ovarian cancer

1. DR. R. RAJKUMAR D.M.
CONSULTANT MEDICAL ONCOLOGIST
VELAMMAL MEDICAL COLLEGE &
SPECIALITY HOSPITAL

2. CASE DISCUSSION

3. CASE DISCUSSION

4. CASE DISCUSSION

5. CASE DISCUSSION

6. CASE DISCUSSION

7. CASE DISCUSSION

8. CASE DISCUSSION

9. CASE DISCUSSION

10. CASE DISCUSSION

11. CASE DISCUSSION

12. CASE DISCUSSION

13. CASE DISCUSSION

14. CASE DISCUSSION

15. CASE DISCUSSION

16. MADURAI 625009
TAMIL NADU INDIA
9842350899 9843292313
CLIENT CODE : C000051601
CLIENT'S NAME AND ADDRESS :
VELAMMAL MEDICAL COLLEGE HOSPITAL & RESEARCH INSTITUTE
VELLAMMAL VILLAGE, MADURAI-TUTICORIAN RING ROAF, ANUPPANADI,
DIAGNOSTIC REPORT
SRL LIMITED
PRIME SQUARE BUILDING,PLOT NO 1,GAIWADI INDUSTRIAL
ESTATE,S.V. ROAD,GOREGAON (W)
MUMBAI, 400062
MAHARASHTRA, INDIA
Tel : 9111591115, Fax : 022 - 67801212
CIN - U74899PB1995PLC045956
Email : connect@srl.in
PATIENT ID :
ACCESSION NO : 0002TI018453 AGE : 55 Years SEX : Female DATE OF BIRTH :
DRAWN : 04/09/2020 00:00 RECEIVED : 07/09/2020 11:40 REPORTED : 28/09/2020 15:50
REFERRING DOCTOR : DR. RAJKUMAR CLIENT PATIENT ID : 1908870083
Final Results
Test Report Status Units
BRCA -NEXT
BRCA1 GENE MUTATIONS
NOT DETECTED
DETECTED
BRCA2 GENE MUTATIONS
NOT DETECTED
DETECTED
Comments
*****KINDLY NOTE: NO DELETERIOUS REPORTED MUTATION WAS FOUND IN BRCA1 OR BRCA2 GENE IN THE
RECEIVED SPECIMEN FOR THIS PATIENT.
Interpretation(s)
BRCA -NEXT-Germline mutations in the BRCA1 and BRCA2 gene significantly increase the risk of breast cancer and ovarian cancer when compared with the cancer risk of a
woman without a BRCA gene mutation. Mutations in these genes also account for a fraction of male breast cancer. Certain variations of the BRCA1 gene lead to an increased
risk for breast cancer as part of a hereditary breast-ovarian cancer syndrome. Women with an abnormal BRCA1 or BRCA2 gene have up to an 80% risk of developing breast
cancer by age 90 increased risk of developing ovarian cancer is about 55% for women with BRCA1 mutations and about 25% for women with BRCA2 mutations.
In this assay, the entire coding region and the splice junction sites of the BRCA1 and BRCA2 genes are PCR amplified and then subjected to massive parallel sequencing using
Next Generation Sequencing (NGS) platform. Hence this assay is designed to identify mutations in all coding region of the BRCA1 and BRCA2 genes. Uncommon genetic
abnormalities such as large deletions/duplications involving one or more exons or Intronic variations cannot be examined with this assay. This assay cannot rule out the
presence of germline mutations in other genes with susceptibility to breast and/or ovarian cancer. Variance of unknown clinical significance or known benign polymorphisms
with no clinical significance is not reported. This test results should only be used in conjunction with the patient’s clinical findings, relevant history and any previous analysis of
appropriate family members.
**End Of Report**
Please visit www.srlworld.com for related Test Information for this accession
Dr. Firoz Ahmad,PhD
Research Scientist and Senior
Manager - R&D
Dr. B. R. Das, PhD
Advisor and Mentor
R&D & Molecular Diagnostics
Dr. (COL) Prabal Deb
Director (Lab Operations) &
Chief Histopathologist
Scan to View Details
Page 1 Of 1

17. CASE DISCUSSION

18. High grade serous or endometrioid Low grade endometrioid Low grade serous Clear Cell Mucinous
Genetic characteristics Up to 50% of cancers have underlying
problems in DNA repair; associated with
TP53 and BRCA mutations
PTEN, ARID1A, PIK3CA
alterations
May have microsatellite
instability
KRAS, BRAF
mutations
PIK3CA, ARID1A,
PTEN
KRAS
Clinical characteristics Cancers are more sensitive to drugs like
platinum (carboplatin and cisplatin)
along with PARP inhibitors
Carcinosarcomas are treated like high
grade serous cancers
Potentially more responsive to
hormonal therapy, although
not established
Hormonal therapies
MEK inhibitors
May be a little more
sensitive to
immunotherapy
Are more resistant
to chemotherapy;
may have
microsatellite
instability
Ovarian Cancer is Not Just One Tumor
Type: Classification Using Molecular
Data

19. BRCA MUTATIONS AND OVARIAN CANCER
Risk of Developing Ovarian Cancer
Mutated BRCA1
39% to 46%
Mutated BRCA2
10% to 27%
Normal BRCA
2%
https://www.acog.org/Patients/FAQs/BRCA1-and-BRCA2-Mutations

20. HOMOLOGOUS RECOMBINATION REPAIR
DNA double-strand break (DSB)
MRN-mediated sensing of the DSB →
ATM activation
MRN-mediated 5’ to 3’ end resection
End processing via BRCA1 & 2-containing complex →
binds directly to RAD 51
Displacement of RPA and assembly of RAD51 onto
ssDNA via BRCA2
Strand invasion into undamaged homologous DNA
leading to repaired DNA
Hosoya. Cancer Sci. 2014;105:370.

21. HRD AND BRCA MUTATIONS
Germline BRCA mutations
Germline non-BRCA mutations in HR pathway
Sporadic (somatic) BRCA mutations
Sporadic non-BRCA mutations in HR pathway
Mutations in HR pathway
↓
HRD

22. GERMLINE VS SOMATIC MUTATIONS
Germline mutations are inherited and found in all cells
Somatic mutations are not inherited and are found within the tumor
Offspring gametes
Germline
mutation
Half of gametes
carry mutation
Embryo
Parental gametes
Entire body
carries
mutation
Somatic
mutation
Mutation only
in affected area
Embryo
Parental gametes
Offspring gametes
No gametes
carry mutation

23. SINGLE-GENE VS MULTIGENE (PANEL)
Single-Gene Testing
Tests for
mutation-specific gene
PCR and direct sequencing
Traditionally used when personal or FH suggests
single inherited
cancer syndrome
Panel Testing
Tests mutation status of multiple
genes with
one sample
Most commonly using NGS
Can be used in place of single-gene testing;
should be considered when negative for single-
gene test but FH suggests an inherited
susceptibility

24. 1960
Cyclophosphamide (1959)
Melphalan
(1964)
Etoposide
(1983)
Carboplatin
(1989)
Altretamine
(1990)
Docetaxel
(1996)
Topotecan
ROC (1996)
PLD-Accelerated
ROC (1999)
PLD-Full
ROC (2005)
Gemcitabine/Carboplatin
PlSOC (2006)
Olaparib
gBRCAmut ROC (2014)
Chemo + Bevacizumab (2014)
PlROC
Rucaparib gBRCAmut/
sBRCAmut ROC (2016)
Chemo + Bevacizumab
PlSOC (2016)
Olaparib
Maintenance PlSOC (2017)
Niraparib
Maintenance PlSOC (2017)
Pembrolizumab
MSI/dMMR ROC (2017)
Cisplatin
(1978)
Paclitaxel
Full (1998)
Paclitaxel
Accelerated
(1992)
Rucaparib
Maintenance PlSOC (2018)
Bevacizumab
1L + Maintenance (2018)
1970 1980 1990 2000 2010 2020
Olaparib
gBRCAmut 1L
Maintenance (2018)
THIRTEEN New FDA Approvals in Ovarian Cancer From
2014 to 2020
Niraparib
1L Maintenance
(2020)
Niraparib
HRD+ ROC (2019)
Olaparib +
Bevacizumab
HRD+ 1L
Maintenance (2020)

25. FDA-Approved PARP Inhibitors:
Current Indications in Ovarian Cancer
Olaparib Niraparib Rucaparib
 First-line maintenance therapy for
BRCA-mutated advanced ovarian cancer
in CR/PR to platinum-based CT
 First-line maintenance therapy in
combination with bevacizumab for ovarian
cancer in CR/PR to platinum-based CT and
with HRD (either a deleterious BRCA
mutation or genomic instability)
 First-line maintenance therapy for
advanced ovarian cancer in CR/PR to
platinum-based CT regardless of
BRCA mutation status
 Maintenance therapy for recurrent ovarian
cancer in CR/PR to platinum-based CT
regardless of BRCA mutation status
 Maintenance therapy for recurrent
ovarian cancer in CR/PR to platinum-
based CT regardless of BRCA
mutation status
 Maintenance therapy for
recurrent ovarian cancer in CR/PR
to platinum-based CT regardless
of BRCA mutation status
 Fourth-line and beyond treatment for
advanced ovarian cancer with germline
BRCA mutations
 Fourth-line and beyond treatment
for advanced ovarian cancer with
HRD (either a deleterious BRCA
mutation or genomic instability)
 Third-line and beyond treatment
for advanced ovarian cancer with
BRCA mutations (germline or
somatic)

26. PFS in Phase III Trials of PARP Inhibitors vs Placebo as
Maintenance in BRCA-Mutated Ovarian Cancer
SOLO-2: Olaparib vs Placebo
in gBRCAm Patients[1]
mPFS,
Mos
Olaparib
(n = 196)
Pbo
(n = 99)
HR
(95% CI)
Inv 19.1 5.5
0.30
(0.22-0.41)
BICR 30.2 5..5
0.25
(0.18-0.35)
mPFS,
Mos
Niraparib
(n = 138)
Pbo
(n = 65)
HR
(95% CI)
Inv 14.8 5.5
0.27
(0.18-0.40)
BICR 21.0 5.5
0.27
(0.17-0.41)
mPFS,
Mos
Rucaparib
(n = 130)
Pbo
(n = 66)
HR
(95% CI)
Inv 16.6 5.4
0.23
(0.16-0.34)
BICR 26.8 5.4
0.20
(0.13-0.32)
NOVA: Niraparib vs Placebo
in gBRCAm Patients[2,3]
ARIEL-3: Rucaparib vs Placebo
in tBRCAm Patients[4]
Slide credit: clinicaloptions.com
1. Pujade-Lauraine. Lancet Oncol. 2017;18:1274. 2. Mirza. NEJM. 2016;375:2154.
3. Fabbro. Gynecol Oncol. 2019;152:560. 4. Coleman. Lancet. 2017;390:1949.
PFS
(%)
33
Mos
0 3 6 9 12 15 18 21 24 27 30
0
20
40
60
80
100
Olaparib
Placebo
0
0
20
40
60
80
100
6 12 18 24 30 36
Rucaparib
Placebo
Mos
24
Mos
0 3 6 8 10 12 14 16 18 20 22
0
20
60
80
100
4
Niraparib
Placebo

27. PFS in Phase III Trials of PARP Inhibitors vs Placebo as
Maintenance in Ovarian Cancer Without BRCAm or HRD
STUDY 19: Olaparib vs Placebo
in BRCAwt Pts[1]
ARIEL-3: Rucaparib vs Placebo
in tBRCAwt/LOH-L Pts[3]
PFS,
%
Months
0 3 6 9 12 15
Months
0
20
40
60
80
100
Olaparib
Placebo
24
NOVA: Niraparib vs Placebo
in BRCAwt/HRD-neg Pts[2]
0
25
50
75
100
0 2 4 6 8 10 12 14 16 18 20 22
Niraparib
Placebo
Months
mPFS,
mo
Olaparib
(n = 57)
Pbo
(n = 61)
HR
(95% CI)
Inv 7.4 5.5
0.54
(0.34-0.85)
BICR -- -- --
mPFS,
mo
Niraparib
(n = 92)
Pbo
(n = 42)
HR
(95% CI)
Inv -- -- --
BICR 6.9 3.8
0.58
(0.36-0.92)
mPFS,
mo
Rucaparib
(n = 106)
Pbo
(n = 52)
HR
(95% CI)
Inv 6.7 5.4
0.58
(0.40-0.85)
BICR -- -- --
0
0
25
50
75
100
6 12 18 24 30 36
Rucaparib
Placebo

28. Testing a Preclinical Hypothesis: Does PARP Inhibitor
Concentration Matter?
Why was niraparib studied in BRCAwt tumors?[1]
Concentration may play an important role in
activity of PARP inhibitors in BRCAwt tumors[2]
Low PARP Inhibitor Concentration Needed High
BRCAwt
BRCAmut Sensitivity
1

29. How much? For how long?
How is it
metabolized? To where?
Pharmacologic Properties of PARP Inhibitors
 PARP inhibitors differ in terms of biochemical properties; hence, data cannot be extrapolated
from one PARP inhibitor to another
 Each PARP inhibitor needs to be assessed based on its approved indication and data
 Biochemical properties are not meant to suggest clinical efficacy
PARP Inhibitor Bioavailability, %
Mean Half-Life
(t1/2), h
Metabolism
(Major Enzymes)
Tissue
Distribution
(VD/F), L
Niraparib[1]
73 36 CEs 1220
Olaparib[2]
NA 14.9 ± 8.2 CYP3A4 167
Rucaparib[3]
36 25.9 CYP2D6 113-262
NH
N
O O
N
F
N
O
O NH2
N
N
NH
F
O N
NH
HN
H

30. Phase III PRIMA Trial of Maintenance Niraparib After
Initial Therapy for Ovarian Cancer
PFS in HRD Population PFS in Overall Patient Population
HR: 0.43 (95% CI: 0.31-0.59; P < .001)
Median PFS, Mos
21.9
10.4
Niraparib
Placebo
HR: 0.62 (95% CI: 0.50-0.76; P < .001)
Median PFS, Mos
13.8
8.2
Niraparib
Placebo
100
80
60
40
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Mos Since Randomization
PFS
(%)
Pts at Risk, n
Niraparib
Placebo
247
126
231
117
215
99
189
79
184
70
168
57
111
34
76
21
66
21
42
11
22
5
19
5
13
4
4
1
0
0
*
*
* *
* * *
*
*
* **
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*
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**
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100
80
60
40
20
0
0 2 4 6 8 10 12 14 16 18 20 22 24 26 28
Mos Since Randomization
PFS
(%)
Pts at Risk, n
Niraparib
Placebo
487
246
454
226
385
177
312
133
295
117
253
90
167
60
111
32
94
29
58
17
29
6
21
6
13
4
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1
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 Patients with newly diagnosed high-grade serous/endometrioid advanced ovarian cancer after CR/PR to first-
line platinum-based CT (N = 730); Primary endpoint: PFS by BICR with hierarchical testing in patients with HRD
(HR benefit: 0.5) followed by the overall patient population (HR benefit: 0.65)

31. Phase III PAOLA-1/ENGOT-ov25 Trial of Maintenance Olaparib
+ Bev After Initial Therapy for Ovarian Cancer
 Patients with newly diagnosed, FIGO stage III-IV, high-grade serous/endometrioid ovarian, fallopian tube or
primary peritoneal cancer after CR/PR to platinum/taxane-based CT and ≥ 3 cycles of bevacizumab (N = 806)
31
Olaparib +
Bevacizumab
Placebo +
Bevacizumab
Events, n/N (%) 280 (52) 194 (72)
Median PFS, mos 22.1 16.6
Median time from first cycle of chemotherapy
to randomization = 7 mos
537 513 461 433 403 374 279 240 141 112 55 37 12 0
3
269 252 226 205 172 151 109 83 50 35 15 9 1 0
1
Olaparib
Placebo
Patients at Risk, n
100
80
70
60
50
40
30
20
10
0
90
0 3 6 9 12 15 18 21 24 30
27
Mos Since Randomization
PFS
(%)
33 36 39 42 45
Olaparib + Bev
Placebo + Bev
Median follow-up ~ 24 mos
HR: 0.59 (95% CI: 0.49-0.72; P < .001)
Primary Endpoint: Investigator Assessed PFS

32. Newly diagnosed
Advanced
HGSOC/HGEOC
BRCAwt HRD
testing
HRD known
HRD unknown or
Unavailable
HRD
HRp
CT  PARPi
CT Bev  Bev
CT  PARPi
CT + Bev  Bev + PARPi
AGM2020
BRCA
testing
BRCAmut
CT  PARPi
CT + Bev  Bev + PARPi
SOLO-1[1]
PRIMA[2]
PAOLA-1[3]
PAOLA-1[3]
GOG-218[4]]
PRIMA[2]
1.
STANDARD SYSTEMIC THERAPIES FOR NEWLY
DIAGNOSED OVARIAN CANCER IN 2020