BRCA – Importance in Hereditary Breast & Ovarian Cancer DGF & WOW India presentation was made by Dr Sharda Jain based on presentation made by Dr Sunil Tadepalli

1. BRCA – Importance in Hereditary
Breast & Ovarian Cancer
Presented in DGF CME on
24th December 2018
Dr. Sunil Tadepalli
Director, Centogene India
December 24th, 2018

2. DGF & WOW India
presentation was made by
Dr Sharda Jain
based on presentation made by
Dr Sunil Tadepalli

3. Breast Cancer is the number one
cancer among Indian women* & it is on rise.

4. Breast Cancer is the number one cancer among Indian women* …he most
investment for prevention, detection, treatment and palliative care
Source: Dr. Ali Shamseddine
*Malvia et al. Asia-Pacific Journal of
Clinical Oncology 2017; 13: 289-295
Estimate that by 2020, India could
have as many as 1.8 Million cases of
Breast Cancer

5. 5-10% OF PATIENTS WITH Breast And / or
ovarian cancer have a hereditary form

6. All breast / ovarian cancer
Hereditary breast / ovarian cancer
BRCA/2 associated cancer

7. For any individual carring a mutation in
BRCA 1 or BRCA 2, the lifetime risk of developing
breast / ovarian cancer increases
from 12% to 50-85%

8. www.centogene.com
BRCA1 and BRCA2 Associated Cancers & Penetrance
Cancer Type General
Population Risk
Mutation Risk
BRCA1 BRCA2
Breast
12% (in India 5-
8%)
50%-80% 40%-70%
Second primary
breast
3.5% within 5
years
Up to 11%
27% within 5
years
12% within 5
years
40%-50% at 20
years
Ovarian 1%-2% 24%-40% 11%-18%
Male breast 0.1% 1%-2% 5%-10%
Prostate 15%-18% <30% <39%
Pancreatic 0.5% 1%-3% 2%-7%

9. FEW FACTS
In the general population ,approximately 12% of
women will develop breast cancer in their lifetime. In
comparison , 55- 65% of women carrying a BRCA2
mutation will develop breast by age 70.

10. By detecting cancer early , patients can have timely
access to preventative measures & proactive
treatment – leading to a better prognosis overall.
Where cancer has been diagnosed, somatic testing of
the BRCA1/2 genes is still highly beneficial & can
significantly improves the prognosis & quality of life
cancer – affected patients.
FEW FACTS

11. WHO SHOULD GET
BRCA 1 & 2 TESTING ?

12. HBOC Testing Criteria - Test affected individual if available first
individual if available first
Meets any one or more
of these criteria
Family with a known deleterious BRCA 1 / 2
mutation
Breast cancer
≤45 y
Breast Cancer
≤50 y
Additional breast primary
≥1 close blood relative with breast cancer at any age
≥1 close blood relative with pancreatic cancer
≥1 close blood relative with prostate cancer – Gleason ≥7
Unknown or limited family history
Breast Cancer
≤60 y
Triple negative breast cancer
Breast cancer at any age ≥1 close blood relative with breast cancer ≤50 y
≥2 close blood relatives with breast cancer at any age
≥1 close blood relative with invasive ovarian cancer
≥2 close blood relatives with pancreatic or prostate cancer
Close male relative with breast cancer
Serous epithelial ovarian cancer

13. Autosomal Dominant Inheritance

14. TESTING STRATEGY FOR HBOC
Full gene
sequencing of
BRCA 1 & 2
Mutation
detected –
provide
genetic
counselin
g
No
mutation
detected
Deletion
Duplication Test
for BRCA 1 & 2
Mutation
detected
– provide
genetic
counselin
g
No
mutation
detected
CentoBreast
Panel
Mutation
detected –
provide
genetic
counselin
g
No
mutation
detected
Whole
Genome
Sequencing
ATM, BARD1, BRCA1,
BRCA2, BRIP1, CDH1,
NBN, PALB2, PTEN,
RAD51C, STK11, TP53

15. Potential Benefits:
Clinical intervention may improve
outcome
Family members at risk can be
identified
Positive health behavior can be
reinforced
Reduction of uncertainty
Risks / Benefits / Limitations of genetic testing -
Positive test result
Potential Risks:
Adverse psychological reaction
Family issues/distress
Uncertainty -incomplete
penetrance
Insurance/job discrimination
Confidentiality issues
Intervention carries risk

16. Variant categorization
• Known pathogenic (condition relevant and
incidental)
• Likely pathogenic
• VUS (variants of undetermined significance)
• Likely benign
• Known benign
ONLY ONE OR
TWO GOOD
LABS CAN DO IT
eg CENTOGENE

17. Positive
Deleterious mutation identified
Negative
Interpretation differs if a mutation has previously been
identified in the family
Mutation known – true negative
Mutation unknown – uninformative
Variant of unknown significance
Significance will depend on how variant tracks through family -
i.e. is variant present in people with disease?
Can use software to predict functional significance
Check with lab to see if reported previously
Results from Genetic Testing

18. Detection rate of new BRCA1/BRCA2 classified and
curated genetic variants (CentoMD®)
Newly detected unique variants vs. previously published genetic variants
(includes pathogenic, likely pathogenic, uncertain, risk factor, modifiers)
BRCA1 BRCA2

19. Patient cohort
20%
vs.
70%
In our total cohort of 1,221 patients in 2016 we identified
240 with pathogenic mutations (20%),
119 with variant of uncertain clinical significance (10%) and
862 no mutation (70%).
26%
vs.
57%
High risk group of young index patients (< 40 yrs) with breast
cancer and positive family history of cancer.
114 carried pathogenic mutation (26%),
24 variant of uncertain significance (17%) and
82 no mutation (57%).
Relevant Clinical Information
• Age of onset
• Family history
• Type of cancer
Detection rate 26%
• 26%by Schneegans et al,
Fam Cancer. 11(2): 181–188.
• 27% by Kast et al, Cancer
Res 69(24):731S-S

20. Anticipation
Statistically significant decreased age of onset
7.9 Years From Mother To Daughter for BRCA1 & BRCA2
mutations
[Litton JK et al. Cancer 2012: 118: 321-5]
6.8 years for BRCA1 & 12.1 years for BRCA2-mutation positive
individuals & earlier age of onset was associated with progressive
telomere shortening
[Martinez-Delgado et al. PLoS Genetics 2011: 7: e10021182]

21. Bilateral risk reduction mastectomy (RRM) decreased the risk of developing breast
cancer by at least 90% in moderate- to high-risk women and in known BRCA1/2
mutation carriers.
[Hartmann LC et al. J Natl Cancer Inst 2001; 93: 1633-1637]
Option of RRM to be offered on a case-by-case basis after appropriate counseling
including risks & benefits of surgery & surgical breast reconstruction options
Risk Reduction Mastectomy (RRM)

22. Absence of early methods of early detection & poor prognosis associated with
advanced ovarian cancer warrant RRSO in women after completion of child bearing
A meta-analysis of 10 studies showed approximately 80% reduction in the risk of
ovarian or fallopian cancer following RRSO
[Rebbeck TR et al. J Natl Cancer Inst 2009; 101:80-87]
RRSO also reduces the risk of breast cancer in carriers or BRCA mutations by ~50%
[Eisen A et al. J Clin Oncol 2005; 23: 7491-7496]
Bilateral Risk Reducing
Salpingo-oophorectomy (RRSO)

23. BRCA Testing in Ovarian Cancer
 NCCN advocates BRCA testing in all women with serous
epithelial ovarian cancers – 20-25% women positive even
without family history.
 Respond better to chemotherapy, FDA (May 2015) has
approved Olaparib for use in BRCA positive ovarian cancers
who relapse.

24. BRCA Testing in Ovarian Cancer

25. HEREDITARY BREAST & OVARIAN CANCER –
OTHER GENES
Gene Clinical Significance
CDH1 Women have a 39%-52% risk for lobular breast cancer
CHEK2 Two to three fold increase in breast cancer in women
PTEN
Cowden Syndrome (CS) – High risk for benign and malignant tumors of
the thyroid, breast and endometrium. Life time risk of developing breast
cancer is 25-50%, with the average age of diagnosis between 38-46 years.
Autosomal dominant inheritance.
STK11
Peutz-Jeghers Syndrome (PJS) - Association of gastrointestinal polyposis
and mucocutaneous pigmentation. 8% of women with PJS developed
breast cancer by age 40 years and 32% by age 60 years.
Autosomal dominant inheritance.
TP53
Li-Fraumeni Syndrome (LFS) - Cancer predisposition syndrome
associated with tissue sarcoma, osteosarcoma, pre-menopausal breast
cancer, brain tumors, adrenocortical carcinoma and leukemias. LFS-
related cancers often occur in childhood or young adulthood and survivors
have an increased risk for multiple primary cancers.
Autosomal dominant inheritance

26. TAKE-HOME MESSAGE
To the Clinicians, gynaecologists & public at large:
• Record detailed family and personal history in every case of breast,
ovarian, colon & endometrial cancer and offer genetic testing in
appropriate families
• Genetic testing offers the possibility of risk evaluation & management
even in the pre-symptomatic stage
• Many patients are quite aware of the possibility of familial cancers and
request testing – but misinformation is widespread
• Germline mutations can be diagnosed easily and have defined
inheritance patterns.
• Both Somatic & Germline mutations are useful in guiding management
of patients.

27. DGF & WOW India
presentation was made by
Dr Sharda Jain
based on presentation made by
Dr Sunil Tadepalli

28. This PPT is made for awarness among gynaecologits
& general public from
Presentation made by Dr Sunil Tadepalli on
24th December 2018
Thank you for your interest
Email: Sunil.Tadepalli@centogene.com
Mobile: +91-99100-17978
Web: www.centogene.com
Email: Shalabh.Saxena@centogene.com
Mobile: +91-95484-66660