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Future directions regarding Hereditary Breast Cancer

Future directions regarding Hereditary Breast Cancer. C. Seynaeve, ErasmusMC-Daniel den Hoed, Rotterdam BMM Brussels, October 13, 2006. HBC: Future Directions. Entities and Risk Assessment Recognition Outcome data: further delineation Clinical practice after a history of BC / OC

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Future directions regarding Hereditary Breast Cancer

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  1. Future directions regarding Hereditary Breast Cancer C. Seynaeve, ErasmusMC-Daniel den Hoed, Rotterdam BMM Brussels, October 13, 2006

  2. HBC: Future Directions • Entities and Risk Assessment • Recognition • Outcome data: further delineation • Clinical practice • after a history of BC / OC • at BC diagnosis • Guidelines • Systemic therapy ? Chemoprevention Advanced/M1 disease

  3. Entities • BRCA1/2 mutation familyCLTR 60-80%, CBC 30-50% •  18-20% of the tested families • mutations are being missed • Strongly increased BC risk (HB(O)C) CLTR 30-40%, CBC …? • frequent occurrence of breast / ovarian cancer • young age at diagnosis • Mildly increased BC risk (Familiar BC) CLTR 20-30% • Occurrence of BC, more frequently than expected • Varying ages at onset (> 50 yrs) • Combinations with other malignancies in family

  4. Risk Assessment Models Limitations Future • CLTR - Risk within following year(s) • All type of mutations - Specified for separate mutations • Only breast cancer - Incorporation of other types of Ca • No modifying factors - Modifying factors incorporated • Cumulative effect of diff. types - Including the effect of preventive of preventive measures and/or measures and/or systemic therapy systemic therapy not yet incor- porated Hereditary Online ?

  5. 2 BC 60 LuC d51 BC d45 BC d31 BC 42 Recognition • young age at onset • family history

  6. Recognition: Histology + IHC

  7. Improving Recognition: Future + ?

  8. Tumour characteristics BRCA2 BRCA1 non-BRCA1/2 Sporadic n=90 n=170 n=238 n=759 Age (yr) 44 (27-85) 42 (23-82) 47 (25-77) 43 (23-82) N status (%) N0 43 63 52 50 N  4+ 27 10 18 24 Histology lobular 9% 4% 11% 10% medullary 2% 7% 1% 2% Differentiation grade (%) I 3 1 8 8 III 65 88 61 63 Receptor status positive (%) ER / PR 84 / 64 27 / 33 73 / 74 67 / 54 OvaCa (%/yr) 0.5% 0.7% 0.1% - * p-value significant (vs BRCA2) C. Brekelmans et al., in press

  9. Local Recurrence Rate after BCT 1.00 0.80 0.60 Cumulative proportion 0.40 0.20 . . . . 0.00 0 years 15 At risk: sporadic 410 289 142 53 17 BRCA1 76 42 27 12 4 BRCA2 33 16 9 4 2 non-BRCA1/2 111 66 38 18 4

  10. Incidence of Contralateral Breast Cancer (CBC) 1.00 0.80 0.60 Cumulative proportion 0.40 0.20 0.00 0 years 15 At risk: sporadic 756 486 236 92 31 BRCA1 161 82 36 15 7 BRCA2 87 39 22 14 5 non-BRCA1/2 228 134 66 33 14 % annually BRCA 3.1% vs. Non- 1% vs. Spor. 0.7%

  11. Breast cancer-specific Survival (BCSS) 1.00 0.80 0.60 Cumulative proportion 0.40 0.20 0.00 0 years 15 At risk: sporadic 759 507 245 98 36 BRCA1 170 97 48 22 9 BRCA2 89 52 31 17 10 non-BRCA1/2 238 143 71 37 18

  12. Prognostic factors for BCSS HBC casesHR (95% CI) p-value T size T1 1.0 T2 1.81 (1.16-2.8) 0.009 T3/4 4.43 (2.3-8.43) < .001 Nodal status negative 1.0 1-3 + 2.52 (1.3-4.9) 0.006  4 + 3.83 (1.89-7.7) < .001 Histological grade1.73 (0.91-3.31) 0.09 ER (pos/neg) 0.49 (0.3-0.8) 0.006 Chemo (y/no) 0.45 (0.2-0.86) 0.02 PBSO (y/no)0.32 (0.1-1.02) 0.061 Not signif.: Age at diagnosis, CBC, PBSO, Horm. therapy

  13. Benefit of PM after BC? Surveillance/FU: MRI ? Systemic Rx?

  14. CBC after unilateral BRCA-BC

  15. Metastases free Survival after unilateral BRCA-BC

  16. Tumor stage T/N • Tumorcharacteristics • Patientcharacteristics: • knowledge, personality, .. Considerations at BC diagnosis + Recognition heredity Risk CBC Reconstruction after mast. and/or RT is more difficult • Accelerated genetic testing ? • Referral to Oncological Centre: Geneticist + Oncologist • Family Cancer TEAM: multidisciplinary approach • surgeon / plastic surgeon, psychologist, ……..

  17. Choice at BC diagnosis BRCA mutation carrier, BC under surveillance n= 25 standard therapy: 7 28% PM (after lump/ablation) 14 56% BC confirmed at PM 4 16% BC before genetic testing result n= 23 regular treatment: 8 35% PM (directly after lump/ablation) 15 65%

  18. Dutch Guideline w.r.t. Follow-up after Breast cancer BRCA mutation carrier + strongly increased BC risk 0-1 yr: every 3 months 2-5 yr: biannual physical, yearly imaging (+ MRI*) 5-10 yr: < 50 yr: biannual physical, yearly imaging (+ MRI*) > 50 yr: yearly exam, and imaging (+ MRI* < 60 yr) Mildly increased risk 0-1 yr every 3 months 2-5 yr biannual physical, yearly imaging >5-10 yr yearly visit, with imaging examination > 10 yr • < / > 50 yr yearly control / population screening * MRI for mutation carrier (and/or dens mammo)

  19. Randomized studies in premenopausal women Zoladex + Tamoxifen versus no treatment Zoladex + Aromatase Inhibitor versus no treatment Zoladex +/- bisphosphonate versus no treatment to be further investigated Value of tamoxifen: unclear value of aromatase inhibitors: IBIS2 study Further ideas EGFR ?? , other targeted therapies ? Prevention ?

  20. Tumour No normal BRCA1/2 BRCA1/2 function impaired Abnormal repair Should BRCA mutant Breast Cancer be treated differently regarding systemic therapy ? Normal tissues • 1 normal copy of BRCA1/2 • retained BRCA1/2 function • Normal repair

  21. Sensitivity of Brca2 null cells to platinum agents

  22. Response to neo-adjuvant Anthracyclin-based chemotherapy in BRCA-mutation (n=11) and non-carriers (n=27) Clinical Response cCR cPR p-value - BRCA1/2 10 (93%) 1 - - Non-carriers Unmatched 8 (30%) 19 0.0009 Matched 2 (18%) 9 0.002 B pCR pPR p value - BRCA1/2 carriers 4* (44%) 5 - - Non-carriers Unmatched 1 (4%) 26 0.009 Matched 0 9 0.08 * 2x BRCA1, 2x BRCA2 # matching for TN stage Chappuis, J.Med. Genet., 2002

  23. BRCA Trial I BRCA1/2 mutation carrier, first-line chemotherapy for M1 breast cancer Randomise 2:1 Carboplatin AUC 6 q3w 6 cycles Response rate Toxicity Time to progression Docetaxel 100mg/m2 6 cycles Upon progression Docetaxel 100mg/m2 6 cycles Response rate Toxicity Time to progression Carboplatin AUC 6 q3w 6 cycles Andrew Tutt, Max Parmar, James MacKay

  24. Poly (ADP-ribose) polymerase (PARP) Involved in DNA base-excision repair Binds directly to DNA damage (SSBs) Produces large branched chains of poly(ADP-ribose)

  25. Brca2-/- cells are Extremely Sensitive to PARP Inhibition Brca2+/+ Brca2+/+ Brca2+/+ Brca2+/- Brca2+/- Brca2+/- Brca2-/- Brca2-/- Brca2-/- KU-0058948 IC50 = 3.4nM KU-0051529 IC50 = 730nM KU-0058684 IC50 = 3.2nM 1250 - 133 Fold Differences in SF50 Brca2-/- v Wildtype

  26. Experiments in mice BRCA2 xenograft PARP1 inhibitor no therapy Tumorgrowth inhibition no growth inhibition no side effects !!! • In humans • phase I study • phase II study • in combination with other cytotoxic drugs

  27. CONCLUSIONS • Growing evidence for separate entities, and the importance of early identification • Concentration of cases • Complex problem, necessitating a Multidisciplinary approach: “ONCO-GENETIC ADVISE” • Individualized local treatment and FU • pipeline: chemoprevention ? • different systemic treatment ??? • new agents ?

  28. Knowledge is power Life is what happens to you when you are busy making other plans J. Lennon

  29. 0 500 300 100 60 50 40 Fold difference in SF50 30 20 10 Sensitivity of Brca1-/- cells to PARP inhibition compared to cisplatin

  30. Genes involved in Hereditary Breast Cancer Gene Chromosome Risk BC BRCA1 17q > 500 mut. 25-65% BRCA2 13q > 300 mut. ..- 55% p53 17p ? Cowden (PTEN) 10q ? ATM 11q ? CHEK2*1100delC 22q 2-fold repair genes MSH, MLH ? Unknown: BRCAx, …., Polygenic model

  31. DCIS: less frequent, … Type: more “medullary” Mitoses:high grade “Pushing” margins often “basal” phenotype ER/PR: negative her2neu: negative p53 mutations: frequent Mitoses / celproliferation: variable data “Pushing” margins Cyclin D overexpression ER/PR: as sporadic BC P53 mutaties: as sporad. BC Recognition: Histology + IHC BRCA1 BRCA2

  32. Tumour characteristics BRCA1 / Sporadic(2) BRCA1 BRCA1 Sporadic p-value (late tested) (unselected) n=53 n=170 n=446 Histology (%) (%) (%) 0.001 Duct/NOS 79 86 88 Lobul ar 2 3 9 Medullary 13 7 2 Histologic grade (%)0.002 I 2 1 5 II 6 7 17 III 43 55 45 Receptor status (%)< .001 ER neg/pos 49 / 15 45 / 17 24 / 48 PR neg/pos 31 / 9 38 / 18 19 / 35 C. Brekelmans, Ann Oncol 2005

  33. Hazard Ratio (HR) of HBC vs sporadic BC BRCA2 BRCA1 Non- BRCA1/2 IBTR 0.85 0.84 1.43 CBC 6.09 5.83 1.67 DDFS 0.75 1.25 0.82 BCSS 0.84 1.21 0.99

  34. Event-free Rate after therapy for primary BC 5 jr 10 jr (%) BRCA2 BRCA1 Non- Spor. BRCA2 BRCA1 non- Spor. IBTR 17 12 12 12 17 16 15 21 CBC17 13 5 3 20 25 6 5 DDFS 73 68 73 64 61 60 61 57 BCSS 80 73 87 78 68 62 70 59

  35. Risk reduction by Preventive measures • Breast Cancer Tamoxifen 40% Prophylactic Ovariectomy (P(S)O) 50% PO + TAM 70% (?) Prophylactic Mastectomy 90-100% • Mortality By Regular MRI + Mammo Screening 25 - 40% (?) by PM: healty women / after unilateral BC ? / NS by Systemic therapy ? by BSO ?

  36. Overall Survival after unilateral BRCA-BC

  37. Results PM vs Surveillance / Healthy women Parameter Cohort Updated 2001 2004 • Number 139 139 • Proph. Mastectomy/Surveillance 76 / 63 79 / 60 • Median follow-up na PM 3.0 yrs 5.4 yrs • Diagnosis Breast Cancer * tijdens surveillance 8 9 * na PM 0 1 (metast.) • 5 year Incidence of BC/surveill. 17% 13% • Protective effect of PM on BC p= 0.003 p= 0.01 • Adjusted for PO/menopause p= 0.01 p= 0.04

  38. Effect of B(S)O Primary BC CBC

  39. Surveillance gezonde vrouw BRCA mutatiedraagster vanaf 25 j LO mammae a 6 mnd, beeldvorming jaarlijks (incl. MRI) 60-75 j jaarlijks LO + beeldvorming vanaf 35 j jaarlijks gyn. Onderzoek, PBSO vanaf 40 j PM ja Sterk verhoogd risico 35-50 j LO mammae a 6 mnd, jaarlijks beeldvorming 50-60 j jaarlijks LO mammae + beeldvorming > 60-75 j bevolkingsonderzoek (alternatief op indicatie) Gyn. Controle: op indicatie Prev. Chirurgie: nee, tenzij ……. Matig 35-50 j jaarlijks LO mammae + mammografie 50-75 j via bevolkingsonderzoek (< 60 j, alternatief op indicatie) ** bij mut.draagsters of i.g.v. dens klierweefsel: MRI

  40. Gezonde vrouw • Status na borstkanker • Diagnose borstkanker • Status na ovariumcarcinoom

  41. Distant disease-free Survival 1.00 0.80 0.60 Cumulative proportion 0.40 0.20 0.00 0 years 15 At risk: sporadic 758 423 201 82 30 BRCA1 167 83 41 21 9 BRCA2 89 47 26 14 9 non-BRCA1/2 237 126 65 31 16

  42. Surgical-oncologist Oncologic Gynaecologist Medical Oncologist Nurse PATIENT Geneticist Radiotherapist Radiologist Psychologist/social worker Epidemiologist Pathologist Family Cancer TEAM + ……..

  43. BRCA Trial I • Hypotheses: • sensitivity of BRCA mutant carriers to Platinum salts? • tolerance of normal tissues in BRCA mutation carriers to Platinum salts? • therapeutic window for Platinum drugs in BRCA mutation carriers ? • Endpoints: • primary: Response rate • secondary: TTP, safety • Stratification factors: • mutation status, adj. Taxane Chemo, • Liver / lung M1, Trastuzumab therapy • Jewish ancestry

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