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A FOCUS ON BRCA MUTATIONS
IN BREAST CANCER
Mohamed Abdulla M.D.
Prof. of Clinical Oncology
Cairo University
Dubai – 11/09/2015
Speaker Disclosures
Member of Advisory Board, Consultant, and Speaker for:
• Amgen, Astellas, Astra Zeneca, Hoffman la Roche, Janssen
Cilag, Merck Serono, Novartis, Pfizer.
Speaker Disclosures:
Breast Cancer:
The Story:
All Women
12%
All Breast Cancer
Cases (100%)
73%
Sporadic Cases “No
Family Clustering”
27%
Familial Breast
Cancer
5 – 10%
Mutation in Single
High Penetrance
Gene
≈ 20%
Mutations in Low
Penetrance Genes
88%
No Breast Cancer
Narod SA. BRCA mutations in the management of breast cancer: the state of the art. Nat Rev Clin
Oncol 2010; 7:702
Cancer Risk in Carriers of Germ Line
Mutations in BRCA1 & BRCA2
Autosomal
Dominant
Inheritance with
High Penetrance
• 50% Chance of
Inheritance.
• Lifetime Risk of
Cancer = 30-70%
Cancer Risk in Carriers of Germ Line
Mutations in BRCA1 & BRCA2
0%
10%
20%
30%
40%
50%
60%
70%
80%
Female
Breast
Male Breast Ovary Pancreas Prostate
BRCA1
BRCA2
Presented by Judy Garber at 2015 ASCO Annual Meeting.
54 – 85%
Presented By Elizabeth Swisher at 2015 ASCO Annual Meeting
Risk of Breast Cancer for Women with
BRCA1 & 2 Mutations:
King, Science, New York Breast Cancer Study, 2003
2%
8% 11%
50%
87%
64%
0%
50%
100%
Breast
cancer by
Age 50
Breast
Cancer by
Age 70
2nd Breast
Cancer by
Age 70
General Population
BRCA Mutation
Risk of Breast Cancer for Women with
BRCA1 & 2 Mutations:
Claus EB, et al. The genetic attributable risk of breast and ovarian cancer. Cancer 1996;77:2318-2324.
Risk of Breast Cancer for Women with
BRCA1 & 2 Mutations:
Adapted from: Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med 2001; 344:276.
BRCA Genes:
Basic Knowledge
Eukaryotic Genome
Constant StressEndogenous Exogenous
Continuous Damage
Continuous Repair
Misrepair Perfect Repair No Repair
Mutations Apoptosis
Tumor Suppressor Genes
Peter J.O’Donovan and David M.Livingston.􏰀 Carcinogenesis vol.31 no.6 pp.961–967, 2010
BRCA1 & BRCA2
• DNA Repair.
• Control of Cell Cycle Checkpoints.
• Control of Mitotic Activity
BRCA Genes:
Basic Knowledge
DNA Repair
NHEJR HR
1 2 1 2
Peter J.O’Donovan and David M.Livingston.􏰀 Carcinogenesis vol.31 no.6 pp.961–967, 2010
G0, G1,
Early S
Late S,
G2
Mutated Non -
Mutated
P
2 Year 96.4% 99.3%
0.025 Year 85.3% 95.9%
10 Year 71.9% 87.2%
Robson M, et al. J. Natl. Cancer Inst. 1999;91(24)2112-2117.
BRCA-Associated Breast Cancer 
 Ipsilateral & Contralateral Recurrences
Breast Cancer with BRCA Mutations:
Poor Prognosis:
Breast Cancer with BRCA Mutations:
Poor Prognosis:
1. Early onset of disease  more years of lost life.
2. High prevalence of poorly differentiated, high grade
and highly proliferative lesions  more common in
BRCA1 mutation cases.
3. Higher prevalence of HR –ve and TNBC.
4. Altered sensitivity to systemic agents:
•  to platinum and PARP inhibitors.
•  to taxanes.
5. Chemotherapy for early small tumors might improve
the outcome.
Rijnsburger et al. JCO 2010;28:5265
Lee et al. Breast Cancer Res Treat 2010; 122:11.
Hemel & Domchek. Hematol Oncol Clin North Am 2010; 24:799.
BRCA Gene Mutations:
Who Should Be Investigated for Mutations?
BRCA Gene Mutations:
Who Should Be Investigated for Mutations?
BRCA Genes Mutation:
Confirmed Detection:
Actions
Taken
Cancer
Surveillance
Reducing
Risk
Therapeutic
Implications
1. Breast Self Examination.
2. Breast Clinical Examination.
3. Mammography/MRI.
1. Surgical Intervention.
2. Chemoprevention.
1. Different Disease Entity?
2. Locoregional Treatment?
3. Systemic Therapy (PARP)
BRCA Mutation:
Cancer Surveillance:
1. Breast Self-Examination: Monthly at age of 18 years.
2. Clinical Breast Examination: 2 – 4 times annually at
age of 25 years.
3. MRI – Breast: 2 times annually (25 – 30 Years).
4. Alternating Mammography/MRI – Breast: annually
after the age of 30.
Age Mammography MRI Mammo + MRI
Sens. Spec Sens. Spec Sense Spec
All Ages 39.6% 93.6% 85.3% 84.7% 93.4% 80.3%
< 50 40% 93% 85.7% 83.5% 93.2% 78.7%
> 50 39.1% 95.9% 84.4% 88.5% 94.1% 85.3%
Warner et al. Ann Intern Med. 2008;148:671.
Xi PA et al. J Clin Oncol. 2015;33:349-56.
BRCA Mutation:
Reducing Risk: Surgical Intervention:
Bilateral Prophylactic
Mastectomy:
• 90% risk reduction.
• Total > S.C. mastectomy.
• Skin sparing +/-
preservation of
nipple/areola complex 
Better cosmoses.
• Immediate reconstruction.
Bilateral Salpingo-
oophorectomy:
 77% risk reduction of all
cause breast cancer
mortality to age of 70 years.
Ingham SL et al. Risk-reducing surgery increases
survival in BRCA1/2 mutation carriers unaffected at
time of family referral.
Breast Cancer Res Treat 2013; 142:611.
Finch AP, et al. Impact of oophorectomy on cancer
incidence and mortality in women with a BRCA1 or
BRCA2 mutation.
J Clin Oncol 2014; 32:1547.
BRCA Mutation:
Reducing Risk: Chemoprevention:
• Tamoxifen (5 Years)  50%  of breast cancer in women
with moderately increased risk:
1. > 60 years.
2. > 35 years with LCIS.
3. 1.66% increased risk (Gail Method).
• NSABP (P-1): TAM 62%  breast cancer risk (BRCA2).
• Role of Raloxifen and AI.
• Chemoprevention < Prophylactic Surgery.
No HBOC
Eisen A, Weber BL. Prophylactic mastectomy for women with BRCA1 and BRCA2 mutations--facts and
controversy. N Engl J Med 2001; 345:207.
Gronwald J, Tung N, Foulkes WD, et al. Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2
carriers: an update. Int J Cancer 2006; 118:2281.
BRCA Mutation:
Reducing Risk: Clinical Decision Making:
Life Expectancy Quality of Life
30 years + BRCA1/2
Prophylactic Mastectomy  3 – 5 years gain.
Oophorectomy  0.3 – 2 years gain
Schrag D, et al.N Engl J Med 1997; 336:1465.
Breast Cancer with BRCA Mutation:
Choice of Loco-Regional Management:
Breast Cancer with BRCA Mutation:
Choice of Loco-Regional Management:
Breast Cancer with BRCA Mutation:
Choice of Loco-Regional Management:
• 655 Patients
• Stage I - III
• BRCA1/2
Mutation
302 Patients  BCT
353 Patients  MRM
Failures:
• Local
• Regional
• Systemic
Pierce et al. Breast Cancer Res Treat. 2010 June ; 121(2): 389–398
Breast Cancer with BRCA Mutation:
Choice of Loco-Regional Management:
Pierce et al. Breast Cancer Res Treat. 2010 June ; 121(2): 389–398
4.1%
10.5%
23.5%
30.2%
1.4%
3.5%
5.5% 5.5%
0.0%
5.0%
10.0%
15.0%
20.0%
25.0%
30.0%
35.0%
5 - Year 10 - Year 15 - Year 20 Year
CumulativeIncidence
Cumulative incidence estimates for local failure as first
failure by type of local treatment.
BCT
MRM
P = < 0.0001
LR = 30%
LF = 70%
7.9%
16.5%
43.7%
53.2%
2.6%
8.1%
10.7% 10.7%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
5 - Year 10 - Year 15 - Year 20 - Year
CumulativeIncidence
Cumulative incidence estimates for local failure as first
failure for patients choosing breast conservation by use of
adjuvant chemotherapy.
BCT
BCT + Cth
Breast Cancer with BRCA Mutation:
Choice of Loco-Regional Management:
Pierce et al. Breast Cancer Res Treat. 2010 June ; 121(2): 389–398
P = < 0.0001
11.4%
24.5%
41.4%
53.2%
11.2%
31.6%
47.6%
56.8%
0.0%
10.0%
20.0%
30.0%
40.0%
50.0%
60.0%
5 - Year 10 - Year 15 - Year 20 - Year
CumulativeIncidence
Cumulative incidence estimates of contralateral breast
cancer by use of adjuvant radiotherapy.
No RTH
RTH
Breast Cancer with BRCA Mutation:
Choice of Loco-Regional Management:
Pierce et al. Breast Cancer Res Treat. 2010 June ; 121(2): 389–398
P = < 0.44
Conclusions:
• L.R.: BCT > MRM (Significant)
• Local Control: BCT + CTH = MRM.
• Distant Failure, DSS, OAS: No Difference.
• CBC: Significantly High Irrespective of RTH Use 
Prophylaxis.
Breast Cancer with BRCA Mutation:
Choice of Loco-Regional Management:
Pierce et al. Breast Cancer Res Treat. 2010 June ; 121(2): 389–398
Breast Cancer with BRCA Mutation:
Contralateral Breast:
Int. J Cancer:136,668-677.(2015)
Breast Cancer with BRCA Mutation:
Contralateral Breast:
Int. J Cancer:136,668-677.(2015)
Number
583 BRCA Mutated PBC
P/HRCRRM Surveillance
242 (42%) 341 (58%)
Contralateral
Breast Cancer
4 (2%) 64 (19%) P = 0.001
Mortality/1000
Persons - Years of
Observation
9.6% 21.6 HR = 0.49
MedianFollowup=11.2years
Take Home Message:
• Hereditary breast cancer is a unique disease with TN and HR –
phenotypes in > 70% of cases and poor prognosis in vast
majority of patients with compromised survival outcome.
• Deleterious BRCA mutations are associated with high risk of
developing breast cancer with higher rates of local and
contralateral failures than sporadic cases.
• Genetic counseling should be offered for high risk population.
• Screening mammography and MRI are complementary.
• Prophylactic Bilateral Mastectomy  90% risk reduction.
• Platinum compounds are key players in management.
• PARP inhibitors carry a promising change of disease
landscape.
Breast Cancer: A focus on BRCA Mutations.

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Breast Cancer: A focus on BRCA Mutations.

  • 1. A FOCUS ON BRCA MUTATIONS IN BREAST CANCER Mohamed Abdulla M.D. Prof. of Clinical Oncology Cairo University Dubai – 11/09/2015
  • 2. Speaker Disclosures Member of Advisory Board, Consultant, and Speaker for: • Amgen, Astellas, Astra Zeneca, Hoffman la Roche, Janssen Cilag, Merck Serono, Novartis, Pfizer. Speaker Disclosures:
  • 3. Breast Cancer: The Story: All Women 12% All Breast Cancer Cases (100%) 73% Sporadic Cases “No Family Clustering” 27% Familial Breast Cancer 5 – 10% Mutation in Single High Penetrance Gene ≈ 20% Mutations in Low Penetrance Genes 88% No Breast Cancer Narod SA. BRCA mutations in the management of breast cancer: the state of the art. Nat Rev Clin Oncol 2010; 7:702
  • 4. Cancer Risk in Carriers of Germ Line Mutations in BRCA1 & BRCA2 Autosomal Dominant Inheritance with High Penetrance • 50% Chance of Inheritance. • Lifetime Risk of Cancer = 30-70%
  • 5. Cancer Risk in Carriers of Germ Line Mutations in BRCA1 & BRCA2 0% 10% 20% 30% 40% 50% 60% 70% 80% Female Breast Male Breast Ovary Pancreas Prostate BRCA1 BRCA2 Presented by Judy Garber at 2015 ASCO Annual Meeting. 54 – 85%
  • 6. Presented By Elizabeth Swisher at 2015 ASCO Annual Meeting Risk of Breast Cancer for Women with BRCA1 & 2 Mutations: King, Science, New York Breast Cancer Study, 2003
  • 7. 2% 8% 11% 50% 87% 64% 0% 50% 100% Breast cancer by Age 50 Breast Cancer by Age 70 2nd Breast Cancer by Age 70 General Population BRCA Mutation Risk of Breast Cancer for Women with BRCA1 & 2 Mutations: Claus EB, et al. The genetic attributable risk of breast and ovarian cancer. Cancer 1996;77:2318-2324.
  • 8. Risk of Breast Cancer for Women with BRCA1 & 2 Mutations: Adapted from: Clemons M, Goss P. Estrogen and the risk of breast cancer. N Engl J Med 2001; 344:276.
  • 9. BRCA Genes: Basic Knowledge Eukaryotic Genome Constant StressEndogenous Exogenous Continuous Damage Continuous Repair Misrepair Perfect Repair No Repair Mutations Apoptosis Tumor Suppressor Genes Peter J.O’Donovan and David M.Livingston.􏰀 Carcinogenesis vol.31 no.6 pp.961–967, 2010 BRCA1 & BRCA2 • DNA Repair. • Control of Cell Cycle Checkpoints. • Control of Mitotic Activity
  • 10. BRCA Genes: Basic Knowledge DNA Repair NHEJR HR 1 2 1 2 Peter J.O’Donovan and David M.Livingston.􏰀 Carcinogenesis vol.31 no.6 pp.961–967, 2010 G0, G1, Early S Late S, G2
  • 11. Mutated Non - Mutated P 2 Year 96.4% 99.3% 0.025 Year 85.3% 95.9% 10 Year 71.9% 87.2% Robson M, et al. J. Natl. Cancer Inst. 1999;91(24)2112-2117. BRCA-Associated Breast Cancer   Ipsilateral & Contralateral Recurrences Breast Cancer with BRCA Mutations: Poor Prognosis:
  • 12. Breast Cancer with BRCA Mutations: Poor Prognosis: 1. Early onset of disease  more years of lost life. 2. High prevalence of poorly differentiated, high grade and highly proliferative lesions  more common in BRCA1 mutation cases. 3. Higher prevalence of HR –ve and TNBC. 4. Altered sensitivity to systemic agents: •  to platinum and PARP inhibitors. •  to taxanes. 5. Chemotherapy for early small tumors might improve the outcome. Rijnsburger et al. JCO 2010;28:5265 Lee et al. Breast Cancer Res Treat 2010; 122:11. Hemel & Domchek. Hematol Oncol Clin North Am 2010; 24:799.
  • 13. BRCA Gene Mutations: Who Should Be Investigated for Mutations?
  • 14. BRCA Gene Mutations: Who Should Be Investigated for Mutations?
  • 15. BRCA Genes Mutation: Confirmed Detection: Actions Taken Cancer Surveillance Reducing Risk Therapeutic Implications 1. Breast Self Examination. 2. Breast Clinical Examination. 3. Mammography/MRI. 1. Surgical Intervention. 2. Chemoprevention. 1. Different Disease Entity? 2. Locoregional Treatment? 3. Systemic Therapy (PARP)
  • 16. BRCA Mutation: Cancer Surveillance: 1. Breast Self-Examination: Monthly at age of 18 years. 2. Clinical Breast Examination: 2 – 4 times annually at age of 25 years. 3. MRI – Breast: 2 times annually (25 – 30 Years). 4. Alternating Mammography/MRI – Breast: annually after the age of 30. Age Mammography MRI Mammo + MRI Sens. Spec Sens. Spec Sense Spec All Ages 39.6% 93.6% 85.3% 84.7% 93.4% 80.3% < 50 40% 93% 85.7% 83.5% 93.2% 78.7% > 50 39.1% 95.9% 84.4% 88.5% 94.1% 85.3% Warner et al. Ann Intern Med. 2008;148:671. Xi PA et al. J Clin Oncol. 2015;33:349-56.
  • 17. BRCA Mutation: Reducing Risk: Surgical Intervention: Bilateral Prophylactic Mastectomy: • 90% risk reduction. • Total > S.C. mastectomy. • Skin sparing +/- preservation of nipple/areola complex  Better cosmoses. • Immediate reconstruction. Bilateral Salpingo- oophorectomy:  77% risk reduction of all cause breast cancer mortality to age of 70 years. Ingham SL et al. Risk-reducing surgery increases survival in BRCA1/2 mutation carriers unaffected at time of family referral. Breast Cancer Res Treat 2013; 142:611. Finch AP, et al. Impact of oophorectomy on cancer incidence and mortality in women with a BRCA1 or BRCA2 mutation. J Clin Oncol 2014; 32:1547.
  • 18. BRCA Mutation: Reducing Risk: Chemoprevention: • Tamoxifen (5 Years)  50%  of breast cancer in women with moderately increased risk: 1. > 60 years. 2. > 35 years with LCIS. 3. 1.66% increased risk (Gail Method). • NSABP (P-1): TAM 62%  breast cancer risk (BRCA2). • Role of Raloxifen and AI. • Chemoprevention < Prophylactic Surgery. No HBOC Eisen A, Weber BL. Prophylactic mastectomy for women with BRCA1 and BRCA2 mutations--facts and controversy. N Engl J Med 2001; 345:207. Gronwald J, Tung N, Foulkes WD, et al. Tamoxifen and contralateral breast cancer in BRCA1 and BRCA2 carriers: an update. Int J Cancer 2006; 118:2281.
  • 19. BRCA Mutation: Reducing Risk: Clinical Decision Making: Life Expectancy Quality of Life 30 years + BRCA1/2 Prophylactic Mastectomy  3 – 5 years gain. Oophorectomy  0.3 – 2 years gain Schrag D, et al.N Engl J Med 1997; 336:1465.
  • 20. Breast Cancer with BRCA Mutation: Choice of Loco-Regional Management:
  • 21. Breast Cancer with BRCA Mutation: Choice of Loco-Regional Management:
  • 22. Breast Cancer with BRCA Mutation: Choice of Loco-Regional Management: • 655 Patients • Stage I - III • BRCA1/2 Mutation 302 Patients  BCT 353 Patients  MRM Failures: • Local • Regional • Systemic Pierce et al. Breast Cancer Res Treat. 2010 June ; 121(2): 389–398
  • 23. Breast Cancer with BRCA Mutation: Choice of Loco-Regional Management: Pierce et al. Breast Cancer Res Treat. 2010 June ; 121(2): 389–398 4.1% 10.5% 23.5% 30.2% 1.4% 3.5% 5.5% 5.5% 0.0% 5.0% 10.0% 15.0% 20.0% 25.0% 30.0% 35.0% 5 - Year 10 - Year 15 - Year 20 Year CumulativeIncidence Cumulative incidence estimates for local failure as first failure by type of local treatment. BCT MRM P = < 0.0001 LR = 30% LF = 70%
  • 24. 7.9% 16.5% 43.7% 53.2% 2.6% 8.1% 10.7% 10.7% 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 5 - Year 10 - Year 15 - Year 20 - Year CumulativeIncidence Cumulative incidence estimates for local failure as first failure for patients choosing breast conservation by use of adjuvant chemotherapy. BCT BCT + Cth Breast Cancer with BRCA Mutation: Choice of Loco-Regional Management: Pierce et al. Breast Cancer Res Treat. 2010 June ; 121(2): 389–398 P = < 0.0001
  • 25. 11.4% 24.5% 41.4% 53.2% 11.2% 31.6% 47.6% 56.8% 0.0% 10.0% 20.0% 30.0% 40.0% 50.0% 60.0% 5 - Year 10 - Year 15 - Year 20 - Year CumulativeIncidence Cumulative incidence estimates of contralateral breast cancer by use of adjuvant radiotherapy. No RTH RTH Breast Cancer with BRCA Mutation: Choice of Loco-Regional Management: Pierce et al. Breast Cancer Res Treat. 2010 June ; 121(2): 389–398 P = < 0.44
  • 26. Conclusions: • L.R.: BCT > MRM (Significant) • Local Control: BCT + CTH = MRM. • Distant Failure, DSS, OAS: No Difference. • CBC: Significantly High Irrespective of RTH Use  Prophylaxis. Breast Cancer with BRCA Mutation: Choice of Loco-Regional Management: Pierce et al. Breast Cancer Res Treat. 2010 June ; 121(2): 389–398
  • 27. Breast Cancer with BRCA Mutation: Contralateral Breast: Int. J Cancer:136,668-677.(2015)
  • 28. Breast Cancer with BRCA Mutation: Contralateral Breast: Int. J Cancer:136,668-677.(2015) Number 583 BRCA Mutated PBC P/HRCRRM Surveillance 242 (42%) 341 (58%) Contralateral Breast Cancer 4 (2%) 64 (19%) P = 0.001 Mortality/1000 Persons - Years of Observation 9.6% 21.6 HR = 0.49 MedianFollowup=11.2years
  • 29. Take Home Message: • Hereditary breast cancer is a unique disease with TN and HR – phenotypes in > 70% of cases and poor prognosis in vast majority of patients with compromised survival outcome. • Deleterious BRCA mutations are associated with high risk of developing breast cancer with higher rates of local and contralateral failures than sporadic cases. • Genetic counseling should be offered for high risk population. • Screening mammography and MRI are complementary. • Prophylactic Bilateral Mastectomy  90% risk reduction. • Platinum compounds are key players in management. • PARP inhibitors carry a promising change of disease landscape.