestones in breast cancer</p> <p>Breast Cancer 2014S D MoodleyWits Donald Gordon Medical Centre</p> <p>MBC milestones2Tamoxifen in MBC</p> <p>1973 Ward. Br Med J 1973; 1: 13-14Ward60-77%Stable disease or responseTamoxifen monotherapy3CMF in MBC33%3 monthsOverall response rateMedian survival1976CanellosCanellos et al. Cancer 1976; 38: 1882-1886CMF vs L-phenylalanine mustardC, cyclophosphamide;M, methotrexate;F, 5-fluorouracil4Paclitaxel in MBCFirst publication: Nabholtz et al. Proc Am Soc Clin Oncol 1993; 12: abs 421993CA139-04829% 4.2 months Paclitaxel monotherapy high vs low doseLatest data (175 mg/m2 dose)Nabholtz et al. J Clin Oncol 1996; 14: 1858-1867Overall response rateTime to progression5Aromatase inhibitors in MBC4.2 monthsMedian survivalFirst publication: Jonat et al. Proc Am Soc Clin Oncol 1995; 14: abs 130Buzdar et al. Cancer 1998; 83: 1142-1152Latest data1995Arimidex Study Group trials 3 and 4Anastrozole vs megestrol acetate6Docetaxel in MBC14.5%Overall response rateFirst publication: Chan et al. Proc Am Soc Clin Oncol 1997; 16: abs 5401997TAX 303Docetaxel vs doxorubicinNabholtz et al. J Clin Oncol 1999; 17: 1413-14242.7 monthsMedian survivalLatest dataDocetaxel vs mitomycin C + vinblastineTAX 304First publication: Nabholtz et al. Proc Am Soc Clin Oncol 1997; 16: abs 519Latest dataChan et al. J Clin Oncol 1999; 17: 2341-23547Herceptin in MBCFirst publication: Slamon et al. Proc Am Soc Clin Oncol 1998; 17: 98a, abs 3771998H0648gHerceptin + chemotherapy vs chemotherapy7 monthsMedian survivalSmith. Anticancer Drugs 2001; 12 (Suppl 4): S3-S10Herceptin + paclitaxel vs paclitaxel (HER2 IHC 3+ )Latest data32%Overall response rate8EBC milestones9Adjuvant CMF21%Risk of recurrenceBonadonna et al. BMJ 2005; 330: 2171976The CMF programmeCMF vs observationC, cyclophosphamide;M, methotrexate;F, 5-fluorouracilFirst publication: Bonadonna et al. N Engl J Med 1976; 294: 405-410Latest data29%Risk of death197610Adjuvant tamoxifen36%29%Risk of recurrenceRisk of deathFirst publication: Lancet 1983; 1: 257-261Br J Cancer 1988; 57: 608-611Latest data1983NATO trialTamoxifen vs observation11Adjuvant anthracyclinesRisk of recurrenceFirst publication: Levine et al. J Clin Oncol 1998; 16: 2651-2658Latest dataLevine et al. J Clin Oncol 2005; 23: 5166-51701998NCIC MA.5CEF vs CMF24%C, cyclophosphamide; E, epirubicin;F, fluorouracil; M, methotrexate12Adjuvant taxanes18%Risk of recurrenceRisk of death1998First publication: Henderson et al. Proc Am Soc Clin Oncol 1998; 17: 101a, abs 390ACALGB 9344ACP vs AC 17%A, doxorubicin;C, cyclophosphamide;P, paclitaxelLatest dataHenderson et al. J Clin Oncol 2003; 21: 976-98313Adjuvant aromatase inhibitors13%Risk of recurrenceFirst publication: Baum et al. Breast Cancer Res Treat 2001; 69: 210, abs 82001ATACAnastrozole vs tamoxifenHowell et al. Lancet 2005; 365: 60-62Latest data14Adjuvant Herceptin36%34%Risk of recurrenceRisk of deathFirst presentation: Piccart-Gebhart et al. ASCO 2005Smith et al. Lancet 2007; 369: 29-36Latest data3 further large studies have also demonstrated similar significant reductions in risk of relapse and risk of death Romond et al. N Engl J Med 2005; 353: 1673-1684; Slamon et al. SABCS 2006; abs 522005HERA1-year Herceptin vs observation after chemotherapy15Herceptin landmarksDefined as key studies in the evolution of Herceptin therapyThedata shownare from themost matureanalyses available from these trials16Preclinical evidence for targeting HER2Anti-HER2 monoclonal antibodies revert transformed cells to non-transformed phenotypeDrebin et al. Cell 1985; 41: 697-706198517HER2 amplified in 15 to 30% of breast cancersLink between HER2 expression and breast cancer progression establishedSlamon et al. Science 1987; 235: 177-182198718Herceptin + chemotherapy in MBCFirst publication: Slamon et al. Proc Am Soc Clin Oncol 1998; 17: 98a, abs 3771998H0648gHerceptin + chemotherapy vs chemotherapy7 monthsMedian survivalSmith. Anticancer Drugs 2001; 12 (Suppl 4): S3-S10Herceptin + paclitaxel vs paclitaxel (HER2 IHC 3+ )Latest data32%Overall response rate19First-line Herceptin monotherapy in MBC2000First publication: Vogel et al. Proc Am Soc Clin Oncol 2000; 19: 71a, abs 376Vogel et al. Oncology 2001; 61 (Suppl 2): 37-42Latest data26% Overall response rate24 months Median survivalH0650g20Herceptin + docetaxel in MBCFirst publication: Extra et al. Breast Cancer Res Treat 2003; 82: 47, abs 2172003M77001Herceptin + docetaxel vs docetaxel8.5 monthsMedian survivalMarty et al. J Clin Oncol 2005; 23: 4265-4274Latest data27%Overall response rate21Herceptin + anastrozole in MBC2.4 monthsProgression-free survivalKaufman et al. Ann Oncol 2006; 17 (Suppl 9): LBA22006TAnDEM14.8%Clinical benefit rateHerceptin + anastrozole vs anastrozole22Adjuvant Herceptin36%34%Risk of recurrenceRisk of deathFirst presentation: Piccart-Gebhart et al. ASCO 2005Smith et al. Lancet 2007; 369: 29-36Latest data3 further large studies have also demonstrated similar significant reductions in risk of relapse and risk of death Romond et al. N Engl J Med 2005; 353: 1673-1684;Slamon et al. SABCS 2006; abs 522005HERA1-year Herceptin vs observation after chemotherapy23Herceptin (trastuzumab) for adjuvant therapy of HER2-positive early breast cancer (EBC)24242424Treatment guidelines for HER2-positive EBC1. Goldhirsch et al 2011; 2. Aebi et al 2011; 3. www.nccn.orgAdjuvant therapyRecommended patient groupsAdministrationSt. Gallen11 year of Herceptin (trastuzumab) HER2-positive tumours 1 cmHER2-positive node-negative tumours 0.51.0 cm (pT1b)Excludes: HER2-positive node-negative tumours 0.10.5 cm (pT1a)Preferred: concurrent use of Herceptin (trastuzumab) with chemotherapyAcceptable: chemotherapy followed by Herceptin (trastuzumab) sequentiallyESMO21 year of Herceptin (trastuzumab) HER2-positive tumours 1 cmUse of Herceptin (trastuzumab) should be discussed with patients with small node-negative HER2-positive breast cancersHerceptin (trastuzumab) may be started in parallel with a taxaneHerceptin (trastuzumab) should not be given concurrently with an anthracycline outside the context of a clinical trialNCCN31 year of Herceptin (trastuzumab) Category 1 recommendation: patients with HER2-positive tumours &gt;1 cmCategory 2A recommendation: patients with HER2-positive node-negative tumours 0.61.0 cmHER2-positive node-negative pT1a or pT1b tumours: use of Herceptin (trastuzumab) to be based on individual benefit:riskPreferred: doxorubicin and cyclophosphamide followed by concurrent administration of Herceptin (trastuzumab) with taxanePreferred: docetaxel, carboplatin and Herceptin (trastuzumab), other regimen see at NCCNAcceptable: chemotherapy followed by Herceptin (trastuzumab) sequentiallyHerceptin (trastuzumab) recommended across international guidelinesReferencesGoldhirsch A, Wood WC, Coates AS, et al. Strategies for subtypes dealing with the diversity of breast cancer: highlights of the St. Gallen International Expert Consensus on the Primary Therapy of Early Breast Cancer 2011. Ann Oncol 2011; 22:1736-1747.Aebi S, Davidson T, Gruber G, et al. Primary breast cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2011; 22 (Suppl. 6):vi12-vi24.NCCN Clinical Practice Guidelines in Oncology. Breast Cancer. Version 1.2012. Available at: www.nccn.org</p> <p>Key Herceptin (trastuzumab) studies in HER2-positive EBCCT, chemotherapy (*selected from a list of approved regimens consisting of 4 cycles); RT, radiotherapy</p> <p>1. Gianni et al 2011; 2. Slamon et al 2011; 3. Perez et al 2011StudyNTreatment armsFollow-up(years)HERA1 5102CT* RT observationCT* RT Herceptin (trastuzumab) 1 year CT* RT Herceptin (trastuzumab) 2 years4BCIRG00623222AC docetaxelAC docetaxel+Herceptin (trastuzumab) Herceptin (trastuzumab) Docetaxel+carboplatin+Herceptin (trastuzumab) Herceptin (trastuzumab) 5NCCTG N983133505AC paclitaxelAC paclitaxel Herceptin (trastuzumab) AC paclitaxel+Herceptin (trastuzumab) Herceptin (trastuzumab) 4NSABP B-3132101AC paclitaxelAC paclitaxel+Herceptin (trastuzumab) Herceptin (trastuzumab) 4Extensive clinical programme involving &gt;12,000 patients26ReferencesGianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244.Slamon D, et al. Adjuvant trastuzumab in HER2-positive breast cancer. N Engl J Med. 2011;365(14):1273-83.Perez EA, Romond EH, Suman VJ, et al. Four-year follow-up of trastuzumab plus adjuvant chemotherapy for operable human epidermal growth factor receptor 2-positive breast cancer: Joint analysis of data from NCCTG N9831 and NSABP B-31. J Clin Oncol 2011; 29:33663373.HERA (BO16348)HERceptin Adjuvant (HERA): a randomised three-arm multicentre comparison of 1 year and 2 years of Herceptin (trastuzumab) versus no Herceptin (trastuzumab) in women with HER2-positive primary breast cancer who have completed adjuvant chemotherapy27HERA: study design*Stratification factors: nodal status, adjuvant CT regimen, hormone receptor status and endocrine therapy, age, region</p> <p>Piccart-Gebhart et al 2005: Smith et al 2007; Gianni et al 2011 RANDOMISATIONObservation(n=1698)1 year of Herceptin (trastuzumab) 8 mg/kg6 mg/kg3-weekly schedule(n=1703)2 years of Herceptin (trastuzumab) 8 mg/kg6 mg/kg3-weekly schedule(n=1701)CROSSOVER(n=885)HER2-positiveinvasive EBC (N=5102)*Surgery + (neo)adjuvantCTRTReferencesGianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244.Smith I, Procter M, Gelber RD, et al; HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369:2936.Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer N Engl J Med 2005; 353:16591672.</p> <p>HERA: endpoints IPrimary endpointDisease-free survival (DFS)Herceptin (trastuzumab) 1 year vs observationHerceptin (trastuzumab) 2 years vs observationSecondary endpoints include:Overall survival (OS) and cardiac safety Herceptin (trastuzumab) 1 year vs observationHerceptin (trastuzumab) 2 years vs observationDFS, OS, RFS, DDFS, TTR, TTDR, cardiac safety, overall safetyHerceptin for 1 year vs Herceptin for 2 yearsSafety and tolerability of HerceptinCardiac dysfunction of Herceptin vs observation</p> <p>Piccart-Gebhart et al 2005: Smith et al 2007; Gianni et al 2011 29292929ReferencesGianni L, Dafni U, Gelber RD, et al; Herceptin Adjuvant (HERA) Trial Study Team. Treatment with trastuzumab for 1 year after adjuvant chemotherapy in patients with HER2-positive early breast cancer: a 4-year follow-up of a randomised controlled trial. Lancet Oncol 2011; 12:236244.Smith I, Procter M, Gelber RD, et al; HERA study team. 2-year follow-up of trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer: a randomised controlled trial. Lancet 2007; 369:2936.Piccart-Gebhart MJ, Procter M, Leyland-Jones B, et al; Herceptin Adjuvant (HERA) Trial Study Team. Trastuzumab after adjuvant chemotherapy in HER2-positive breast cancer N Engl J Med 2005; 353:16591672.</p> <p>HERA: disease-free survival at all time pointsCI, confidence interval; HR, hazard ratio</p> <p>1. Piccart-Gebhart et al 2005; 2. Smith et al 2007; 3. Gianni et al 20111 year1Medianfollow-up 2 years24 years3Number of DFS events Herceptin (trastuzumab) vs observation127 vs 220p</p>

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