It describes the prevalence of Breast Cancer among BRCA 1/2 mutations with special consideration to biological background, detection and screening, actions taken upon discovering mutation carriers and whether we have a different therapeutic algorithm than sporadic cases. Special emphasis on the role of PARP inhibitors in the management of metastatic disease.

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.