Validation of a normal tissue complication probability model for late unfavourable aesthetic outcome after breast-conserving therapy

Figures & data

Table 1. Comparison of patient, tumor and treatment characteristics in the development and validation cohort.

	Development cohort		Validation cohort
	(n = 121)		(n = 175)		Comparison
Characteristic	Median	IQR *	Median	IQR	p-value
Age at diagnosis (years)	60	52.8; 65.4	58	51.0;65.0	.34
Characteristic	n	%	n	%
Breast cup					<.001
A	4	3.3	18	10.3
B	27	22.3	59	33.7
C	40	33.1	50	28.6
D	31	26.6	34	19.4
E	15	12.4	10	5.7
F	2	1.7	3	1.7
G	2	1.7	1	0.6
Breast band size (EU)					.28
70	15	12.4	23	13.1
75	26	21.5	43	24.6
80	27	22.3	39	22.3
85	20	16.5	34	19.4
90	14	11.6	21	12.0
95	10	8.3	9	5.1
100	5	4.1	6	3.4
≥ 105	4	3.3	0	0.0
Chemotherapy					.50
No	87	71.9	127	72.6
Yes	34	28.1	48	27.4
Hormonal therapy					.19
No	11	9.1	23	13.1
Yes	110	90.9	152	86.9
Trastuzumab					.39
No	110	90.9	156	89.1
Yes	11	9.1	19	10.9
Whole-breast irradiation					<.001
25 x 2 Gy	84	69.4	70	40.0
16 x 2.66 Gy	37	30.6	105	60.0
Boost modality					.21
Brachytherapy	62	51.2	80	45.7
EBRT **	59	48.8	95	54.3
Lymphadenectomy	11	9.1	23	13.1	.19
None
Sentinel	81	66.9	129	73.7	.13
ALND ***	29	24.0	23	13.1	.01
Position of tumor					.25
6h	9	7.4	8	4.6
12 h	13	10.7	15	8.6
retro-areolar	2	1.7	2	1.1
upper inner	19	15.7	32	18.3
upper outer	46	38.0	84	48.0
lower inner	5	4.1	17	9.7
lower outer	8	6.6	18	20.3
3/9h inner	5	4.1	7	4.0
3/9h outer	14	11.6	15	8.6
Pathologic T-stage					.51
is	12	9.9	25	14.3
0	3	2.5	0	0.0
1	70	57.9	103	58.9
2	36	29.8	47	26.9
Re-resection					.42
No	114	94.2	167	95.4
Yes	7	5.8	8	4.6
Seroma					.20
No	94	77.7	127	72.6
Yes	27	22.3	48	27.4
Characteristic	mean	range	mean	range
BMI (kg/m²)	26.8	17.7; 41.5	25.3	16.3; 39.7	<.01
Surgical specimen weight (g)	46.7	5.0; 248.0	31.2	1.0;101.0	.07
Volume breast (cm³)	902.8	210.9; 2125.4	742.2	103.4;2058.5	<.001
Dmean breast (EQD2) (Gy) ****	51.1	46.1; 64.1	50.9	45.9; 60.9	.70
V30 (EQD2) (%) *****	96.4	93.4; 99.7	96.0	92.6; 98.3	.14
V35 (EQD2) (%)	93.2	88.9; 98.5	92.8	86.5; 96.2	.41
V40 (EQD2) (%)	89.0	82.4; 96.0	88.7	78.6; 93.9	.76
V45 (EQD2) (%)	82.3	69.6; 91.8	82.4	66.4; 90.6	.56
V50 (EQD2) (%)	52.1	10.0; 84.9	51.0	10.1; 81.7	.51
V55 (EQD2) (%)	20.4	4.8; 65.4	19.5	2.6; 46.6	.99
V60 (EQD2) (%)	12.8	2.0; 52.0	12.4	0.0; 40.2	.56
V65 (EQD2) (%)	6.8	0.0; 40.6	5.9	0.0; 24.0	.76
V70 (EQD2) (%)	2.9	0.0; 25.4	3.2	0.0; 19.5	.58

*IQR: interquartile range; **EBRT: external beam radiotherapy; ***ALND: axillary lymph node dissection; **** EQD2: equivalent dose in 2 Gy fractions using an α∕β : 3.6 Gy [15]; *****V30–70: relative volume of breast tissue receiving 30–70 Gy; significant parameters are highlighted in bold.

Figure 1. ROC curve for the validation cohort.

Figure 2. Calibration plot for model training.

Figure 3. Calibration plot for model validation.

Table 2. Performance of the NTCP model.

	NTCP model 1 (V55, ALND, seroma) optimized in development cohort	NTCP model 1 (V55, ALND, seroma) tested in validation cohort	NTCP model 2 (V45, seroma) optimized in validation cohort
AUC*	0.75 (0.64; 0.85)	0.66 (0.56; 0.76)	0.75 (0.65; 0.83)
Discrimination slope	0.21	0.11	0.13
Nagelkerke R^2	0.27	0.13	0.17
Calibration-in-the-large	0.01	0.04	−0.01
Calibration slope	0.98	0.74	1.02

* AUC: area under the curve.

Table 3. Univariable analysis for unfavourable aesthetic outcome in development and validation cohort.

		Development cohort			Validation cohort
Variable		Odds Ratio	95% CI *	p-value	Odds Ratio	95% CI	p-value
Age at diagnosis (years)	+1 year	0.99	0.96; 1.03	.64	1.03	1.00;1.07	.07
Breast cup	+1 unit	1.21	0.88; 1.65	.24	1.30	0.97;1.73	.07
Breast band size (EU)	+1 unit	1.13	0.92; 1.39	.24	1.40	1.12;1.75	.003
Chemotherapy	Yes vs No	2.64	1.17; 5.96	.02	1.18	0.55;2.53	.67
Hormonal therapy	Yes vs No	1.58	0.40; 6.31	.51	1.62	0.51;5.11	.41
Trastuzumab	Yes vs No	3.45	0.95; 12.54	.06	0.99	0.33;2.93	.98
Whole-breast irradiation Ref. [25] x 2 Gy	16 x 2.66 Gy	0.41	0.16; 1.09	.08	0.82	0.36; 1.83	.62
Boost modality	Brachy vs external beam radiotherapy	1.07	0.51; 2.24	.86	1.96	0.98;3.94	.06
Lymphadenectomy Ref. Sentinel	None	0.50	0.10; 2.47	.39	0.71	0.22; 2.26	.21
	Axillary lymphadenectomy	3.17	1.32; 7.62	.01	2.25	0.87; 5.85	.06
Position of tumor	Inner quadrants	0.83	0.33; 2.09	.69	0.67	0.30; 1.49	.33
Ref. Outer quadrants **	12 o'clock	2.14	0.65; 7.09	.21	0.35	0.07; 1.63	.18
Pathologic T-stage Ref. [1] ***	is	0.47	0.09; 2.32	.35	0.58	0.18; 1.87	.37
	2	2.33	1.02; 5.35	.05	1.25	0.58; 2.71	.57
Re-resection	Yes vs No	1.34	0.28; 6.26	.71	NA ****	NA	NA
Seroma	Yes vs No	2.80	1.17; 6.73	.02	4.71	2.24;9.94	<.001
BMI (kg/m²)	+1 unit	1.09	1.00; 1.18	.04	1.12	1.03;1.21	.007
Surgical specimen weight (g)	+1 unit	1.02	1.00; 1.03	.01	1.011	1.00;1.02	.009
Surgical specimen weight >75g	Yes vs No	2.54	0.92; 7.01	.07	2.37	0.96; 5.84	.06
Volume breast (cm³)	+100 units	1.09	0.99; 1.19	.08	1.09	1.00;1.18	.04
Dmean breast (EQD2) (Gy) *****	+1 Gy	1.18	1.02; 1.37	.03	1.05	0.92; 1.19	.49
V30 (EQD2) (%) ******	+1%	1.42	1.04; 1.94	.03	1.40	1.02;1.93	.04
V35 (EQD2) (%)	+1%	1.28	1.03; 1.60	.02	1.26	1.03;1.55	.03
V40 (EQD2) (%)	+1%	1.20	1.02; 1.42	.03	1.18	1.03;1.35	.02
V45 (EQD2) (%)	+1%	1.12	1.01; 1.25	.03	1.12	1.02;1.22	.01
V50 (EQD2) (%)	+1%	1.02	1.00; 1.05	.10	1.01	0.99;1.03	.21
V55 (EQD2) (%)	+1%	1.05	1.01; 1.10	.008	0.98	0.94;1.02	.29
V60 (EQD2) (%)	+1%	1.07	1.01; 1.12	.012	0.96	0.91;1.01	.12
V65 (EQD2) (%)	+1%	1.09	1.02; 1.16	.02	1.00	0.93;1.06	.91
V70 (EQD2) (%)	+1%	1.05	0.96; 1.15	.32	1.02	0.94;1.11	.67

* 95% CI: 95% confidence interval; ** nipple-areolar complex: only 2 patients, none with unfavourable AO; *** 0: only 3 patients, all with unfavourable AO; **** NA: not available: no re-resections in unfavourable AO group; ***** EQD2: equivalent dose in 2 Gy fractions using an α∕β : 3.6 Gy [15]; ****** V30-70: relative volume of breast tissue receiving 30–70 Gy; significant parameters are highlighted in bold.

Figure 4. Average DVHs for favourable and unfavourable aesthetic outcome in the development and validation cohort.

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