Association Between Event-Free Survival and Overall Survival in Early-Stage Triple-Negative Breast Cancer

Figures & data

Table 1. Key characteristics of studies included in the base case analysis of individual-level association.

Study characteristics	Publications included, N = 45	Sample size of TNBC population, N = 7522
Study type, n (%)
RCT	12 (26.67)	4251 (56.51)
Single-arm trial	2 (4.44)	114 (1.52)
Cohort study	31 (68.89)	3157 (41.97)
Geographic region, n (%)
North America	8 (17.78)	1697 (22.56)
Europe	10 (22.22)	1757 (23.36)
Asia-Pacific	16 (35.56)	1210 (16.09)
Multi-regional	4 (8.89)	2088 (27.76)
Others	7 (15.56)	770 (10.24)
Publication year, median (range)	2019 (2007–2022)
Follow-up time, median (range) months	43.7 (18.6–100.6)
Age, median (range) years	49 (42.6–53)
Reported 3-year EFS and 5-year OS, n (%)	32 (53.33)	3700 (49.19)
Reported 5-year EFS and 5-year OS, n (%)	38 (63.33)	4539 (60.34)
Reported 3-year EFS and 3-year OS, n (%)	54 (90.00)	6683 (88.85)
TNBC ER/PR positivity threshold, n (%)
10%	12 (26.67)	1911 (25.41%)
1%	16 (35.56)	3979 (52.90)
Not reported	17 (37.78)	1632 (21.70)
Adjuvant therapy use, n (%)
Yes	12 (26.67)	1816 (24.14)
No	9 (20.00)	1313 (17.46)
Not reported	24 (53.33)	4393 (58.40)

EFS: Event-free survival; ER: Estrogen receptor; OS: Overall survival; PR: Progesterone receptor; RCT: Randomised clinical trial; TNBC: Triple-negative breast cancer.

Table 2. Key characteristics of randomized controlled trials included in the base case analysis of individual-level and trial-level associations.

Trial name	Observation (comparison)	Neoadjuvant therapy intervention	Trial phase	Geographic region	Median follow-up time, month	Median age, year	Sample size	Hazard ratio of OS (experiment vs control)	Hazard ratio of EFS (experiment vs control)	Ref.
NSABP B-40^¶	a	B + (T → AC, capecitabine + T → AC, G + T → AC) vs T → AC, capecitabine + T → AC, G + T → AC	Phase III	USA, Canada and Puerto Rico	56.4^†	NR	479	0.790	0.960	[33]
NATT	b	TAC vs TC	Phase III	China	52.9^†	47.2–48^‡	49	0.124	0.354	[34]
BrighTNess	c	Pac + carboplatin + veliparib vs Pac	Phase III	USA, Canada, Europe, Asia-pacific, etc.	54	49–51	474	0.820	0.630	[35]
	d	Pac + carboplatin + veliparib vs Pac + carboplatin					476	1.250	1.120
	e	Pac + carboplatin vs Pac					318	0.630	0.570
GeparSixto	f	Carboplatin + Pac + non-pegylated liposomal doxorubicin + B vs Pac + non-pegylated liposomal doxorubicin + B	Phase II	Germany	47.3^†	47–48^§	315	0.600	0.560	[36]
GeparNuevo	g	Durvalumab → Durvalumab + nab-Pac →Durvalumab + EC vs Nab-Pac → EC	Phase II	Germany	43.7	49.5	174	0.240	0.480	[37]
SWOG S0800	h	B + nab-Pac + ddAC + pegfilgrastim vs Nab-Pac + ddAC + pegfilgrastim	Phase II	USA	36^†	51.3–51.7^§	67	0.490	0.460	[38]
Keynote-522	i	Pembrolizumab + (Pac + carboplatin → AC) vs Pac + carboplatin → AC	Phase III	USA, Canada, Europe, Asia-pacific, etc.	37.8	48–49	1174	0.720	0.630	[39]
GeparOcto	j	Pac/non-pegylated liposomal dd + carboplatin vs intense dose-dense E + Pac + C	Phase III	Germany	47	48^§	403	0.660	0.730	[40]
NeoSTOP	k	Carboplatin + Pac → dd + C vs Carboplatin + T	Phase II	USA	38	51	100	0.794	0.837	[41]
CALGB (Alliance) 40603	L	Carboplatin + Pac + ddAC +/- B vs Pac + ddAC +/- B	Phase II	USA	94.8	NR	443	1.120	0.940	[42]
	m	B + Pac + ddAC +/- carboplatin vs Pac + ddAC +/- carboplatin				NR	443	0.970	0.920
GeparSepto	n	Nab-Pac → E + C vs Pac → E + C	Phase III	Germany	49.6^†	48–49^§	276	0.740	0.620	[43]
GBG 44 - GeparQuinto^¶	o	ECB→TB vs EC→T	Phase III	Germany	45.6^†	48–49^§	663	1.020	0.990	[44]
	p	Pac + everolimus vs Pac				50–51^§	109	1.080	1.330
NCT01276769	q	Pac + carboplatin vs E + Pac	Phase II	China	55	47	85	0.650	0.447	[45]
NeoCART	r	T + carboplatin vs E + C→T	Phase II	China	37	50	88	0.960	0.760	[46]
IMpassion031^¶	s	Atezolizumab + nab-Pac → dd + C vs nab-Pac → dd + C	Phase III	USA, Canada, Europe, Asia-pacific, etc.	Intervention: 20.6 Control: 19.8	51	333	0.690	0.760	[47]

† The follow-up time of the whole study population was used as a proxy for the follow-up time of patients with TNBC.

‡ The mean age was reported in NATT trial.

§ The median age of the whole study population was used as a proxy for the median age of patients with TNBC.

¶ The three studies NSABP B-40 [33], GBG 44 - GeparQuinto [44] and IMpassion031 [47] were only included in the analysis of trial-level association as they did not report the landmark EFS or OS outcomes for the analysis of individual-level association.

A: Anthracycline; B: Bevacizumab; C: Cyclophosphamide; dd: Doxorubicin; ddAC: Doxorubicin plus cyclophosphamide; E: Epirubicin; EFS: Event-free survival; ER: Estrogen receptor; F: Fluorouracil; G: Gemcitabine; M: Methotrexate; NR: Not reported; OS: Overall survival; Pac: Paclitaxel; PR: Progesterone receptor; RCT: Randomized controlled trial; T: Docetaxel; TC: Non-anthracycline-containing docetaxel plus cyclophosphamide; TNBC: Triple-negative breast cancer.

Figure 1. Individual-level association between EFS and OS.

The primary outcome was (A) 3-year EFS and 5-year OS, and secondary outcomes were (B) 5-year EFS and 3-year OS and (C) 3-year EFS and 3-year OS. Each circle represents one observation, with the size of the circle representing the sample size. The red solid lines are the regression lines presenting the prediction models for OS rate by EFS rate. The blue dotted lines represent the 95% prediction limits for the regression lines.

EFS: Event-free survival; OS: Overall survival; R²: Coefficient of determination.

Figure 2. Trial-level association between EFS and OS in the models.

(A) Without and (B) with fixed intercept. HRs were plotted in the figures and weighted linear regressions were performed using log(HR) of EFS as the independent variable and log(HR) of OS as the dependent variable. Individual observations are identified by letters listed in Table 2. Each circle represents one comparison, with the size of the circles representing the sample size. The red solid lines are regression lines representing the prediction models for OS HR by EFS HR. The blue dotted lines represent the 95% prediction limits for the regression lines. The black horizontal lines provide a reference where OS HR equals 1.

EFS: Event-free survival; HR: Hazard ratio; OS: Overall survival; R²: Coefficient of determination; STE: Surrogate threshold effect.

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