Frequency of germline mutations in BRCA1 and BRCA2 in ovarian cancer patients and their effect on treatment outcome

Figures & data

Table 1 Patient characteristics

Patient characteristics	Negative for BRCA1/2 mutations N=(82) %		Positive for BRCA1/2 mutations N=(22) %		P-value
Age at diagnosis	51.81	±11.00	49.32	±11.53	0.76
Age groups					0.04
>50	37	(66.07)	19	(33.92)
≥50	45	(93.75)	3	(6.25)
Ancestry					0.63
Arab	50	(78.1%)	14	(21.9%)
Asian	26	(76.5%)	8	(23.5%)
European	4	(100%)	0
African	2	(100%)	0
Family history					0.005
Yes	22	(56.4)	17	(43.6)
No	60	(92.3)	5	(7.7)
Personal breast cancer history					0.46
No	77	(79.4)	20	(20.6)
Yes	5	(71.4)	2	(28.6)
Figo stage					0.05
I	24	(88.9)	3	(11.1)
II	12	(80)	3	(20)
III	38	(70.4)	16	(29.6)
IV	8	(100)	0	0
Pathological subtype	65		17		0.07
Serous	55	(74.3)	19	(25.7)
Clear cell	2	(100)	0	(0)
Endometrioid	14	(93.33)	1	(6.67)
Others	11	(84.6)	2	(15.4)

Table 2 Location of BRCA gene mutations

Gene	Exon/intron	Variation	AA Change	Variant effect	Ancestry	Age	Class	Frequency	Previously reported
BRCA1	Exon 11	c.1140dupG	p.Lys381Glufs*3	Frame Shift	Asian	50	5	1	Yes
BRCA1	Exon 8	c.512dupT	p.Gin172Thrfs*10	Frame Shift	Asian	44	5	1	Yes
BRCA1	Intron 17	c.5074+1G>A		Splice site	Asian	47	5	1	Yes
BRCA1	Exon 11	c.2719G>T	p.GIu907*	Nonsense	Asian	45	5	1	Yes
BRCA1	Exon 11	c.3607C>T	p.Arg1203*	Nonsense	Arab	47	5	1	Yes
BRCA1	Intron 7	c.441+1G>A		Splice site	Arab	45	5	2	Yes
BRCA1	Exon 17	c.5030_5033del 4	p.Thr1677IIefs*2	Frame Shift	Asian	45	5	1	Yes
BRCA1	Exon 20	c.5229_5230del AA	p.Arg1744Lysfs*	Frame Shift	Arab	38	5	1	Yes
BRCA1	Exon 11	c.4065_4068del 4	p.Asn1355Lysfs*	Frame Shift	Arab	46	5	1	Yes
BRCA1	Exon 11	c.2679_2682del GA	p.Lys893Asnfs*106	Frame Shift	Arab	44	5	1	Yes
BRCA1	Exon 11	c.3919del	p.Thr1307Leufs*11	Frame Shift	Arab	35	5	1	Novel
BRCA1	Exon 15	c.4658del	p.Leu1553Cysfs*6	Frame Shift	Arab	47	5	1	Novel
BRCA1	Exon 2	185delAG	p.Leu22-Glu23LeuValfs	Frame Shift	Arab	34	5	1	Yes
BRCA1	Exon 11	c.3548A>G	p.Lys1183Arg	Missense	Arab	46	1	1	Yes
BRCA 2	Exon 11	c.4631del	p.Asn1544Thrfs*24	Frame Shift	Arab	44	5	1	Yes
BRCA 2	Exon 23	c.9019A>T	pArg3007*	Missense	Arab	69	3	1	Yes
BRCA 2	Exon 11	c.4570_4573del 4	phe1524IIefs*18	Frame Shift	Asian	46	5	1	Yes
BRCA 2	Exon 11	c.4631delA	pAsn1544Thrfs*24	Frame Shift	Asian	56	5	1	Yes
BRCA 2	Exon 11	c.4415-4418delAGAA	p.Lys1472Thrfs	Frame Shift	Arab	43	5	1	Yes
BRCA 2	Exon 11	c.4859delA	p.Asn1544Thrfs	Frame Shift	Asian	36	5	1	Yes
BRCA 2	Exon 11	c.3971del T	p.Leu1324Glnfs	Frame Shift	Arab	48	5	1	Yes

Notes: *Class (ACMG): 1=benign. 2=likely benign. 3=mutation of uncertain significance. 4=likely pathogenic. 5=pathogenic.

Abbreviations: AA Change, Amino Acid Change; ACMG, American College of Medical Genetics and Genomics.

Table 3 Primary treatment received

Primary treatment received	N=104
Neoadjuvant chemotherapy	N	%
No. of patients	33	(31.7%)
Chemotherapy regimen	Paclitaxel/carboplatin
Median no. of cycles	4	(3–6)
Responsive to neoadjuvant therapy	33
CR	1	(3%)*
PR	30	(90.9%)*
SD	1	(3%)*
PD	1	(3%)*
Surgery	104	(100%)
Optimal	76	(73.1%)
Suboptimal	28	(26.9%)
Adjuvant chemotherapy
No. of patients	89	(85.6%)
Chemotherapy regimen	Paclitaxel/carboplatin
Avastin added	15	(14.4%)
Median no. of chemotherapy cycles	3	(3–4)
Median no. of avastin cycles	8	(4–12)

Note: *Percent of cases receiving neoadjuvant therapy.

Abbreviations: CR, complete remission; PR, partial remission; SD, stationary disease; DP, disease progression.

Table 4 Pattern of relapse and treatment received at relapse

	n	%
Relapsed patients	47	(45.2%)
Site of relapse
Local	37	(78.7%)
Distant	10	(21.3%)
Platinum sensitivity
Sensitive	39	(82.98%)
Resistant	8	(17.02%)
Chemotherapy regimen
Paclitaxel/carboplatin	35	(74.47%)
Gemcitaben/carboplatin	4	(8.51%)
Caelyx	8	(17.02%)
Avastin added	11	(23.4)
Median no. of chemotherapy cycles	6	(3–9)
Median no. of avastin cycles	12	(4–45)
Response
CR	8	(17%)
PR	30	(63.8%)
SD	3	(6.4%)
DP	6	(12.8%)

Abbreviations: CR, complete remission; PR, partial remission; SD, stationary disease; DP, disease progression.

Table 5 Association of relapse pattern with BRCA1/2 mutation status

	Negative for BRCA1/2 mutations N=(38) %		Positive for BRCA1/2 mutations N=(9) %		P-value
Sensitivity to platinum-based chemotherapy after primary therapy					0.59
Sensitive	31	(79.49)	8	(20.5)
Resistant	7	(87.5)	1	(12.5)
Site of relapse					0.01
Local recurrence	33	(89.2)	4	(10.8)
Distant metastasis	5	(50)	5	(50)
Response to second-line therapy					0.12
CR + PR	29	(76.3%)	9	(23.7%)
SD + PD	9	(100%)	0	(0%)

Figure 1 Relationship of overall survival with BRCA1/2 mutation status.

Figure 2 Relationship of relapse free survival with BRCA1/2 mutation status.

Table 6 Univariate analysis for the association of tumor characteristics with progression-free survival

Progression-free survival	Median, months	(95% CI)	P-value
BRCA1/2 mutation status			0.08
Negative	22.24	(14.83–29.58)
Positive	42.43	(32.04–52.83)
Pathological subtype			0.47
Serous	28.19	(12.05–44.33)
Others	26.35	(7.33–45.37)
Stage			>0.001
I	NR*
II	NR*
III	20.66	(11.99–29.35)
IV	14.44	(2.3–29.23)
Surgery			>0.001
Optimal	42.43	(29.46–55.4)
Suboptimal	16.05	(12.16–19.94)

Abbreviation: NR, not reached.

Table 7 Univariate analysis for the association of tumor characteristics with overall survival

Overall survival	Median, months	(95% CI)	P-value
BRCA1/2 mutation status			0.04
Negative	56.63	(50.05–63.21)
Positive	64.32	(38.09–90.06)
Pathological subtype			0.87
Serous	64.32	(53.29–73.36)
Others	NR
Stage			>0.001
I	NR
II	NR
III	59.72	(51.34–67.89)
IV	39.53	(8.43–70.63)
Surgery			>0.001
Optimal	NR
Suboptimal	45.6	(34.1–57.1)

Abbreviation: NR, not reached.