Breast Cancer Epidemiology Australia Australian Institute of Health and Welfare 2014 ACIM Australian Cancer Incidence and Mortality Books Canberra AIHW Overall is the third leading cause of cancer ID: 1033274
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1. Adjuvant Therapy For Breast Cancer
2. Breast Cancer | Epidemiology- AustraliaAustralian Institute of Health and Welfare 2014. ACIM (Australian Cancer Incidence and Mortality) Books. Canberra. AIHWOverall is the third leading cause of cancerMost common cause of cancer in women
3. Incidence rates higher in economically developed regions Inc. Australia, Western Europe, Nth. AmericaIncreased Incidence in 1980-1990 increased screening Decline in incidence in since 2000HRT relatedWorldwide increase in incidence Developing CountriesBreast Cancer | Worldwide Incidence
4. FactorRelative RiskGender (female vs. male)100Age (<50 vs. >50)6.7Endocrine Factors-Age of menarche (<10)-Age at first birth (>35)-Nulliparity-Age at menopause (>55)1.4-1.91.71.41.3Benign Breast Disease- ADH, LCIS4.0 -5.0Family HistoryFirst degree relativeBRCA1/ BRCA2 mutationP53 (Li- Fraumeni)PTEN (Cowden Syndrome)2.0 -7.010-301.5-6.02.0-4.0Ethnicity (Ashkenazi Jewish)1.4Therapeutic radiation35Breast Cancer | Established Risk Factors: FIXED
5. FactorRelative RiskExogenous HormonesOCPOestrogen replacement (>10 years)Oestrogen and Progesterone 0.9-1.01.11.4-3.0Obesity (>30)2.5Exercise (>3 hours/ week)0.6Alcohol Use1.1-2.2Diet 1.0Mammographic Density2.2-3.5Breast Cancer | Established Risk Factor: MODIFIABLE
6. All breast cancer patients need consideration of adjuvant therapyThere are multiple possible treatment options which can be used individually or combined Includes not only chemotherapy but endocrine and targeted therapyWho to treat with which agents….Prognostic factorsPredictive factorsBreast Cancer | Who needs Adjuvant Therapy?
7. Patient AgePerformance StatusBreast Cancer | The patient in front of youGradeECOG Performance Status0Fully active1Restricted in physically strenuous activity but ambulatory and able to carry out work of light or sedentary nature2Ambulatory and capable of all self care. Up > 50% of waking hours3Capable of only limited self care, confined to bed or chair for > 50% of working hours4Completely disabled. Cannot carry on any self care. Totally confined to bed or chair
8. Breast Cancer | Staging: AJCC Tumour Staging
9. Breast Cancer | Staging: AJCC TNM StagingPRIMARY TUMOURTXCan not be assessedT0Tumour not presentTisCarcinoma in situT1<2.0cmT2>2.0cm but <5cmT3>5.0cmT4Any size tumour with extension through the chest wall or skin ulceration/ nodules or bothT4dInflammatory breast cancerREGIONAL LYMPH NODESNXCan not be assessedN0Nodes not involved N1Clinical/ Pathological involvement of axillary/ internal mammary LNN2 Ipsilateral axillary LN or clinically apparent internal mammary LN in the absence of clinically +ve axillary LNN3Ipsilateral infraclavicular, supraclavicularMETASTASESM0No Metastatic diseaseM1Metastatic diseaseAJCC Cancer Staging Manual, 7th Edition (2010) Springer Science and Business Media LLC
10. Both prognostic and predicative informationBreast Cancer | Intrinsic Molecular SubtypesSubtypeLuminal AER/PR strongly +ve, low proliferationBest overall prognosisLuminal BER/PR +ve, high proliferationBasal LikeTriple negative (ER, PR, HER2 –ve)More common in BRCA-1Worst prognosisHER2 richHER2+, ER/PR-veNormalSynder R. Update of breast cancer FRACP Pt1. (2013)
11. Gene expression profilingAssessment of the risk of both local and systemic recurrence among breast cancers with a more FAVOURABLE profileThose with low risk are unlikely to significantly benefit from CTxOncotype DX ( 21 genes) Breast Cancer | Gene Expression SignaturesVa de Vijver et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. NEJM. 2002: 347: 1999-2009Paik et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. NEJM: 2004: 351: 2817-2826
12. Breast Cancer | Oncotype
13. Breast Cancer | Oncotype
14. Breast Cancer | TAILORx Trial
15. Breast Cancer | Anatomical LN InvolvementWithout Systemic Treatment1-3 LN: 25-35% recurrence rate4-9 LN: 25-55% recurrence rate >10 LN: >70% recurrence rateQuiet et al. Natural History of node positive breast cancer: the curability of small cancers with a limited number of positive nodes. J Clin Oncol. 1996; 14:3105-3111
16. Breast Cancer | HistologyHistological ClassificationDuctal (75%)Lobular (10%)Tubular (1-4%)MucinousMedullaryPapillaryMicropapillary
17. Breast Cancer | Stage I and IILocal Disease ControlSurgeryBreast Conservation SurgeryMastectomyWith sentinel lymph node biopsy in bothRadiationWhole Breast RadiotherapyApplied to the tumour bed, over a course of 5-6 week, or in older patients this can be shortened to a 2-3 week periodMajority of local tumour recurrences occur at or around the tumour bed or localised lymph nodes
18. Things taken into account when planning adjuvant therapy Age ECOGTumour sizeTumour HistologyLymphatic InvasionProliferative RateHormone Receptor StatusHER2 Status Intrinsic Molecular SubtypesGene Expression SignaturesPatient PreferenceBreast Cancer | Therefore….
19. Breast Cancer | Chemotherapy
20. Breast Cancer | Historical Chemotherapy TimelineVerrill M, Chemotherapy for early-stage breast cancer: a brief history. British Journal of Cancer (2009)
21. CMF (Cyclophosphamide, Methotrexate, 5-FU)AC (Doxorubicin, Cyclophosphamide)FEC (5-FU, Epirubicin, Cyclophosphamide)AC-docetaxel, AC-paclitaxelDose Dense ACFEC-TBreast Cancer | Historical Chemotherapy Timeline
22. Breast Cancer | What is Gold Standard?Peto, R San Antonia Breast Cancer Symposium on behalf of the Early Breast Cancer Trialists’ Collaborative Group
23. EBCTCG meta-analysis (2011)Anthracycline- containing regimensDecreased risk of recurrence resulting in an absolute reduction of 8%Reduction of BC mortality to an absolute decreased of 6.5%Reduction in overall mortality to an absolute of 5.0% CMFDecrease in the risk of recurrence in an absolute reduction of 10.2%Reduction in BC mortality to an absolute decreased of 6.2%Reduction in overall mortality to absolute decrease of 4.7%Breast Cancer | Rationale for Adjuvant Therapy
24. Breast Cancer | Adjuvant CTx: General PrinciplesMaintain full dose densityWomen > 70 need more individualised decisionsThere is no added benefit to dose escalation in adjuvant treatmentPoly-chemotherapy is preferred
25. Breast Cancer | High Grade Basal DiseaseAccounts for 10-15% of all breast cancerMore common in young and/or black patientsCommonly presents as higher gradePrognosis is more difficult Does not correlate as closely with tumour size or nodal involvementRequires treatment with adjuvant CTx at a smaller tumour size
26. Hormone Receptors Oestrogen/ ProgesteroneRegulate gene expression through interaction with hormone response elements. Breast Cancer | Oestrogen and Progesterone Receptors
27. Positive prognostic indicatorLate disease recurrenceER/PR –ve: greatest risk < 5 years, then dramatic declineER/PR +ve: Slower rise in recurrence and more gradual declinePredictive indicatorOf response to endocrine therapyHigher degrees of positivity indicate increased responseBreast Cancer | Oestrogen and Progesterone Receptors
28. Endocrine TherapyReduces the risk of systemic recurrenceIncreased overall survivalAll women regardless of age, menopausal status, nodal involvement, tumour size, HER2 status or use of chemotherapyTherefore almost universal use across the population of HR +ve patientsBreast Cancer | Hormone Receptor +ve disease
29. The diagnosis of menopause is made at the time of diagnosisTamoxifen for 5 years is the current standard therapyAromatase Inhibitors are not active for women with intact ovarian function Including amenorrhic women secondary to chemotherapy Ovarian SuppressionOvarian ablation/ OophorectomyLHRH agonistBreast Cancer | Endocrine Therapy: Pre-menopausal
30. Breast Cancer | Endocrine Therapy: Tamoxifen
31. Breast Cancer | Aromatase InhibitorsSuppress plasma oestrogen levels by inhibiting or inactivating aromatase
32. AnastrozoleLetrozoleExemestane (steroidal inhibitor) Comparable in efficacySimilar SE profileArthralgias, myalgias, reduction in bone densityBreast Cancer | Postmenopausal HR+ve
33. Breast Cancer | Tamoxifen or AI
34. Breast Cancer | Tamoxifen then AI
35. Breast Cancer | Big 1-98 trialDFSOSLetrozole alone78.6%87.5%Letrozole2/ Tamoxifen 377.8%87.7%Tamoxifen2 / Letrozole 377.3%85.9%
36. Breast Cancer | Adjuvant Endocrine TherapyStudyEndocrine therapy and duration Relative risk of recurrenceRelative Risk of mortalityEBCTCTamoxifen (5 years)0.610.70ATACAnastrozole vs. Tamoxifen (5yr)0.901.00BIG 1-98Letrozole vs. Tamoxifen (5yr)0.880.81Sequential TherapyBIG 1-98Tamoxifen/ Letrozole vs. letrozole1.051.13BIG 1-98Letrozole/ Tamoxifen vs. Letrozole0.960.9Extended TherapyNCIC CTG MA. 17Tamoxifen (5 yrs) then Letrozole (5 yrs)0.680.98
37. Member of the epidermal growth factor receptor tyrosine kinase family EGFR-1, HER2, HER3, HER4Breast Cancer | HER-2
38. Breast Cancer | HER2 Overamplification
39. Overexpression of the HER2 protein is a consequence of gene amplification Occurs in 20% of BCStrong predictive indicatorIncreased efficacy of certain CTx agentsIncreased resistance to endocrine therapyModest prognostic indicatorIndependent of other prognostic indicatorsBreast Cancer | HER2 Overamplification
40. Trastuzumab (Herceptin)Adjuvant: survival advantageIV delivery ? Role for s/c in futureSide effect profileModify cardiac muscles response to stress5% of patients experience asymptomatic decrease in EFIncreased risk with advanced age, HTN, poor initial EF Breast Cancer | Trastuzumab
41. TrialEligibility RequirementsTreatmentHR for Disease Free SurvivalNSABP B-31Node +ve diseaseAC-T vs AC-TH0.48NCCTG N9831Node +ve or high risk node –veAC-T vs. AC-TH (concurrent)0.48AC-T vs. AC-T-H0.86BCIRG 006Node +ve or high risk node –veAC-D vs. AC-DH0.61FinHERNode +ve or high risk node –veD or V +FEC vs. D or V+ FEC + HFNCLCC-PACS 04Node +veFEC or ED vs. FEC of ED + H0.86Breast Cancer | Seminal Adjuvant Trastuzumab Trials
42. HER2 is a tyrosine kinase receptor that activates downstream oncogenic signaling pathwaysHER2/HER3 Dimers may provide an escape mechanism for trastuzumabTherefore it has been postulated that a combination of HER2 receptor targets may have synergistic effectsBreast Cancer | New Therapies
43. PertuzumabShows survival benefit in neo-adjuvant and metastatic settingNCCN guidelines 2014 indicate that it can be incorporated into adjuvant treatment alongside CTx and trastuzumabAdjuvant trials ongoing Breast Cancer | Other HER2 receptor based therapy
44. TRASTUZUMABPERTUZUMABTrastuzumab continually suppresses HER2 activityInhibits HER formation of dimer pairsFlags cells for destruction by the immune systemSuppresses multiple HER signalling pathwaysDoes not inhibit HER2 dimerizationFlags cell for destruction by immune systemBreast Cancer | Other HER2 receptor based therapy
45. Trial ArmComplete Pathological ResponseER/PR-veA (107)29.0% (31 0f 107)36.8% B (107)45.8% (49 of 107)63.2%C (107)16.8% (18 of 107) 29.1%D (96)24.0% (24 of 96)30.0%Improvement in pCR with use of dual HER2 blocking therapy and CTxIncreased efficacy in the patients with ER/PR –ve diseaseBreast Cancer | Neo-Sphere trial
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