A total of 61 women were eligible for analysis. The median age at diagnosis was 52 years (IQR: 44–61.5). BRCA mutations were found in 25 women (41%), including 23 with BRCA1 mutations and 2 with BRCA2 mutations. The patient and disease characteristics stratified by BRCA status are shown in Table 1. The main presenting symptom was abdominal distension (35 patients, 57.3%). The logistic regression revealed a significant association between family history of malignancy and BRCA mutations (p = 0.03). However, BRCA mutations were not statistically significantly associated with age and stage at diagnosis, patient region, or history of primary cancer.
Table 1
Patient, disease, and treatment characteristics stratified by BRCA status (n = 61)
|
|
BRCA mutant
n = 25 (41%)
|
BRCA wild type
n = 36 (59%)
|
|
Characteristics
|
|
N (Frequency)
|
N (Frequency)
|
P-VALUE*
|
Age at diagnosis
|
|
|
|
|
Median (IQR)
|
|
50 (43–56)
|
55 (46–66)
|
0.13
|
Age ≤ 50
Positive personal history of cancer
|
|
14 (56)
5 (20)
|
15 (41.7)
1 (2.9)
|
0.27
0.04
|
Positive family history of cancer
|
|
7 (28)
|
2 (5.6)
|
0.02
|
Presence of comorbidities*
|
|
19 (76)
|
24 (66.7)
|
0.43
|
Histology
|
High-grade serous
Endometrioid
|
100%
|
97.1%
2.9%
|
0.39
|
High grade
FIGO stage
|
|
25 (100)
|
34 (94.4)
|
0.48
|
|
Stage 1
IA
IB
IC
|
6
2
2
2
|
3
0
1
2
|
0.65
|
|
Stage 2
IIA
IIB
|
1
1
0
|
4
1
3
|
|
|
Stage 3
IIIA
IIIB
IIIC
|
15 (58)
0
1
14
|
21 (55)
2
2
17
|
|
|
Stage 4
|
4
|
10
|
|
High CA125
|
|
20 (80)
|
26 (72.2)
|
0.46
|
Initial management
No. of lines, median (IQR)
|
PDS
NAC
|
48%
52%
3 (1–5)
|
50%
50%
3 (2–4.75)
|
0.87
0.79
|
Lines of treatment
|
|
|
|
|
First line (n = 61)
PBC
Non PBC
|
|
(n = 25)
100%
|
(n = 18)
100%
|
0.26
|
Second line (n = 49)
PBC
Non PBC
|
|
(n = 18)
88.9
11.1
|
(n = 31)
83.4
16.6
|
0.79
|
Third line (n = 39)
PBC
Non PBC
|
|
(n = 13)
73.1
26.9
|
(n = 26)
64
36
|
0.42
|
Fourth line (n = 23)
PBC
Non PBC
|
|
(n = 10)
50%
50%
|
(n = 13)
23.1%
76.9%
|
0.38
|
Fifth line (n = 13)
PBC
Non PBC
|
|
(n = 7)
-
100%
|
(n = 5)
-
100%
|
0.68
|
Categorical values were compared with the Chi-square test or Fisher’s exact test, and continuous values were described as the median with interquartile range (IQR) and compared using the Mann-Whitney U test |
Comorbidities: hypertension, DM, hypothyroidism, bronchial asthma, dyslipidemia, or osteoarthritis. PBC; platinum-based chemotherapy; non PBC, non-platinum-based chemotherapy (Paclitaxel, Liposomal doxorubicin, Etoposide, Gemcitabine, Topotecan, Letrozole, Tamoxifen)
|
There were 15 different pathogenic variants identified, including 13 with BRCA1 mutations and 2 with BRCA2 mutations.he three most common deleterious germline BRCA1 mutations were c.1140dupG (9 patients, 39%), c.5530del (3 patients, 13%), and c.5095C > T (2 patients, 8%). The other pathogenic variants were each observed once. Table 2 presents all pathogenic variants of the mutated genes, age, geographical region of the patients, and personal and family histories of cancer. The univariant analysis revealed no association between c.1140dupG, the most common deleterious mutation, and age, stage at diagnosis, relapse rate, platinum sensitivity, or patient region; however, all the OC cases from the western province (3 patients) and 29% (4 patients) from the central region carried the c.1140dupG pathogenic variant of the BRCA1 gene mutation. Of the BRCA wild-type patients, two had a positive family history of cancer, including a mother with a brain tumor and a sister with colon cancer; one patient had a personal history of cervical cancer.
Table 2
Patients, age and regions, family history, and deleterious mutations (n = 25)
Age
|
Region*
|
Personal cancer
|
Family members/ type of cancer
|
Gene
|
Mutation
|
Protein change
|
60
|
South
|
|
-
|
BRCA1
|
c1140dupG
|
p.Lys381Glufs*3
|
38
|
Central
|
|
-
|
BRCA1
|
c.2410_2413del
|
p.gln804Valfs*10
|
56
|
Southern
|
|
Sister (breast)
|
BRCA1
|
c.1426_1433del
|
p.His476*
|
45
|
Central
|
Breast Ca
|
-
|
BRCA1
|
c.1140dupG
|
p.Lys381Glufs*3
|
49
|
Central
|
Breast Ca
|
-
|
BRCA1
|
c.5530del
|
p.Leu1844Serfs*11
|
52
|
Western
|
Breast Ca
|
Sister (breast)
|
BRCA1
|
c.1140dupG
|
p.Lys381Glufs*3
|
52
|
Central
|
|
-
|
BRCA1
|
c.1140dupG
|
p.Lys381Glufs*3
|
41
|
Central
|
|
-
|
BRCA2
|
c.5762_5772del
|
p.Phe1921Serfs*3
|
62
|
Northern
|
|
-
|
BRCA1
|
c.5074 + 2T > T
|
|
50
|
Northern
|
|
-
|
BRCA1
|
c.5095C > T
|
p.Arg1699Trp
|
48
|
Western
|
|
-
|
BRCA1
|
c.1140dupG
|
p.lys381Glufs*3
|
40
|
Eastern
|
|
-
|
BRCA1
|
c1140dupG
|
p.Lys381Glufs*3
|
53
|
Central
|
|
Sister (breast/ovarian) Father (Colon)
|
BRCA1
|
c.135-1del
|
|
45
|
Central
|
|
Sister (breast/ovarian) Father (Lung)
|
BRCA1
|
c.1140dupG
|
p.Lys381Glufs*3
|
43
|
Central
|
Breast Ca
|
mother and sister (breast)
|
BRCA1
|
c.1140dupG
|
p.Lys381Glufs*3
|
48
|
Central
|
Pheochromocytoma, Breast Ca
|
Brother (colon Ca)
|
BRCA1
|
c.2405_2406del
|
p.Val802Glufs*7
|
43
|
Central
|
|
-
|
BRCA1
|
c.1016del
|
p.Lys339Argfs*2
|
56
|
Central
|
|
-
|
BRCA1
|
c.69del
|
p.Glu23Valfs*17
|
56
|
Central
|
|
Sister (breast)
|
BRCA1
|
c.5095C > T
|
p.Arg1699Trp
|
69
|
Southern
|
|
-
|
BRCA1
|
c.2572C > T
|
p.Gln858*
|
41
|
Eastern
|
|
-
|
BRCA1
|
c.1140dupG
|
p.Lys381Glufs*3
|
67
|
Central
|
|
-
|
BRCA1
|
c.5530del
|
p.Leu1844Sarfs*11
|
35
|
Southern
|
|
-
|
BRCA1
|
c.708_711dupTGAA
|
p.His228*
|
59
|
Northern
|
|
-
|
BRCA1
|
c.5530del
|
p.Leu1844Serfs*11
|
50
|
Northern
|
|
-
|
BRCA2
|
c.7007G > A
|
p.Arg2336His
|
• Regions according to the Saudi cancer registry: Central region (Riyadh, Qassim, and Hail), Northern region (Madinah, Tabuk, Jouf, and Northern), Western region (Makkah, Madinah, Jeddah, and Taif), Eastern region (Dammam and Ahsa), and Southern region (Jizan, Naran, Baha, and Asir)
|
All women in this cohort underwent debulking surgery and received chemotherapy during their treatment; 49% received PDS and then adjuvant chemotherapy, and 51% started with neoadjuvant chemotherapy and IDS with no statistical difference (p = 0.98). All women received PBC as the first-line treatment. A total of 87% of both groups received a regimen consisting of IV cisplatin and paclitaxel every three weeks. The patients received a median of three chemotherapy lines; specifically, 21%, 17%, and 62% of patients received one, two, and three or more chemotherapy lines, respectively. The platinum sensitivity dropped with subsequent lines; 14%, 41%, and 73% of women received non-platinum-based therapy as the second-line, third-line, and fourth-line treatments, respectively, and 100% (13 patients) received non-platinum-based therapy as the fifth-line treatment. The ORR to the first line of management was 100%, with a higher complete response (CR) in BRCA mutant women than in wild-type women (92% vs 72.7%, p = 0.08). The relapse rate was 84%, and the majority (85%) were platinum-sensitive. Additionally, 84% of BRCA mutant vs. 80% of BRCA wild-type patients experienced platinum-sensitive relapse after first-line therapy (p = 0.43). In the subsequent lines of treatment, the ORR also was higher in the BRCA mutant group compared with the BRCA wild-type group: second-line (94.4% vs 64.5%, p = 0.01), third-line (84.7% vs 30.6%, p = 0.002), and fourth-line (40% vs 22.2%, p = 0.40) (Table 3). Thirteen out of 25 women with BRCA mutation received a PARP-inhibitor, namely Olaparib, and over half of the patients received Olaparib after third relapse. (54%, n = 7). Olaparib was discontinued due to disease progression in eleven patients and anemia in one patient. Olaparib treatment was still ongoing for one patient. The sample size limited further analysis.
Table 3
Response rate to different lines of chemotherapy based on BRCA status.
Best Response
|
First line (n = 61)
|
Second line (n = 49)
|
Third line (n = 39)
|
Fourth line (n = 23)
|
|
BRCAm
n = 25
|
BRCAw
n = 36
|
BRCAm
n = 18
|
BRCAw
n = 31
|
BRCAm
n = 13
|
BRCAw
n = 26
|
BRCAm
n = 10
|
BRCAw
n = 13
|
CR
|
92%
|
72.7%
|
50%
|
29%
|
46.2%
|
7.7%
|
20%
|
7.7%
|
PR
|
8%
|
27.3%
|
44.4%
|
35.5%
|
38.5%
|
19.2%
|
20%
|
7.7%
|
SD
|
-
|
-
|
5.6%
|
9.7%
|
-
|
26.9%
|
10%
|
15.4%
|
PD
|
-
|
-
|
-
|
25.8
|
15.4%
|
34.6%
|
50%
|
38.5%
|
NA
|
-
|
3 patients
|
-
|
-
|
-
|
3 patients
|
-
|
4 patients
|
ORR
|
100%
|
100%
|
94.4%
|
64.5%
|
84.7%
|
30.6%
|
40%
|
22.2%
|
P-Value*
|
|
0.01
|
0.002
|
0.40
|
* Chi−square or Fisher’s exact test ; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; NA, not available; ORR, objective response rate |
The median follow-up duration was 59 months (IQR: 42–79). The median DFS was longer in the BRCA mutant women 25 (95% CI: 21.7–28.2) vs. 17 (95% CI: 8.7–25) months, p = 0.02) (Fig. 1). The Cox regression analysis for DFS adjusted by age and comorbidities was statistically significant for BRCA mutant vs. wild-type patients (hazard ratio (HR) = 0.52, 95% CI: 0.23–0.92, p = 0.02). The median DFS of second-line treatment (50 patients) in the BRCA mutant group was 20 months (95% CI: 18.2–21.7) vs. 12 months (95% CI: 7.8–16.1) in the wild-type group (p = 0.051) (Fig. 2). The median OS was not reached. However, the five-year OS rate for BRCA mutant patients was 90.9% vs. 66.7% for wild-type patients (p = 0.19) (Fig. 3).