Concurrent TP53 mutations predict poor outcomes of EGFR-TKI treatments in Chinese patients with advanced NSCLC

Figures & data

Table 1 Characteristics between TP53-mut and TP53-wt groups of patients with TKI treatments (n=71)

	Total (n=71) (%)	TP53-mut (n=43) (%)	TP53-wt (n=28) (%)	P-value
Age (year)				0.657
Median (range)	61(31–78)	62(31–78)	61(47–77)
Gender				0.386
Female	49(69.0)	28(65.1)	21(75.0)
Male	22(30.1)	15(34.9)	7(25.0)
Smoking status				0.242
Smoker	12(16.9)	9(20.9)	3(10.7)
Never smoker	59(83.1)	34(79.1)	25(89.3)
ECOG PS				0.524
0–1	64(90.1)	38(88.4)	26(92.9)
2–	7(9.9)	5(11.6)	2(7.1)
Line of therapy				0.856
First line	39(54.9)	24(55.8)	15(53.6)
Non-first line	32(45.1)	19(44.2)	13(46.4)
PFS (month)				0.035*
0–3	17(23.9)	14(32.6)	3(10.7)
3–	54(76.1)	29(67.4)	25(89.3)
OS (month)				0.26
0–6	12(16.9)	9(20.9)	3(10.7)
6–	59(83.1)	34(79.1)	25(89.3)

Note: *P<0.05.

Abbreviations: TKI, tyrosine kinase inhibitor; PFS, progression-free survival; OS, overall survival; ECOG-PS, Eastern Cooperative Oncology Group performance status.

Table 2 Univariate analyses of selected factors for PFS and OS of EGFR-mut NSCLC patients (N=71)

Characteristics	N	PFS		OS
HR (95% CI)	P-value	HR (95% CI)	P-value
Age	71	0.99(0.97–1.02)	0.529	1.00(0.97–1.05)	0.705
Gender			0.979		0.912
Male	22(31.0)	1		1
Female	49(69.0)	0.99(0.56–1.77)		1.05(0.48–2.30)
Smoking status			0.128		0.298
Smoker	12(16.9)	1		1
Non-smoker	59(83.1)	0.56(0.27–1.19)		0.62(0.25–1.54)
ECOG PS			0.838		0.538
0–1	64(90.1)	1		1
≥2	7(9.9)	1.10(0.44–2.77)		1.40(0.48–4.05)
TP53 mutation			0.029*		0.024*
Wt	28(39.4)	1		1
Mut	43(60.7)	1.86(1.06–3.28)		2.45(1.10–5.43)
EGFR mutation			0.838		0.001*
Del19/L858R	51(71.8)	1		1
Uncommon mutations	20(28.2)	1.66(0.91–3.02)		3.24(1.51–6.94)
Line of therapy			0.032*		0.076
First line	39(54.9)	1		1
Non-first line	32(45.1)	1.85(1.05–3.25)		1.11(0.53–2.33)

Note: *P<0.05.

Abbreviations: NSCLC, non-small-cell lung cancer; PFS, progression-free survival; OS, overall survival; ECOG-PS, Eastern Cooperative Oncology Group performance status.

Table 3 Multivariate analyses of selected factors for PFS and OS of EGFR-mut NSCLC patients (N=71)

	PFS		OS
HR (95% CI)	P-value	HR (95% CI)	P-value
TP53 mutation		0.03*		0.017*
Wt	1		1
Mut	1.87(1.06–3.29)		2.73(1.20–6.21)
EGFR mutation		0.032*		0.002*
Del19/L858R	1		1
Other mutation	1.98(1.06–3.70)		3.58(1.61–7.94)
Line of therapy		0.017*		0.825
First line	1		1
Non-first line	2.02(1.14–3.58)		1.09(0.51–2.32)

Note: *P<0.05.

Abbreviations: NSCLC, non-small-cell lung cancer; PFS, progression-free survival; OS, overall survival

Figure 1 Kaplan–Meier curves of survival. (A) Comparison of PFS between TP53-mut and TP53-wt patients (N=71). (B) Comparison of OS between TP53-mut and TP53-wt subgroups (N=71). (C) Comparison of PFS between TP53-mut and TP53-wt patients in the subgroup of patients with Del19/L8585R EGFR mutations (N=51). (D) Comparison of PFS between TP53-mut and TP53-wt patients in the subgroup of patients with first-line TKIs therapy (N=39).

Abbreviations: PFS, progression-free survival; OS, overall survival; NSCLC, non-small cell lung cancer; ECOG, Eastern Cooperative Oncology Group; PS, performance status; mut, mutant; wt, wild type.

Table 4 Comparison of PFS and OS of patients stratified based on different characteristics

	N (%)	PFS (month)			OS (month)
Median	95%CI	Log-rank P-value	Median	95%CI	Log-rank P-value
Overall
TP53-mut	43(60.7)	6.5	3.44–9.56	0.025*	28.0	8.74–47.26	0.023*
TP53-wt	28(39.4)	14.0	9.43–18.60		52.0	35.63–69.37
Del19/L858R or uncommon mutations
Del19/L858R	51(71.8)	12.0	8.76–15.24	0.067	52.5	37.12–67.88	0.001*
Uncommon mutations	20(28.2)	5.0	2.84–7.06		14.0	0.00–38.31
Treatment line
First line	39(54.9)	14.5	6.95–22.05	0.055	40.0	26.0–51.95	0.567
Non-first line	32(45.1)	8.4	5.29–11.52		39.0	20.11–59.89
Subgroup of classic Del19/L858R mutations
TP53-mut	30(58.8)	9.0	4.70–13.30	0.181	NA	NA	0.057
TP53-wt	21(41.2)	14.0	10.05–17.95		39.0	15.29–62.71
Subgroup of uncommon mutations
TP53-mut	13(65.0)	4.0	0.54–7.46	0.124	10.5	9.16–11.84	0.137
TP53-wt	7(35.0)	8.5	NA		40.0	1.98–78.02
Subgroup of first line treatment
TP53-mut	24(61.5)	6.0	2.42–9.58	0.160	21.2	NA	0.398
TP53-wt	15(38.5)	12.0	6.70–12.30		40.0	0–46.00
Subgroup of non-first line treatment
TP53-mut	19(59.4)	9.0	0–18.66	0.072	NA	NA	0.095
TP53-wt	13(41.6)	21.0	4.60–37.44		28.0	2.02–53.98
Comparison of PFS and OS between patients with exon19 deletion and L858R point mutations
Del19	25(49.02)	14.0	8.44–19.56	0.730	59.0	NA	0.286
L858R	26(50.98)	9.5	5.77–13.23		39.0	11.25–66.75
Comparison of PFS and OS between patients with Del19/TP53-mut and L858R/TP53-mut genotypes
Del19/TP53-mut	12(40.00)	11.0	1.54–20.46	0.640	59.0	NA	0.561
L858R/TP53-mut	18(60.00)	9.0	6.47–11.53		39.0	12.5–65.50

Note: *P<0.05.

Abbreviations: PFS, progression-free survival; OS, overall survival

Table 5 TP53 mutational status based on sites and subtypes

	Exon	Number of patients (N=43) (%)
Mutations on DNA binding domain (N=32, 74.42%)	Exon 5	10(23.25)
	Exon 6	6(13.95)
	Exon 7	9(20.93)
Exon 8	7(16.28)
Mutations on other sites (N=11, 25.58%)	Exon 4	6(13.95)
	Intron 9	1(2.33)
	Exon 10	3(6.98)
Exons 1+3	1(2.33)
Missense/non-missense mutation	Missense	27(62.79)
Non-missense mutation	16(37.21)
Disruptive/non-disruptive	Disruptive	32(74.42)
Non-disruptive	11(25.58)

Figure 2 Kaplan–Meier curves of survival. (A and B) Comparison of PFS/OS between patients with TP53 non-disruptive mutations (N=11) and TP53 wild type cases (N=28). (C and D) Comparison of PFS/OS between patients with TP53 non-missense mutations (N=16) and TP53 wild type cases (N=28). (E and F) Comparison of PFS/OS between patients with TP53 mutations in exon 6 (N=6) and TP53 wild type cases (N=28). (G and H) Comparison of PFS/OS between patients with TP53 mutations in exon 7 (N=9) and TP53 wild type cases (N=28). (I and J) Comparison of PFS/OS between patients with TP53 mutations in exons other than 5–8 (N=11) and TP53 wild type cases (N=28).

Abbreviations: PFS, progression-free survival; OS, overall survival.