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.
Cardiac Output, Venous Return, and Their Regulation
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.
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.
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.