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Hereditary breast and ovarian cancer clinic Leuven

Hereditary breast and ovarian cancer clinic Leuven. K. Leunen GNC UZ Leuven-Belgium. 1994 -1995 Miki & Wooster Encoding for large proteins Expression in ≠ tissues Mostly during G1 en S fase Enrolled DNA DS repair Regulation transcription Cell cycle controle  « Care takers ».

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Hereditary breast and ovarian cancer clinic Leuven

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  1. Hereditary breast and ovarian cancer clinic Leuven K. Leunen GNC UZ Leuven-Belgium

  2. 1994 -1995 Miki & Wooster Encoding for large proteins Expression in ≠ tissues Mostly during G1 en S fase Enrolled DNA DS repair Regulation transcription Cell cycle controle  « Care takers » BRCA genes

  3. « Genetic » cancer ≠ !! • Sporadic • Genetic • Familial 15% of the breast cancer cases have a family history but only 1-2 % can be attributed to BRCA mutations OvC: 10%

  4. Who will we refer for genetic testing ? Who’s at risk to be a carrier ?

  5. Hallmarks of hereditary Ca • Can present at (very) young age • Multiple primary tumors in the same or joint organs (bilaterality) • Tumors in different organs (frequently combinations of tumors) • Positive familial history (« it’s in the family »)

  6. Evaluation of risk : • Empiric risk-models (prevalence tables): • Myriad tables • Gail model • Couch model • Genetische modellen • Claus tables: single gene tabel • IBIS: Fam history and other risk factors • BRCAPRO: effect of BRCA 1-2, FH (-) • BOADICEA: polygenic Fam. History

  7. Table van Claus

  8. IBIS risk model

  9. Evaluation of the risk and chance to find a BRCA mutation… Evans et al. J Med Genet 2004; 41:474-480.

  10. Os T et al. Patient care 2002, 29:13-20

  11. Multidisciplinary team • Genetici • Psychologist, lab-workers • Clinici: MD, surgeons, gynaecologists, plastic surgeons • Nurses and social workers All needed for good counseling and an optimal follow-up of patients at high risk for breast and/or ovarian cancer

  12. Probability of being a BRCA mutation carrier Screeningof a family membre with cancer • Family tree • Personal history • Evaluating the risk of being a carrier • When this risk is > 10% (ASCO guidelines 2003)  performing the test When a mutation is found  then possibility to perform predictive test for patients without any cancer.

  13. BRCA 1 BrC65-80% early onset contralateral BrC 40% binnen de 10j OvC28-44% (1.8%) Onset: young First 2/3 :OvC > BrC BRCA 2 BrC 45% Male BrC OvC10-20% Onset: Later , >50j ( BRCA1) OCCR : OvC > BrC Risk Mostly: BrC preceeds Ovc; rarely contrary

  14. BrC risk – BRCA1 BrC risk – BRCA2 57%  49% OvC risk – BRCA1 OvC risk – BRCA2 18% 40%  Sining Chen et al. JCO 2007;24:863-871

  15. Figuur uit Thompson en Easton: The genetic epidemiology of Breast cancer genes Journal of mammary gland biology and neoplasm 2004; 9(3):221

  16. Other organs • Colorectale tumors (BRCA 1, not confirmed) studies : Am J Hum Genet 1995;56:265 Lancet 1994; 342:692-695 NEJM 1997; 336: 1401-1408 • Endometrial Ca: serous (BRCA 1) • Prostate Ca (BRCA 2) • Pancreas, galbladder, stomach en malign melanoma (BRCA 2)

  17. Clinical options for mutation carriers Primary cancer prevention • Chemoprevention • Profylactic surgery (pME-pBSO)  PREVENT ! Secundary cancer prevention • Close and frequent follow-up  EARLY DIAGNOSIS !

  18. A. Secundary Prevention A. BREAST Close follow-up : SPECIALISED CENTRE ! • Clinic • Self examination • Clin Exam by doctor • Radiologic • Rx mammo/echo • MRI breasts • Gynecologic ultrasound • Biochemistry

  19. Secundary Prevention Close follow-up : SPECIALISED CENTRE ! • Clinic • Self examination • Clin Exam by doctor • Radiologic • Rx mammo/echo • MRI breasts • Gynecologic ultrasound • Biochemistry

  20. Overall sensitivity of diagnostic Rx : 93% Mammografy: 33% Ultrasound : 40% Mammo+US : 49% MRI : 91% In de high risk group*: 25% 100% Sentivity radiology Kuhl et al. J Clin Oncol(2005)23:8469-8476

  21. High risk group (with or without mutation) • Rx mammo / US  enough • MRI : has to be integral part of screening in the high risk group • Higher sensitivity • Earlier detection of IS or invasive tumors MRI  ? Better survival ? Frequent Rx exposition  ? Risk  BrC ? Kuhl et al. J Clin Oncol(2005)23:8469-8476

  22. A. Secundary Prevention B. OVARY • Exact sensitivity of follow-up is difficult to assess:  big differences in definitions & study design • 49-100% [ Bell et al. Br J Obstet Gynaecol 1998; 105:1136-47] In most cases: detection at early stage (which is the purpose of surveillance) is not reached !  positive effect of surveillance is not proven, and this because of factors

  23. SO: • Surveillance = restricted value • Low sensitivity • High number of fals positives • Can lead to unnecessary surgery unclear of this FU can  mortality and/or morbidity of OvC. • Pat has to know this ! Counseling ! • Untill now: pBSO = most optimal risk-reducing strategy in hihg risk population (+ BrC risk !) Fields MM, Cevlen E. Clin J Oncol Nurs. 2006 Feb;10(1):77-81

  24. B. Primary prevention • Preventive surgery • pME • pBSO • Chemo-prevention and others + less fear lower cancer risk perception - Endocrine changings Sexual symptoms Psychologicalproblems

  25. 1.Profylactic surgery A. MASTECTOMY • « all » breast tissue has to be removed • Total mastectomy • With removal of nipple (Skin-sparing) with reconstruction • No ALND (MRM) • Sensibility of the breast • +/- immediate reconstruction • Prothesis • Autologuous tissue

  26. Reconstruction • Immediately or later ? • Type ? • Prosthesis/tissue expander • Autologuous material • (LDF) • (TRAM) • DIEP • S-GAP • SIEA

  27. ‘Skin-sparing’ mastectomy

  28. SGAP

  29. Even after skin sparing ME, there is still minimal quantity of breast tissue reduction of risk  0 !!! • still 2-3% risk of BrC • Persistent clinical FU is necessary • No standard US/mammo/MRI

  30. B. PROFYLACTIC BSO (pBSO) • Laparoscopic versus -tomy • Adnexae + tubae • Tubal carcinomata in BRCA carriers (Aziz 2001, Leeper 2002, Lu 2000) • « ovarian Ca » • +/- hysterectomy (LAVH) • Prevent reintervention for benign lesions Villella et al Gyn Oncol, 2006 • Intramural part of tuba ( vooral terminaal deel tubae / ampulla en isthmus) Podratz 1986, Paley 2001, Colgan 2001 • Serous endometriumCa ? • Simplifying hormonale substitution • Risk reduction BrC (50%) • Importance of histologic examination of specimens

  31. 2. Chemo prevention • Oral contraception : controverse • Standard population: Risk OvC :  • In high risk group: (HBOC, BRCA) :  ? • Narod 1998: OR = 0.5 (any use) risk  with use >6j: 60% reduction • Modan 2001: OAc  risk reduction in non carriers  no risk reduction in carriergroep  However : Parity protects in both groups (12%/birth) •  risk BrC in BRCA 1 groep(>5j, in jonge populatie groep)  OAc als standardchemoprevention O V A R I U M

  32. Ligation of the tubes • different studies: risk reduction :  > 1/3 Daly et al, Semin Oncol 1993; Hankinson et al, JAMA 1993 • BRCA 1 carriers :  60% reductie (OR = 0.37) Narod, Lancet 2001 OAc + Tubaligatuur : OR = 0.28 • Parity • Seems protective in both groups, carriers and non carriers • Progestagenen, Cox-2 inhibitors, vit D, retinoiden, … Modugno et al. Gynecol Oncol 2003;91:15-31 O V A R I U M

  33. Oophorectomy: • Rebbeck (EJC, 2002): HR : 0.53 (BRCA1) • Eisen (JCO 2005 ): risk reduction of 56% (OR=0.44) in BRCA1 & 46% in BRCA2 pat, with most important reduction <40y • Kramer (JCO, 2005) • Effect van BSO is groter naarmate leeftijd afneemt (<40j  75% risico reductie) • Tamoxifen(Nolvadex) • NSABP trial (King 2001, JAMA): only clear risk reduction (62%) in BRCA 2, not in BRCA1, but small groups (n=19) • Narod et al: RR = 0.38 for BRCA 1 > RR = 0.63 for BRCA2, (bigger study here) • Tam + BSO (OR = 0.36) vs Tam - BSO (OR= 0.48) • Gronwald(Int J Cancer, 2006) • OR = 0.5 for BRCA1 • = 0.42 for BRCA2 • = 0.83 for pBSO pat • E-depletion at young age ? Combination with HST • Short duration • Geen Progestageen • Combination Anti-E + HST not well investigated B R E A S T

  34. BRCA 1 BRCA 2 Average penetrance estimates BrC BrC OvC OvC Antoniou, 2003

  35. Guidelines University Hospitals Leuven Mutation carriers Clin Exam : 1x /6m + US /6m Rx mammo/US + MRI: 1x/j Inconclusives(strong fam history but no BRCA mutation retained): • Clin Exam : 1x/6m • RX mammo/US: 1x/j • MRI breasts alternating

  36. UZ Leuven: prophylactic surgery pBSO

  37. Thanks …

  38. Leuven: untill 2007 > 1550 patients tested  1063 families 90 BRCA 1  126 pat 78 BRCA 2  142 pat

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