Published on December 16, 2016
1. Early Breast CancerEarly Breast Cancer “Standard Care”“Standard Care” Dr. Shad Salim AkhtarDr. Shad Salim Akhtar MBBS, MD, MRCP(UK), FRCP(Edin)MBBS, MD, MRCP(UK), FRCP(Edin) Member Association of Fellows UICCMember Association of Fellows UICC Consultant Medical OncologistConsultant Medical Oncologist Medical DirectorMedical Director King Fahd Specialist Hospital &King Fahd Specialist Hospital & Prince Faisal Oncology CenterPrince Faisal Oncology Center Buraidah, Al-Qassim, KSABuraidah, Al-Qassim, KSA
2. Narrated Hadhrate Aisha (RAA) The Prophet (SAW) said, “Indeed Allah loves among you the one who does the work (what ever he does) in the best way”
3. Breast Cancer ManagementBreast Cancer Management DiagnosisDiagnosis – Clinical diagnosisClinical diagnosis – HistopathologyHistopathology SurgerySurgery RadiotherapyRadiotherapy Systemic medical therapySystemic medical therapy
4. SurgeryLump Diagnostic Evaluation Clinical examination Mammography FNA Ultrasound Triple Assessment
5. Biochemical markers are essentialBiochemical markers are essential Chest X-ray RoutineChest X-ray Routine LUS/BS only if biochemicalLUS/BS only if biochemical abnormalities?abnormalities? CT scan/MRI/PETCT scan/MRI/PET Breast Cancer-Preoperative StagingBreast Cancer-Preoperative Staging
6. Breast Cancer-Standard SurgeryBreast Cancer-Standard Surgery NCI Consensus StatementNCI Consensus Statement Complete excision of breast cancer withComplete excision of breast cancer with negative marginsnegative margins Level I/II axillary lymph node dissectionLevel I/II axillary lymph node dissection Jardines L et al: Breast Cancer in Cancer Management: PPR 2002; 173-
7. BCT-Need for RTBCT-Need for RT InterventionIntervention Local FailureLocal Failure %% BCT+AxD+RTBCT+AxD+RT 6-136-13 BCT+AxDBCT+AxD 18-3618-36 Local Failure rate at 10 years follow up Percent reduction in local rec with RT 56-75%
8. Post mastectomy RadiotherapyPost mastectomy Radiotherapy Current ConsensusCurrent Consensus Incomplete resection (micro/macro)Incomplete resection (micro/macro) >=4 positive nodes>=4 positive nodes T3 N+ tumorsT3 N+ tumors T3 GII/III & or Vascular InvasionT3 GII/III & or Vascular Invasion Diffusely growing tumors in >1 quadrantDiffusely growing tumors in >1 quadrant In T1 node positive (<3) trials neededIn T1 node positive (<3) trials needed Benefit should be maximum when noBenefit should be maximum when no occult disease is presentoccult disease is present Overgaard M: Eur J Cancer 2001; 37 (s7):33
9. Post mastectomyPost mastectomy Axillary RadiotherapyAxillary Radiotherapy >= 4 nodes in level II>= 4 nodes in level II 50% removed nodes positive50% removed nodes positive Palpable metastatic lymph node >2 cmsPalpable metastatic lymph node >2 cms Margin of surgery <5mmMargin of surgery <5mm Extra nodal spreadExtra nodal spread Axillary recurrence rate lower than chestAxillary recurrence rate lower than chest wallwall Bartelink H: Ann Oncol 2000; 11(3):7
10. Post mastectomy RadiotherapyPost mastectomy Radiotherapy What is the optimal timing?What is the optimal timing? Interval between Surgery & RT effects LRInterval between Surgery & RT effects LR Retrospective studies suggest max 6 wksRetrospective studies suggest max 6 wks gapgap Batelink H Ann Oncol 2000: 11 (s3):7
11. Post mastectomy RadiotherapyPost mastectomy Radiotherapy What is the optimal timing?What is the optimal timing? CT vs RT timing?CT vs RT timing? Joint Center for Radiation StudyJoint Center for Radiation Study – CT before RT betterCT before RT better – Distant failure lessDistant failure less – OS betterOS better – Benefit in node positive patients onlyBenefit in node positive patients only Sandwich approachSandwich approach – Danish studyDanish study – British Columbia studyBritish Columbia study Overgaard M: Eur J Cancer 2001; 37 (7):33
12. Breast Cancer-TreatmentBreast Cancer-Treatment Halsted hypothesisHalsted hypothesis – Local control improves survivalLocal control improves survival Systemic hypothesisSystemic hypothesis – Local control has no impact onLocal control has no impact on survivalsurvival Present UnderstandingPresent Understanding – Maximal disease controlMaximal disease control LocoregionalLocoregional SystemicSystemic
13. Adjuvant Medical TherapyAdjuvant Medical Therapy EndocrineEndocrine ChemotherapyChemotherapy OthersOthers Who shall get itWho shall get it How long shall it be givenHow long shall it be given What typeWhat type What doseWhat dose
14. TamoxifenTamoxifen Should be used in all ER +ve ptsShould be used in all ER +ve pts regardless of:regardless of: – AgeAge – Menopausal statusMenopausal status – Axillary node involvementAxillary node involvement – Tumor sizeTumor size NIH and St Gallen Consensus Conferences
15. Tamoxifen How Long?Tamoxifen How Long? TrialTrial DesignDesign StatusStatus TargetTarget ResultResult NSABPNSABP B-14B-14 5yrs vs5yrs vs ContdContd ReportedReported 11721172 Equivalence for OSEquivalence for OS Long use more End CaLong use more End Ca ECOGECOG E4181E4181 5 yrs vs5 yrs vs ContdContd ReportedReported Equivalence for RFSEquivalence for RFS ScottishScottish 5 yrs vs5 yrs vs ContdContd ReportedReported 342342 Equivalence for RFSEquivalence for RFS Long use more End CaLong use more End Ca ATLASATLAS 5 yrs vs 105 yrs vs 10 yrs in ER+yrs in ER+ OpenOpen 2000020000 N/AN/A ATTOMATTOM 5yrs vs 105yrs vs 10 yrs ER +?yrs ER +? OpenOpen ?? N/AN/A Lohrisch C et al: Eur J Cancer 2001; 37 (s7):45
16. Tamoxifen When?Tamoxifen When? Sequential better ?Sequential better ? Data from ECOG trialData from ECOG trial – PremenopausalPremenopausal – Node positiveNode positive – ER positiveER positive – CAF vs CAF+OA vs CAF+OA+TAMCAF vs CAF+OA vs CAF+OA+TAM – Last combination superiorLast combination superior Davidson N et al: Proc Am Soc Oncol 1999; 18:67a (abstract 249)
17. Intergroup 0100 trialIntergroup 0100 trial CAFT+TCAFT+T CAF+TCAF+T Postmenopausal ptsPostmenopausal pts Node +Node + HR +HR + 8 yrs follow up8 yrs follow up Tamoxifen When?Tamoxifen When?
18. Tamoxifen When?Tamoxifen When? Regimen DFS CAFT+T 62% CAF+T 67% Albian KS et al: Proc ASCO:2002. Sequential tamoxifen better
19. Adjuvant Medical TherapyAdjuvant Medical Therapy Oxford Overview 2000-Ovarian AblationOxford Overview 2000-Ovarian Ablation In the absence of CT Ovarian Ablation inIn the absence of CT Ovarian Ablation in <50 yrs of age<50 yrs of age – Reduces Br Ca Rec-8.5%Reduces Br Ca Rec-8.5% – Improves survival-9.8%Improves survival-9.8% OA + CT no such benefitOA + CT no such benefit Specific focus on HR+ premenopausal ptsSpecific focus on HR+ premenopausal pts not availablenot available
20. Ovarian AblationOvarian Ablation OA+/- Tam vs CTOA+/- Tam vs CT 8 randomized trials8 randomized trials Conclusion: OA+/- Tam=CMFx6Conclusion: OA+/- Tam=CMFx6 To note:To note: – CMF not anthracyclines were triedCMF not anthracyclines were tried – Tam was not used wth CMFTam was not used wth CMF May be used as an alternative to CT in ERMay be used as an alternative to CT in ER rich ptsrich pts – Definite premenopausalDefinite premenopausal – Tam must be addedTam must be added Davidson N ASCO 2002 Education Book; 156
21. Tamoxifen+Ovarian AblationTamoxifen+Ovarian Ablation No dataNo data Trials are onTrials are on
22. ATAC TrialATAC Trial AnastrozoleAnastrozole TamoxifenTamoxifen Comb(%)Comb(%) Total(%)Total(%) Ist eventIst event 31253125 31163116 31253125 93669366 LRLR 6767 8383 8181 231231 DRDR 158158 182182 204204 544544 ContralContral CaCa 1414 3333 2828 7575 DeathsDeaths before Rbefore R 7878 8181 7070 229229 TotalTotal 317317((10.1%)10.1%) 379379((12.2%)12.2%) 383383((12.312.3)) 10791079((11.5)11.5) ATAC Trialists Group: Lancet 2002; 359:2131
23. Shall we stop using TamoxifenShall we stop using Tamoxifen NONO Single trialSingle trial Short follow upShort follow up Safety for 5 yrs?Safety for 5 yrs? Additive effect over years?Additive effect over years? Carry over effect?Carry over effect?
24. When to use Anastrozole?When to use Anastrozole? As adjuvant inAs adjuvant in – Postmenopausal ptPostmenopausal pt – HR +ve tumourHR +ve tumour May be considered in pts with TamMay be considered in pts with Tam contraindicationcontraindication NO IndicationNO Indication – To switch from Tam to AnastrozoleTo switch from Tam to Anastrozole – To add after 5 yrs of TamTo add after 5 yrs of Tam – Other AI equivalent?Other AI equivalent?
25. Risk of Recurrence Node negativeRisk of Recurrence Node negative Risk level Rec at 10yrs Low Risk <10 % High Risk ~20 % Intermediate Risk 10-20% EBCTG: Lancet 1992; 339:1
26. Risk of Recurrence Node PositiveRisk of Recurrence Node Positive Risk level 10 yr surv 1-3 nodes 40-60 % >=4 nodes 25% EBCTG: Lancet 1992; 339:1
27. Absolute reduction in mortality –Absolute reduction in mortality – effect of medical therapyeffect of medical therapy 10 yr risk of death Abs benefit in 100 women from breast cancer if therapy reduces ann (%) odds of death by 10-20 4 2 20-40 8 4 40-80 12 6 EBCTG: Lancet 1992; 339:1 30% <15 %
28. Adjuvant Medical Therapy 2000 Oxford OverviewAdjuvant Medical Therapy 2000 Oxford Overview 3-6 months Chemotherapy3-6 months Chemotherapy Pre -ve 7% Pre +ve 11% Post -ve 2% Post +ve 3% 2000 Review unpublished data Menop Node Imp in Surv Regardless of tamoxifen usage
29. Chemotherapy in Premenopausal PtsChemotherapy in Premenopausal Pts Regardless of HR statusRegardless of HR status All node positive patientsAll node positive patients Node negative with non low risk statusNode negative with non low risk status In very low risk HR-ve otherwise goodIn very low risk HR-ve otherwise good prognosis role unknown, most would use itprognosis role unknown, most would use it In very low risk node-ve disease uncertainIn very low risk node-ve disease uncertain Lohrisch C et al: Eur J Cancer 2001; 37 (s7):45
30. Chemotherapy in PostmenopausalChemotherapy in Postmenopausal PtsPts 50-69 yrs old50-69 yrs old Irrespective of addition of TamIrrespective of addition of Tam Node Positive/Node NegativeNode Positive/Node Negative ER –ve or ER ? Greatest advantageER –ve or ER ? Greatest advantage Offering CT to ER+ pts considerOffering CT to ER+ pts consider – Pt/tumor characteristicsPt/tumor characteristics – Co morbid conditionsCo morbid conditions Lohrisch C et al: Eur J Cancer 2001; 37 (s7):45
31. Which Chemotherapy?Which Chemotherapy?
32. Which Chemotherapy?Which Chemotherapy? Standard regimens consist ofStandard regimens consist of – CMF/Anthracycline based CTCMF/Anthracycline based CT Anthracyclin vs CMFAnthracyclin vs CMF – 4% absolute reduction as compared to CMF for4% absolute reduction as compared to CMF for death and recurrencedeath and recurrence In node negative setting (1.7%) ? LessIn node negative setting (1.7%) ? Less benefitbenefit Both regimens have toxicityBoth regimens have toxicity Piccart M et al: ASCO Education Book 2002; 144
33. Which Chemotherapy?Which Chemotherapy? Anthracycline basedAnthracycline based – Premenopausal womenPremenopausal women Node positiveNode positive Node negative high riskNode negative high risk CMFCMF – In patientsIn patients With high risk of cardio toxicityWith high risk of cardio toxicity Low risk diseaseLow risk disease Piccart M et al: ASCO Education Book 2002; 144
34. Which Chemotherapy?Which Chemotherapy? Taxanes vs no TaxanesTaxanes vs no Taxanes CALGB Trial 9344CALGB Trial 9344 – DFS increased in Node+ve pts ACx4+Tx4DFS increased in Node+ve pts ACx4+Tx4 – Reanalysis- Benefit only in ER-ve ptsReanalysis- Benefit only in ER-ve pts NSABP B-28NSABP B-28 – ACx4+Tx4 no benefitACx4+Tx4 no benefit Br C Int Res Gp 001 (33 months FU)Br C Int Res Gp 001 (33 months FU) – FAC vs TACFAC vs TAC – TAC improved DFS and OSTAC improved DFS and OS – Advantage in 1-3 node +ve ptsAdvantage in 1-3 node +ve pts No established role yet as adjuvantNo established role yet as adjuvant Piccart M et al: ASCO Education Book 2002;
35. Chemotherapy- Optimum Dose?Chemotherapy- Optimum Dose? CMFCMF 2 trials I/V CMF 3 vs 62 trials I/V CMF 3 vs 6 – EquivalentEquivalent – Short follow upShort follow up IBCSG Oral CMF 3 vs 6 cyclesIBCSG Oral CMF 3 vs 6 cycles – CMF x6 betterCMF x6 better Oral CMF better?Oral CMF better? Reserve I/V cyclo for non toleranceReserve I/V cyclo for non tolerance Hortobagyi IC st al: J Natl Cancer Inst Monogram 2001; 30:72
36. Chemotherapy-Optimum Dose/Cycles?Chemotherapy-Optimum Dose/Cycles? AnthracyclinesAnthracyclines NSABP B-15 & B-23NSABP B-15 & B-23 – 4 cycles AC equivalent to CMF4 cycles AC equivalent to CMF Canadian TrialCanadian Trial – CEFx6 vs CMFx6CEFx6 vs CMFx6 – CEF betterCEF better
37. Two populations of br ca-peak incid ofTwo populations of br ca-peak incid of recurrecur – 2 years2 years – 5 years5 years 6 cycles important in former6 cycles important in former Superiority of Anthracycline regimen in 3Superiority of Anthracycline regimen in 3 drug combinationsdrug combinations In non high risk patients 4 (F)AC or 6 CMFIn non high risk patients 4 (F)AC or 6 CMF may be enoughmay be enough In high risk patients 6 FAC (FEC)In high risk patients 6 FAC (FEC) Chemotherapy-Optimum Dose/Cycles?Chemotherapy-Optimum Dose/Cycles?
38. Chemotherapy When to Start?Chemotherapy When to Start? IBCSG Trials reviewIBCSG Trials review ER –ve ptsER –ve pts – Within 21 days of surgery 10 yr DFS 60%Within 21 days of surgery 10 yr DFS 60% – After 21 days 10 yr DFS 34 %After 21 days 10 yr DFS 34 % ER positive pts no differenceER positive pts no difference Should be instituted within 4-6 (12) wks ofShould be instituted within 4-6 (12) wks of surgerysurgery
39. Tamoxifen+ ChemotherapyTamoxifen+ Chemotherapy Postmenopausal womenPostmenopausal women CT+Tam have additive effect?CT+Tam have additive effect? In ER+ pts no definite added benefitIn ER+ pts no definite added benefit confirmedconfirmed – Trials are on stillTrials are on still – In high risk patients CT may be added toIn high risk patients CT may be added to hormonal agenthormonal agent Keep in mind the benefit and toxicityKeep in mind the benefit and toxicity
40. Tamoxifen+ ChemotherapyTamoxifen+ Chemotherapy Premenopausal womenPremenopausal women Trials are on to answer this questionTrials are on to answer this question Overview found a highly significant survOverview found a highly significant surv benefitbenefit Side effects are lowSide effects are low May be given pending the results of theMay be given pending the results of the trialstrials In node –ve low risk Tam or noneIn node –ve low risk Tam or none
41. Ovarian Ablation + CT Added Benefit?Ovarian Ablation + CT Added Benefit? Oxford Review 2000 OA added to CTOxford Review 2000 OA added to CT Non significant increase in deathNon significant increase in death Non significant decrease in recurrence rateNon significant decrease in recurrence rate Three Randomized trialsThree Randomized trials – Intergroup 0100 CAFx6 vs CAF+Z (+/- Tam toIntergroup 0100 CAFx6 vs CAF+Z (+/- Tam to either)either) – CAF+Z+T improved survivalCAF+Z+T improved survival – CAF+Z vs CAF no differenceCAF+Z vs CAF no difference
42. Ovarian Ablation + CT Added Benefit?Ovarian Ablation + CT Added Benefit? IBCSG Trial VIIIIBCSG Trial VIII – Node –ve/any receptorNode –ve/any receptor – CMFx6 vs Gx18 vs CMF+GCMFx6 vs Gx18 vs CMF+G – Equivalence in ER +ve ptsEquivalence in ER +ve pts ZIPP TrialZIPP Trial – Tam vs No TamTam vs No Tam – Z vs No ZZ vs No Z – CT vs No CTCT vs No CT – Addition of Z betterAddition of Z better – Reanalysis-no improvement in pts who hadReanalysis-no improvement in pts who had CT+TamCT+Tam
43. Ovarian Ablation + CT Added Benefit?Ovarian Ablation + CT Added Benefit? In view of the available data this cannot be recommended at this stage
44. Predictive Markers Do We Have?Predictive Markers Do We Have? 9 large and many small trials9 large and many small trials Suggested a predictive factorSuggested a predictive factor – Neu/erb2Neu/erb2 – Over expression CMF does not workOver expression CMF does not work – Over expression low or mod dose CAF does notOver expression low or mod dose CAF does not workwork Relation to response to TamRelation to response to Tam – Conflicting reportsConflicting reports Pritchard KI: ASCO Education Book 2002; 161
45. Predictive Markers Do We Have?Predictive Markers Do We Have?
46. Adjuvant Medical TherapyAdjuvant Medical Therapy Endocrine non Responsive Chemotherapy Endocrine Responsive Node negative Minimal /lowrisk Average/high risk OA+Tam CT+Tam Tam OA Tam Nil Postmenop Tam Tam+CT Premenop Node positive CT+Tam OA+Tam Postmenop Tam Tam+CT Premenop
47. Adjuvant Medical TherapyAdjuvant Medical Therapy Unsolved ProblemsUnsolved Problems Elderly patients HR-veElderly patients HR-ve < 1 cms tumor size< 1 cms tumor size Average/high risk node negative HR+Average/high risk node negative HR+ – OA/CT/TamOA/CT/Tam Post CT OA in premenopausal HR+Post CT OA in premenopausal HR+ patientspatients