Table 2 Multivariable Cox proportional hazard regression analyses for subsequent breast cancer in female 5-year childhood cancer survivors (primary cancer diagnosis year 1946–2012)

From: Subsequent female breast cancer risk associated with anthracycline chemotherapy for childhood cancer

Characteristic	Total (n)	%	No. of SBC (n)^c	%	Model I^a		Model II^b
Characteristic	Total (n)	%	No. of SBC (n)^c	%	HR	95% CI	HR	95% CI
Cumulative doxorubicin dose (mg m⁻²)
0	11,170	62.4	431	55.1	1.0	Ref.	–
<100	912	5.1	16	2.0	1.76	0.88–3.51
100–199	1,795	10.0	69	8.8	1.77	1.30–2.42
200–299	1,026	5.7	67	8.6	2.50	1.85–3.40
300–399	1,012	5.7	64	8.2	2.33	1.68–3.23
≥400	779	4.4	58	7.4	2.78	1.99–3.88
Unknown	1,209	6.8	77	9.8	–	–
Continuous variable: cumulative doxorubicin dose (per 100 mg m⁻²)	–	–	–	–	–	–	1.24	1.18–1.31
Cumulative daunorubicin dose (mg m⁻²)
0	14,630	81.7	684	87.5	1.0	Ref.	–
<100	623	3.5	7	0.9	0.98	0.46–2.09
100–199	953	5.3	16	2.0	0.98	0.55–1.75
≥200	645	3.6	17	2.2	1.22	0.69–2.17
Unknown	1,052	5.9	58	7.4	–	–
Continuous variable: cumulative daunorubicin dose (per 100 mg m⁻²)	–	–	–	–	–	–	1.10	0.95–1.29
Epirubicin
No	16,637	92.9	717	91.7	1.0	Ref.	1.0	Ref.
Yes	325	1.8	9	1.2	3.40	1.66–6.98	3.25	1.59–6.63
Unknown	941	5.3	56	7.2	–	–	–	–
Chest radiotherapy field and dose
No chest radiotherapy	13,004	72.6	250	32.0	1.0	Ref.	1.0	Ref.
High-dose mantle (≥36 Gy; median: 40 Gy, IQR: 39–44 Gy)	698	3.9	238	30.4	8.99	7.00–11.53	9.12	7.09–11.75
Low-dose mantle (<36 Gy; median: 26 Gy, IQR: 21–30 Gy)	524	2.9	93	11.9	4.72	3.48–6.41	5.23	3.86–7.09
Mediastinal (median: 26 Gy, IQR: 21–36 Gy)	469	2.6	33	4.2	1.65	1.02–2.67	1.71	1.06–2.78
TBI (median: 12 Gy, IQR: 11–13 Gy)	371	2.1	22	2.8	7.05	4.11–12.10	7.18	4.18–12.33
Whole lung (median: 16 Gy, IQR: 12–23 Gy)	184	1.0	23	2.9	7.58	4.68–12.27	8.00	4.94–12.95
Other (median: 28 Gy, IQR: 21–36 Gy)	1,316	7.4	63	8.1	2.61	1.87–3.64	2.68	1.91–3.75
Unknown	1,337	7.5	60	7.7	–	–	–	–
Pelvic radiotherapy ≥5 Gy
No	13,751	76.8	505	64.6	1.0	Ref.	1.0	Ref.
Yes	2,911	16.3	222	28.4	0.95	0.78–1.17	0.94	0.77–1.16
Unknown	1,241	6.9	55	7.0	–	–	–	–
Age at primary childhood cancer diagnosis (year)
<5	7,376	41.2	66	8.4	1.0	Ref.	1.0	Ref.
5–9	3,788	21.2	65	8.3	1.13	0.76–1.69	1.12	0.75–1.67
10–14	3,930	22.0	273	34.9	2.03	1.48–2.79	2.04	1.49–2.81
15–21	2,809	15.7	378	48.3	1.83	1.31–2.55	1.84	1.32–2.57
CED^d (mg m⁻²)
None	7,951	44.4	301	38.5	1.0	Ref.	1.0	Ref.
<6,000	3,069	17.1	94	12.0	0.87	0.67–1.14	0.95	0.73–1.25
6,000–17,999	3,899	21.8	192	24.6	1.02	0.82–1.27	1.07	0.86–1.32
≥18,000	1,117	6.2	47	6.0	1.20	0.83–1.74	1.23	0.85–1.77
Unknown	1,867	10.4	148	18.9	–	–	–	–

^aModel I included categorical variables of cumulative doxorubicin and daunorubicin dose by steps of 100 mg m⁻².
^bModel II included continuous variables of cumulative doxorubicin and daunorubicin dose per 100 mg m⁻².
^cOne survivor had SBC before 5 years after primary cancer.
^dCED calculation: CED (mg m⁻²) = 1.0 (cumulative cyclophosphamide dose (mg m⁻²)) + 0.244 (cumulative ifosfamide dose (mg m⁻²)) + 0.857 (cumulative procarbazine dose (mg m⁻²)) + 14.286 (cumulative chlorambucil dose (mg m⁻²)) + 15.0 (cumulative BCNU (carmustine) dose (mg m⁻²)) + 16.0 (cumulative CCNU (lomustine) dose (mg m⁻²)) + 40 (cumulative melphalan dose (mg m⁻²)) + 50 (cumulative Thio-TEPA (thiotepa) dose (mg m⁻²)) + 100 (cumulative nitrogen mustard dose (mg m⁻²)) + 8.823 (cumulative busulfan dose (mg m⁻²)).

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Table 2 Multivariable Cox proportional hazard regression analyses for subsequent breast cancer in female 5-year childhood cancer survivors (primary cancer diagnosis year 1946–2012)

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