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Università degli Studi di Palermo Centro Interdipartimentale di Ricerca in Oncologia Clinica

Università degli Studi di Palermo Centro Interdipartimentale di Ricerca in Oncologia Clinica (Dir.: Prof. N. Gebbia ). “ Hereditary Breast and Ovarian cancer. Antonio Russo. Roma 5-6 ottobre 2007, Mediterranean School of Oncology. Sporadic. Sporadic. 75-80%. 90%. 5-10%. 10%. 15-20%.

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Università degli Studi di Palermo Centro Interdipartimentale di Ricerca in Oncologia Clinica

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  1. Università degli Studi di Palermo Centro Interdipartimentale di Ricerca in Oncologia Clinica (Dir.: Prof. N. Gebbia) “Hereditary Breast and Ovarian cancer Antonio Russo Roma 5-6 ottobre 2007, Mediterranean School of Oncology

  2. Sporadic Sporadic 75-80% 90% 5-10% 10% 15-20% Hereditary Familial Hereditary BREAST AND OVARIAN CANCER Breast Cancer Ovarian Cancer

  3. HEREDITARY BREAST AND/OR OVARIAN CANCER SYNDROME Hereditary Breast and Ovarian Cancer (HBOC) Others (Li Fraumeni S., Cowden S., Peutz Jeghers S.,Gorlin S. Ataxia Telangiatxia S.) Hereditary Non Poliposis Colorectal Carcinoma (HNPCC) 20-30% <1% 10-15% 10-15% 60-75% Hereditary Ovarian Cancer (HOC) Hereditary Breast Cancer (HBC)

  4. Sporadic Familial 15-20% 75-80% 5-10% Hereditary CAUSES OF HEREDITARY SUSCEPTIBILITY TO BC

  5. BRCA1 BRCA2 70% 20% 8-10% 2% MMR (MSH1, MLH2) Other genes 10% Hereditary CAUSES OF HEREDITARY SUSCEPTIBILITY TO OC Sporadic 90%

  6. BRCA1-ASSOCIATED CANCERS: LIFETIME RISK Breast cancer: 50-85% Second primary breast cancer: 40-60% Ovarian cancer: 15-45% Male Breast cancer: <1% Possible increased risk of other cancers (prostate, colon)

  7. BC 45 OC 59 BC 42 BC 36 Non carrier Affected with BC Affected with OC Affected with other cancer BRCA1-LINKED HEREDITARY BREAST AND OVARIAN CANCER (HBOC)

  8. OC 59 BRCA1-LINKED HEREDITARY OVARIAN CANCER (HOC) OC 50 OC 42 OC 40 Non carrier Affected with BC Affected with OC Affected with other cancer

  9. BRCA2-ASSOCIATED CANCERS: LIFETIME RISK Breast cancer: 50-85% Ovarian cancer: 10-20% Male Breast cancer: 5-10% Increased risk of prostate, laryngeal and pancreatic cancers

  10. BC 61 BC 59 BC 52 Prostatic cancer Non carrier Affected by BC Affected by OC Affected by other cancer BRCA2-LINKED HEREDITARY BREAST CANCER (HBC) BC 52

  11. GENETIC FEATURES OF BRCA GENES

  12. BRCA1 GENE • Tumor supressor gene on chromosome 17 (17q21) • 24 exons: 22 encoding • 5529 nucleotides • Autosomal dominant transmission

  13. BRCA1 PROTEIN STRUCTURE BARD1 1 1863aa FUNCTIONAL DOMAINS AND INTERACTING PROTEINS

  14. BRCA2 GENE • Tumor supressor gene on chromosome 13 (13q12) • 27 exons: 24 encoding • 10534 nucleotides • Autosomal dominant transmission

  15. BRCA2 PROTEIN STRUCTURE 1 3418 aa INTERACTING PROTEINAND FUNCTIONAL DOMAIN

  16. BRCA GENES FUNCTIONS

  17. PATHWAYS BRCA-MEDIATED BRCA genes involved in: • the manteinance of genomic stability • cell cycle checkpoints • remodeling of chromatin • DNA damage response • estrogen responsivness • is a coactivator of p53 responsive genes Narod et al., Nature Reviews Cancer, 2004

  18. BRCA1 AND BRCA2 MUTATIONS

  19. BRCA MUTATIONS BRCA1 (~ 600 different pathogenic mutations reported) BRCA2 (~ 300 different pathogenic mutations reported) • Not hot spot mutations • Prevalence of specific mutation in particular geographic areas and ethnic groups (founder effect) • New germinal mutations Database BIC (Breast Cancer Information Core), 2006

  20. BRCA1/2 FOUNDER MUTATIONS IN EUROPEAN POPULATIONS

  21. FAM64 FAM92 65 Ov 65 55 Br 53 Br 52 42 Ov 40 41 Hep 40 42 Lung 39 70 Leu 68 57 Br 44 40 Br 39 55 44 48 Ov 42 50 41 36 33 28 24 34 31 28 21 20 23 21 Symbol definitions Male Female 4843delC (ter1600) Unaffected Carrier Deceased Affected Deceased affected 4843delC NOVEL MUTATION COULD BE SICILIAN FOUNDER MUATION The homogeneity of the ethnic group of the two families unrelated and the SNPs analysis of probands led us to perform a study of the allelotype of the various members of families to determinate common allele and whether 4843delC might be due to a Sicilian founder effect. Russo A., Calò V., 2007

  22. HAPLOTYPE ANALYSIS OF BRCA1 GENE IN THE FAMILIES • Twelve members of two families were enrolled for the study. • Non-carriers of the mutation and none of the 50 healthy Sicilian controls had the 4-2-8-2-3 haplotype associated with the 4843delC mutation. • Allelotype analysis highlighted the presence of a ancester common allele in the affected individuals and healthy carriers, therefore suggesting the presence of a founder effect. Russo A., Calò V., 2007

  23. BRCA1-RELATED BREAST CANCER • Are of higher histological grade (70% are G3) • Show increased alterations in tumor suppressor gene : TP53 (55-90%) • Are frequently triple negative phenotype (ER, PgR e c-erb2 negative, > 80 %) • Show an increased proliferative capacity (higher S-phase fraction) • Are often DNA-aneuploid tumors

  24. BRCA1-RELATED OVARIAN CANCER • Are of higher histological grade (G3) • High stage • Are frequently serous epithelial carcinomas • Longer survival • Better response to chemotherapy (platinum)

  25. CLINICAL APPLICATIONS

  26. FEATURES THAT INDICATE INCREASED LIKELIHOOD OF HAVING BRCA MUTATIONS • Multiple cases of early onset breast cancer • Ovarian cancer (with family history of breast or ovariancancer) • Multiple caseswith family historyof ovarian cancer • Breast and ovarian cancer in the same woman • Bilateral breast cancer • Male breast cancer

  27. BC AND OC LIFETIME RISK ESTIMATED IN BRCA1 AND BRCA2 CARRIERS * Breast Cancer Linkeage Consortium, supported by the European Commission (2002) ** New York Breast Cancer Study Group (2003)

  28. CANCER GENETIC COUNSELLING

  29. At risk individual Affected Healthy with positive familial anamnesis Oncology Unit Verify of criteria fulfillment Clinical Data Collection + Pedigree Construction + Risk Estimation IC Genetic-oncologic counselling MULTISTEP CANCER GENETIC COUNSELLING MODEL Palma et al., Critical Reviews in Oncology/Hematology, 2006

  30. Clinical Data Collection Personal information • Age Hormonal factors: • Age at menarche and menopause • Age at first live birth • Number of children • Number of previous breast biopsies (whether positive ornegative) • At least one biopsy with atypical hyperplasia • BC/OC • Age of diagnosis • Treatment

  31. Pedigree Construction Pedigree that spans at least three generations Family factors: • Number of first-degree relatives with BC and/or OC or other cancers • Other chronic diseases in the family • Ethnic background • Age of diagnosis • Treatment • Age of death

  32. Revised pedigree based on pathology reports Verbally reported pedigree Ovarian K dx 43, d.49 Stomach K Breast K Dx 45, d. 59 Bone K d. 59 Prostate K Benign Prostatic hyperplasia Pedigree Construction Verify family history

  33. Initial History 1 years later Breast K, 40 Breast K, 40 Ovarian K, 44 Pedigree Construction Family cancer histories are dinamic

  34. Risk Estimation Factors Considered for estimating the likehood of finding a BRCA Mutation

  35. MULTISTEP CANCER GENETIC COUNSELLING MODEL At risk individual Affected Healthy with positive familial anamnesis Oncology Unit Verify of criteria fulfillment Clinical Data Collection + Pedigree Construction + Risk Estimation IC Risk Communication Genetic-oncologic counselling Genetic Testing Considered IC Not Performed Performed Blood Sampling Molecular Genetic Unit Genetic testing MULTISTEP CANCER GENETIC COUNSELLING MODEL Palma et al., Critical Reviews in Oncology/Hematology, 2006

  36. METHODS FOR MUTATIONAL SCREENING Palma et al., Critical Reviews in Oncology/Hematology, 2006

  37. MULTISTEP CANCER GENETIC COUNSELLING MODEL At risk individual Affected Healthy with positive familial anamnesis Oncology Unit Verify of criteria fulfillment Clinical Data Collection + Pedigree Construction + Risk Estimation IC Risk Communication Genetic-oncologic counselling Genetic Testing Considered IC Not Performed Performed Blood Sampling Molecular Genetic Unit Genetic testing Positive Result Negative Result Not Informative Result 2nd Blood Sampling MULTISTEP CANCER GENETIC COUNSELLING MODEL Palma et al., Critical Reviews in Oncology/Hematology, 2006

  38. Positive Result Prevention strategy Consider BRCA1/BRCA2 testing for specific mutation to other family membrers Not performed Ruotine breast screening as general population Positive Result Negative Result Prevention strategy • Emphasize risk of unidentified familial mutation • Provide individualized risk-management plan Negative Result Genetic testing • Cancer risk associated with mutation cannot be assessed • Possible to test other family members to verify the segregation of mutation • Provide individualized risk-management plan • Carry on additional investigation (functional and epidemiological studies) Not Informative Result (Variants of Uncertain Clinical Significance)

  39. At risk individual Affected Healthy with positive familial anamnesis Oncology Unit Prevention Strategies Definition Verify of criteria fulfillment Clinical Data Collection + Pedigree Construction + Risk Estimation IC Risk Communication Genetic-oncologic counselling Genetic Testing Considered Report given to the patient IC Not Performed Performed Blood Sampling Molecular Genetic Unit Genetic testing Positive Result Negative Result Not Informative Result 2nd Blood Sampling Report Trasmission MULTISTEP CANCER GENETIC COUNSELLING MODEL Oncology Unit Genetic-oncologic counselling Molecular Genetic Unit

  40. PREVENTION STRATEGY OPTIONS IN BRCA MUTATION CARRIERS Positive BRCA1 or BRCA2 test result increased surveillance

  41. INCREASED SURVEILLANCE • Recommended for breast cancer detection in women • Monthly self-examination of the breast (18 years) • Clinician breast exam, every 6 months (25 years) • Echography every 6 months and/or mammography and MRI every year: • - < 35 ys (25 years): Echographyevery 6 mts • - > 35 ys: Echography every 6 mts + MRI and mammography every year • - 5-10 ys prior to the youngest diagnosis of BC in the family Reduces mortality by approximately 25-30% in women in their 50s 18% in women in their 40s National Comprehensive Cancer Network – Practice Guidelines in Oncology (2006)

  42. INCREASED SURVEILLANCE • Recommended for breast cancer detection in men • Monthly self-examination of the breast • Annual clinician breast exam • Annual mammography • Adhere to population screening guidelines for prostate cancer National Comprehensive Cancer Network – Practice Guidelines in Oncology (2006)

  43. INCREASED SURVEILLANCE • Recommended for ovarian cancer detection • Pelvic examination annually (>18 years) • Transvaginal ultrasound,every6 months(25-35 years) • Serum Ca 125, 6-12 months (25-35 years) Not prevent cancer, but it can diagnose cancer at earlier stage (associated with better survival) National Comprehensive Cancer Network – Practice Guidelines in Oncology (2006)

  44. PREVENTION STRATEGY OPTIONS IN BRCA MUTATION CARRIERS Positive BRCA1 or BRCA2 test result Increased Surveillance Lifestyle Change

  45. LIFESTYLE CHANGE • Overweight, fat intake, alchool intake, physical activity • Difficult valutation of above-mentioned factors • Long time to really define if the change of lifestyle could cause a risk’s decrease • Hormone Replacement Therapy (HRT) Women on prolonged hormone replacement therapy (> 4 years) have a slightly increased risk of BC • Oral Contraceptives Continuative use (6 years): 60% reduction in frequency of OC, but significant correlation with risk of BC (RR = 1.2) National Comprehensive Cancer Network – Practice Guidelines in Oncology (2006)

  46. PREVENTION STRATEGY OPTIONS FOR BC IN BRCA MUTATION CARRIERS Positive BRCA1 or BRCA2 test result Increased Surveillance Lifestyle Change Chemo-prevention

  47. CHEMOPREVENTION TAMOXIFEN • Four randomized trials have evaluated Tamoxifen as chemoprevention agent in the treatment of high risk pts • Significant reduction of invasive BC incidence in the two major trials(NSABP-1 and IBIS I) • No significant results in the Royal Marsen Hospital Trial and Italian Trial OTHER CHEMOPREVENTION TRIALS • STAR (tamoxifen vs raloxifen) • MAP.3 (anastrazole vs placebo) and ApreS (exemestane vs placebo)

  48. CHEMOPREVENTION SOME CONSIDERATIONS FOR BRCA MUTATION CARRIERS • BCs developed in BRCA1 carriers were mostly ER negative (>80%) while those developed in BRCA2 carriers were prevalently ER positive (75-80%) • Thus, BRCA2 mutation carriers may be the subset that benefits the most from anti-estrogen PMT while chemoprevention by estrogen blockade, in BRCA1, is yet to be elucidated. Review literature, 2006

  49. CHEMOPREVENTION TRIALS SOME CONSIDERATIONS SOME OPEN QUESTIONS: • Durability of the preventive effect • Type of preventive treatment • Which subsets benefit from treatment • Interaction with HRT • Preventive effect in BRCA1/2 carriers

  50. PREVENTION STRATEGY OPTIONS IN BRCA MUTATION CARRIERS Positive BRCA1 or BRCA2 test result Increased Surveillance Lifestyle Change Prophilactic Surgery Chemo-prevention

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