World J Oncol

World Journal of Oncology, ISSN 1920-4531 print, 1920-454X online, Open Access

Article copyright, the authors; Journal compilation copyright, World J Oncol and Elmer Press Inc

Journal website https://wjon.elmerpub.com

Original Article

Volume 17, Number 3, June 2026, pages 380-393

Real-World Data on the Use of Cyclin-Dependent Kinase 4/6 Inhibitors in Hormone Receptor–Positive/Human Epidermal Growth Factor Receptor 2–Negative Advanced/Metastatic Breast Cancer

↓ Figure 1. Univariate forest plot model for mPFS of patients receiving CDK4/6i. CDK4/6i: cyclin-dependent kinase 4 and 6 inhibitors; ECOG: Eastern Cooperative Oncology Group; PFS: progression-free survival.

↓ Figure 2. Univariate forest plot model for mOS of patients receiving CDK4/6i. CDK4/6i: cyclin-dependent kinase 4 and 6 inhibitors; ECOG: Eastern Cooperative Oncology Group; mOS: median overall survival.

↓ **Table 1.** Clinical Characteristics of Patients With HR+/HER2– a/mBC Receiving CDK4/6i-Containing Regimens
Characteristic^a	Overall (n = 269)	Palbociclib (n = 149)	Ribociclib (n = 103)	Abemaciclib (n = 17)	P value^b
^aN (%), unless otherwise specified. ^bKruskal-Wallis rank sum test; Fisher’s exact test. ^cMean ± SD (range). ^dPatients can have multiple metastatic sites. ECOG: Eastern Cooperative Oncology Group; SD: standard deviation; a/mBC: advanced/metastatic breast cancer; CDK4/6i: cyclin-dependent kinase 4 and 6 inhibitors; HER2–: human epidermal growth factor receptor 2–negative; HR+: hormone receptor–positive.
Age (years) at initial diagnosis^c	51 ± 11 (29–82)	49 ± 9 (30–75)	55 ± 13 (29–82)	51 ± 12 (35–70)	0.002
Breast cancer orientation at initial diagnosis					0.4
Left breast	177 (66%)	102 (68%)	66 (64%)	9 (53%)
Right breast	92 (34%)	47 (32%)	37 (36%)	8 (47%)
Breast cancer subtype at initial diagnosis					0.2
Ductal carcinoma	190 (71%)	111 (74%)	66 (64%)	13 (76%)
Lobular carcinoma	79 (29%)	38 (26%)	37 (36%)	4 (24%)
Breast cancer grade at initial diagnosis					0.6
1	24 (8.9%)	15 (10%)	8 (7.8%)	1 (5.9%)
2	145 (54%)	80 (54%)	53 (51%)	12 (71%)
3	100 (37%)	54 (36%)	42 (41%)	4 (24%)
Breast cancer stage at initial diagnosis					0.001
Early stage I	23 (8.6%)	3 (2.0%)	17 (17%)	3 (18%)
Early stage II	112 (42.1%)	79 (53%)	30 (28.9%)	3 (18%)
Locally advanced stage III	36 (13%)	22 (15%)	9 (8.7%)	5 (29%)
De novo metastatic stage IV	98 (36%)	45 (30%)	47 (46%)	6 (35%)
Menopausal status at time of CDK4/6i treatment					0.5
Postmenopausal	237 (88%)	134 (90%)	88 (85%)	15 (88%)
Premenopausal	32 (12%)	15 (10%)	15 (15%)	2 (12%)
ECOG performance status at time of CDK4/6i treatment					0.002
0	27 (10%)	14 (9%)	11 (10%)	2 (10%)
1	89 (33%)	47 (32%)	38 (37%)	4 (25%)
2	78 (29%)	38 (26%)	33 (32%)	7 (41%)
3	75 (28%)	49 (33%)	22 (21%)	4 (24%)
Metastatic sites at time of CDK4/6i treatment^d
Bones	75 (28%)	94 (63%)	68 (66%)	16 (94%)	0.038
Lungs	115 (43%)	36 (24%)	30 (29%)	9 (53%)	0.043
Lymph nodes	178 (66%)	15 (10%)	26 (25%)	4 (24%)	0.003
Brain	45 (17%)	31 (21%)	23 (22%)	1 (5.9%)	0.3
Liver	55 (20%)	55 (37%)	54 (52%)	6 (35%)	0.041

↓ Table 1. Clinical Characteristics of Patients With HR+/HER2– a/mBC Receiving CDK4/6i-Containing Regimens

Characteristic^a

Overall (n = 269)

Palbociclib (n = 149)

Ribociclib (n = 103)

Abemaciclib (n = 17)

P value^b

^aN (%), unless otherwise specified. ^bKruskal-Wallis rank sum test; Fisher’s exact test. ^cMean ± SD (range). ^dPatients can have multiple metastatic sites. ECOG: Eastern Cooperative Oncology Group; SD: standard deviation; a/mBC: advanced/metastatic breast cancer; CDK4/6i: cyclin-dependent kinase 4 and 6 inhibitors; HER2–: human epidermal growth factor receptor 2–negative; HR+: hormone receptor–positive.

Age (years) at initial diagnosis^c

51 ± 11 (29–82)

49 ± 9 (30–75)

55 ± 13 (29–82)

51 ± 12 (35–70)

0.002

Breast cancer orientation at initial diagnosis

0.4

Left breast

177 (66%)

102 (68%)

66 (64%)

9 (53%)

Right breast

92 (34%)

47 (32%)

37 (36%)

8 (47%)

Breast cancer subtype at initial diagnosis

0.2

Ductal carcinoma

190 (71%)

111 (74%)

66 (64%)

13 (76%)

Lobular carcinoma

79 (29%)

38 (26%)

37 (36%)

4 (24%)

Breast cancer grade at initial diagnosis

0.6

24 (8.9%)

15 (10%)

8 (7.8%)

1 (5.9%)

145 (54%)

80 (54%)

53 (51%)

12 (71%)

100 (37%)

54 (36%)

42 (41%)

4 (24%)

Breast cancer stage at initial diagnosis

0.001

Early stage I

23 (8.6%)

3 (2.0%)

17 (17%)

3 (18%)

Early stage II

112 (42.1%)

79 (53%)

30 (28.9%)

3 (18%)

Locally advanced stage III

36 (13%)

22 (15%)

9 (8.7%)

5 (29%)

De novo metastatic stage IV

98 (36%)

45 (30%)

47 (46%)

6 (35%)

Menopausal status at time of CDK4/6i treatment

0.5

Postmenopausal

237 (88%)

134 (90%)

88 (85%)

15 (88%)

Premenopausal

32 (12%)

15 (10%)

15 (15%)

2 (12%)

ECOG performance status at time of CDK4/6i treatment

0.002

27 (10%)

14 (9%)

11 (10%)

2 (10%)

89 (33%)

47 (32%)

38 (37%)

4 (25%)

78 (29%)

38 (26%)

33 (32%)

7 (41%)

75 (28%)

49 (33%)

22 (21%)

4 (24%)

Metastatic sites at time of CDK4/6i treatment^d

Bones

75 (28%)

94 (63%)

68 (66%)

16 (94%)

0.038

Lungs

115 (43%)

36 (24%)

30 (29%)

9 (53%)

0.043

Lymph nodes

178 (66%)

15 (10%)

26 (25%)

4 (24%)

0.003

Brain

45 (17%)

31 (21%)

23 (22%)

1 (5.9%)

0.3

Liver

55 (20%)

55 (37%)

54 (52%)

6 (35%)

0.041

↓ **Table 2.** Dosing Schedule of CDK4/6i-Containing Regimens
	Overall (n = 269)	Palbociclib (n = 149)	Ribociclib (n = 103)	Abemaciclib (n = 17)	P value^a
^aKruskal-Wallis rank sum test; Fisher’s exact test. ^bDaily dose level 1: 125 mg for palbociclib; 600 mg for ribociclib; 300 mg for abemaciclib (FDA-recommended starting daily dose). Daily dose level 2: 100 mg for palbociclib; 400 mg for ribociclib; 150 mg for abemaciclib. Daily dose level 3: 75 mg for palbociclib; 200 mg for ribociclib. CDK4/6i: cyclin-dependent kinase 4/6 inhibitor; SD: standard deviation; FDA: FDA: Food and Drug Administration.
Line of therapy, n (%)					< 0.001
1	182 (68%)	113 (76%)	61 (59%)	8 (47%)
2	66 (25%)	31 (21%)	32 (31%)	3 (18%)
3	21 (7.8%)	5 (3.4%)	10 (9.7%)	6 (35%)
Starting total daily dose of CDK4/6i, n (%)^b					< 0.001
75 mg	1 (0.4%)	1 (0.7%)	0	0
100 mg	28 (10%)	28 (19%)	0	0
125 mg	120 (45%)	120 (81%)	0	0
150 mg	3 (1.1%)	0	0	3 (18%)
200 mg	2 (0.7%)	0	2 (1.9%)	0
300 mg	14 (5.2%)	0	0	14 (82%)
400 mg	20 (7.4%)	0	20 (19%)	0
600 mg	81 (30%)	0	81 (79%)	0	< 0.001
Ending total daily dose of CDK4/6i, n (%)^b
75 mg	10 (3.7%)	10 (6.7%)	0	0
100 mg	73 (27%)	73 (49%)	0	0
125 mg	66 (25%)	66 (44%)	0	0
150 mg	7 (2.6%)	0	0	7 (41%)
200 mg	11 (4.1%)	0	11 (11%)	0
300 mg	10 (3.7%)	0	0	10 (59%)
400 mg	34 (13%)	0	34 (33%)	0
600 mg	58 (22%)	0	58 (56%)	0
Endocrine therapy given in combination with CDK4/6i, n (%)					< 0.001
Fulvestrant	79 (29%)	33 (22%)	36 (35%)	10 (59%)
Letrozole	190 (71%)	116 (78%)	67 (65%)	7 (41%)
Line of endocrine therapy in combination with CDK4/6i, n (%)					< 0.001
1	92 (34%)	44 (30%)	43 (45%)	5 (31%)
2	136 (51%)	98 (66%)	33 (35%)	5 (31%)
3	31 (12%)	6 (4.1%)	19 (20%)	6 (38%)
CDK4/6i dose reduction, n (%)	99 (37%)	63 (42%)	32 (31%)	4 (24%)
Time to CDK4/6i dose reduction (in days)					< 0.001
Number of observations	269	149	103	17
Mean (SD)	79 (39)	84 (29)	67 (17)	38 (15)
CDK4/6i dose discontinuation, n (%)	180 (67%)	105 (70%)	69 (67%)	6 (35%)
Time to CDK4/6i discontinuation (in days)					< 0.001
Number of observations	269	149	103	17
Mean (SD)	845 (153)	942 (93)	755 (95)	541 (134)

↓ Table 2. Dosing Schedule of CDK4/6i-Containing Regimens

Overall (n = 269)

Palbociclib (n = 149)

Ribociclib (n = 103)

Abemaciclib (n = 17)

P value^a

^aKruskal-Wallis rank sum test; Fisher’s exact test. ^bDaily dose level 1: 125 mg for palbociclib; 600 mg for ribociclib; 300 mg for abemaciclib (FDA-recommended starting daily dose). Daily dose level 2: 100 mg for palbociclib; 400 mg for ribociclib; 150 mg for abemaciclib. Daily dose level 3: 75 mg for palbociclib; 200 mg for ribociclib. CDK4/6i: cyclin-dependent kinase 4/6 inhibitor; SD: standard deviation; FDA: FDA: Food and Drug Administration.

Line of therapy, n (%)

< 0.001

182 (68%)

113 (76%)

61 (59%)

8 (47%)

66 (25%)

31 (21%)

32 (31%)

3 (18%)

21 (7.8%)

5 (3.4%)

10 (9.7%)

6 (35%)

Starting total daily dose of CDK4/6i, n (%)^b

< 0.001

75 mg

1 (0.4%)

1 (0.7%)

100 mg

28 (10%)

28 (19%)

125 mg

120 (45%)

120 (81%)

150 mg

3 (1.1%)

3 (18%)

200 mg

2 (0.7%)

2 (1.9%)

300 mg

14 (5.2%)

14 (82%)

400 mg

20 (7.4%)

20 (19%)

600 mg

81 (30%)

81 (79%)

< 0.001

Ending total daily dose of CDK4/6i, n (%)^b

75 mg

10 (3.7%)

10 (6.7%)

100 mg

73 (27%)

73 (49%)

125 mg

66 (25%)

66 (44%)

150 mg

7 (2.6%)

7 (41%)

200 mg

11 (4.1%)

11 (11%)

300 mg

10 (3.7%)

10 (59%)

400 mg

34 (13%)

34 (33%)

600 mg

58 (22%)

58 (56%)

Endocrine therapy given in combination with CDK4/6i, n (%)

< 0.001

Fulvestrant

79 (29%)

33 (22%)

36 (35%)

10 (59%)

Letrozole

190 (71%)

116 (78%)

67 (65%)

7 (41%)

Line of endocrine therapy in combination with CDK4/6i, n (%)

< 0.001

92 (34%)

44 (30%)

43 (45%)

5 (31%)

136 (51%)

98 (66%)

33 (35%)

5 (31%)

31 (12%)

6 (4.1%)

19 (20%)

6 (38%)

CDK4/6i dose reduction, n (%)

99 (37%)

63 (42%)

32 (31%)

4 (24%)

Time to CDK4/6i dose reduction (in days)

< 0.001

Number of observations

269

149

103

Mean (SD)

79 (39)

84 (29)

67 (17)

38 (15)

CDK4/6i dose discontinuation, n (%)

180 (67%)

105 (70%)

69 (67%)

6 (35%)

Time to CDK4/6i discontinuation (in days)

< 0.001

Number of observations

269

149

103

Mean (SD)

845 (153)

942 (93)

755 (95)

541 (134)

↓ **Table 3.** Toxicity Occurring in the Cohort of HR+/HER2– a/mBC Patients Receiving CDK4/6i-Containing Regimens
	Overall (n = 269)	Palbociclib (n = 149)	Ribociclib (n = 103)	Abemaciclib (n = 17)	P value^a
Follow-up time stopped at the time of CDK discontinuation or end of the study period, whichever came first. ^aFisher’s exact test. AE: adverse event; a/mBC: advanced/metastatic breast cancer; CDK4/6i: cyclin-dependent kinase 4 and 6 inhibitors; HER2–: human epidermal growth factor receptor 2–negative; HR+: hormone receptor–positive; AST: aspartate aminotransferase; ALT: alanine aminotransferase.
Experienced ≥ 1 protocol-defined AEs, n (%)
ALT/AST increase grade 1	15 (5.6%)	0	13 (13%)	2 (12%)	6.81 × 10^–6
ALT/AST increase grade 3	21 (7.8%)	0	21 (20%)	0	2.03 × 10^–9
Diarrhea grade 1	52 (19%)	38 (26%)	14 (14%)	0	0.005
Diarrhea grade 2	19 (7.1%)	11 (7.4%)	0	8 (47%)	2.52 × 10^–8
Diarrhea grade 3	4 (1.5%)	0	0	4 (24%)	1.12 × 10^–5
Neutropenia grade 1	35 (13%)	13 (8.7%)	19 (18%)	3 (18%)	0.048
Neutropenia grade 2	8 (3.0%)	0	8 (7.8%)	0	0.001
Neutropenia grade 3	47 (17%)	44 (30%)	3 (2.9%)	0	6.01 × 10^–9
Neutropenia grade 4	19 (7.1%)	19 (13%)	0	0	7.35 × 10^–5
Prolonged QT interval	5 (1.9%)	0	5 (4.9%)	0	0.025
Thrombocytopenia	13 (4.8%)	13 (8.7%)	0	0	0.002
Pneumonia grade 1	8 (3.0%)	0	8 (7.8%)	0	0.001
Pneumonia grade 2	14 (5.2%)	11 (7.4%)	3 (2.9%)	0	0.24
Erythematous rash	9 (3.3%)	0	9 (8.7%)	0	4.32 × 10^–4
Shortness of breath	3 (1.1%)	3 (2.0%)	0	0	0.4
Dose reduction due to AE, n (%)	99 (37%)	63 (42%)	32 (28%)	4 (24%)	1.89 × 10^–4
ALT/AST increase grade 3	21 (7.8%)	0	21 (20%)	0	2.03 × 10^–9
Neutropenia grade 3	47 (17%)	44 (30%)	3 (2.9%)	0	6.01 × 10^–9
Neutropenia grade 4	19 (7.1%)	19 (13%)	0	0	7.35 × 10^–5
Prolonged QT interval	5 (1.9%)	0	5 (4.9%)	0	0.025
Pneumonia grade 2	3 (1.2%)	1 (0.6%)	2 (1.9%)	0	0.24
Diarrhea grade 3	4 (1.6%)	0	0	4 (24%)	1.6 × 10^–5
CDK4/6i discontinuation due to AE, n (%)
Neutropenia grade 4	3 (1.1%)	3 (2.0%)	0	0	0.4

↓ Table 3. Toxicity Occurring in the Cohort of HR+/HER2– a/mBC Patients Receiving CDK4/6i-Containing Regimens

Overall (n = 269)

Palbociclib (n = 149)

Ribociclib (n = 103)

Abemaciclib (n = 17)

P value^a

Follow-up time stopped at the time of CDK discontinuation or end of the study period, whichever came first. ^aFisher’s exact test. AE: adverse event; a/mBC: advanced/metastatic breast cancer; CDK4/6i: cyclin-dependent kinase 4 and 6 inhibitors; HER2–: human epidermal growth factor receptor 2–negative; HR+: hormone receptor–positive; AST: aspartate aminotransferase; ALT: alanine aminotransferase.

Experienced ≥ 1 protocol-defined AEs, n (%)

ALT/AST increase grade 1

15 (5.6%)

13 (13%)

2 (12%)

6.81 × 10^–6

ALT/AST increase grade 3

21 (7.8%)

21 (20%)

2.03 × 10^–9

Diarrhea grade 1

52 (19%)

38 (26%)

14 (14%)

0.005

Diarrhea grade 2

19 (7.1%)

11 (7.4%)

8 (47%)

2.52 × 10^–8

Diarrhea grade 3

4 (1.5%)

4 (24%)

1.12 × 10^–5

Neutropenia grade 1

35 (13%)

13 (8.7%)

19 (18%)

3 (18%)

0.048

Neutropenia grade 2

8 (3.0%)

8 (7.8%)

0.001

Neutropenia grade 3

47 (17%)

44 (30%)

3 (2.9%)

6.01 × 10^–9

Neutropenia grade 4

19 (7.1%)

19 (13%)

7.35 × 10^–5

Prolonged QT interval

5 (1.9%)

5 (4.9%)

0.025

Thrombocytopenia

13 (4.8%)

13 (8.7%)

0.002

Pneumonia grade 1

8 (3.0%)

8 (7.8%)

0.001

Pneumonia grade 2

14 (5.2%)

11 (7.4%)

3 (2.9%)

0.24

Erythematous rash

9 (3.3%)

9 (8.7%)

4.32 × 10^–4

Shortness of breath

3 (1.1%)

3 (2.0%)

0.4

Dose reduction due to AE, n (%)

99 (37%)

63 (42%)

32 (28%)

4 (24%)

1.89 × 10^–4

ALT/AST increase grade 3

21 (7.8%)

21 (20%)

2.03 × 10^–9

Neutropenia grade 3

47 (17%)

44 (30%)

3 (2.9%)

6.01 × 10^–9

Neutropenia grade 4

19 (7.1%)

19 (13%)

7.35 × 10^–5

Prolonged QT interval

5 (1.9%)

5 (4.9%)

0.025

Pneumonia grade 2

3 (1.2%)

1 (0.6%)

2 (1.9%)

0.24

Diarrhea grade 3

4 (1.6%)

4 (24%)

1.6 × 10^–5

CDK4/6i discontinuation due to AE, n (%)

Neutropenia grade 4

3 (1.1%)

3 (2.0%)

0.4

↓ **Table 4.** Univariate and Multivariate Cox-Proportional Hazards Model for Median PFS of Patients Receiving CDK4/6i
Univariate analysis	Multivariate analysis
HR: hazard ratio; BC: breast cancer; CDK4/6i: cyclin-dependent kinase 4 and 6 inhibitors; CI: confidence interval; ECOG: Eastern Cooperative Oncology Group; PFS: progression-free survival; ref: reference.
Age at diagnosis (ref: < 65 years)	≥ 65 years	29.37 vs 25.4	1.52	1.04–2.21	0.03	1.49	1.15–2.54	0.022
Menopausal status (ref: postmenopause)	Premenopause	28.43 vs 26.37	1.01	0.65–1.57	0.96	-	-	-
Breast cancer histology at initial diagnosis (ref: ductal carcinoma)	Lobular carcinoma	29.37 vs 27.4	0.94	0.72–1.23	0.67	-	-	-
Breast cancer grade at initial diagnosis (ref: grade 1)	Grade 2	31.43 vs 28.33	1.45	1.02–2.23	0.04	1.06	0.7–1.9	0.8
	Grade 3	31.43 vs 26.45	1.74	1.11–2.75	0.016	1.52	1.15–2.28	0.032
Breast cancer stage at initial diagnosis (ref: stage I)	Stage II	31.4 vs 29.5	0.79	0.6–1.04	0.1	-	-	-
	Stage III	31.4 vs 27.2	1.25	0.86–1.97	0.42	-	-	-
	De novo metastatic stage IV	31.4 vs 26.4	1.51	1.1–1.95	7.38 × 10^–5	1.87	1.18–2.9	0.04
Number of metastatic sites at time of CDK4/6i treatment (ref: n = 1)	N = 2	31.42 vs 27.37	2	1.57–2.77	4.51 × 10^–3	1.4	0.6–4.07	0.52
	N = 3	31.42 vs 26.33	1.53	1.09–2.14	0.014	1.9	1.23–4.03	0.059
	N = 4	31.42 vs 23.30	5.86	2.14–8.6	1.41 × 10^–6	2.35	1.37–5.61	0.045
Bone metastasis (ref: no)	Yes	30.4 vs 26.37	1.16	0.9–1.49	0.26	-	-	-
Lung metastasis (ref: no)	Yes	29.38 vs 27.33	1.17	0.89–1.55	0.25	-	-	-
Lymph node metastasis (ref: no)	Yes	30.37 vs 25.33	1.82	1.31–2.51	3.17 × 10^–4	1.76	1.14–4.03	0.033
Brain metastasis (ref: no)	Yes	31.8 vs 23.10	2.3	1.21–3.6	0.02	2.1	0.9–2.19	0.175
Liver metastasis (ref: no)	Yes	30.47 vs 26.37	1.43	1.12–1.83	4.09 × 10^–3	1.32	0.8–2.94	0.2
ECOG performance at time of CDK4/6i treatment (ref: ECOG 1)	ECOG 2	31.4 vs 29.9	1.35	1.09–1.97	0.04	1.18	0.71–2.46	0.73
	ECOG 3	31.4 vs 27.4	1.47	1.06–1.98	0.011	1.25	1.06–1.97	3.09 × 10^–3
CDK4/6i (ref: abemaciclib)	Palbociclib	20.27 vs 31.43	1.5	1.11–2.8	4.96 × 10^–8	0.8	0.43–0.9	2.7 × 10^–4
	Ribociclib	20.27 vs 25.37	1.9	1.5–2.9	7.59 × 10^–5	0.92	0.62–1.67	0.48
Line of CDK4/6i treatment (ref: first line)	Second line	31.5 vs 26.3	1.84	1.37–2.47	5.29 × 10^–5	1.17	1.08–3.46	2.39 × 10^–3
	Third line	31.5 vs 21.27	5.7	4.13–6.86	1.34 × 10^–4	5.38	2.04–7.08	8.06 × 10^–3
Partner drug–endocrine therapy (ref: letrozole)	Fulvestrant	31.4 vs 28.37	1.2	0.9–1.45	0.29	-	-	-

↓ Table 4. Univariate and Multivariate Cox-Proportional Hazards Model for Median PFS of Patients Receiving CDK4/6i

Univariate analysis

Multivariate analysis

Reference

No reference

Median PFS (months)

95% CI

P value

95% CI

P value

HR: hazard ratio; BC: breast cancer; CDK4/6i: cyclin-dependent kinase 4 and 6 inhibitors; CI: confidence interval; ECOG: Eastern Cooperative Oncology Group; PFS: progression-free survival; ref: reference.

Age at diagnosis (ref: < 65 years)

≥ 65 years

29.37 vs 25.4

1.52

1.04–2.21

0.03

1.49

1.15–2.54

0.022

Menopausal status (ref: postmenopause)

Premenopause

28.43 vs 26.37

1.01

0.65–1.57

0.96

Breast cancer histology at initial diagnosis (ref: ductal carcinoma)

Lobular carcinoma

29.37 vs 27.4

0.94

0.72–1.23

0.67

Breast cancer grade at initial diagnosis (ref: grade 1)

Grade 2

31.43 vs 28.33

1.45

1.02–2.23

0.04

1.06

0.7–1.9

0.8

Grade 3

31.43 vs 26.45

1.74

1.11–2.75

0.016

1.52

1.15–2.28

0.032

Breast cancer stage at initial diagnosis (ref: stage I)

Stage II

31.4 vs 29.5

0.79

0.6–1.04

0.1

Stage III

31.4 vs 27.2

1.25

0.86–1.97

0.42

De novo metastatic stage IV

31.4 vs 26.4

1.51

1.1–1.95

7.38 × 10^–5

1.87

1.18–2.9

0.04

Number of metastatic sites at time of CDK4/6i treatment (ref: n = 1)

N = 2

31.42 vs 27.37

1.57–2.77

4.51 × 10^–3

1.4

0.6–4.07

0.52

N = 3

31.42 vs 26.33

1.53

1.09–2.14

0.014

1.9

1.23–4.03

0.059

N = 4

31.42 vs 23.30

5.86

2.14–8.6

1.41 × 10^–6

2.35

1.37–5.61

0.045

Bone metastasis (ref: no)

Yes

30.4 vs 26.37

1.16

0.9–1.49

0.26

Lung metastasis (ref: no)

Yes

29.38 vs 27.33

1.17

0.89–1.55

0.25

Lymph node metastasis (ref: no)

Yes

30.37 vs 25.33

1.82

1.31–2.51

3.17 × 10^–4

1.76

1.14–4.03

0.033

Brain metastasis (ref: no)

Yes

31.8 vs 23.10

2.3

1.21–3.6

0.02

2.1

0.9–2.19

0.175

Liver metastasis (ref: no)

Yes

30.47 vs 26.37

1.43

1.12–1.83

4.09 × 10^–3

1.32

0.8–2.94

0.2

ECOG performance at time of CDK4/6i treatment (ref: ECOG 1)

ECOG 2

31.4 vs 29.9

1.35

1.09–1.97

0.04

1.18

0.71–2.46

0.73

ECOG 3

31.4 vs 27.4

1.47

1.06–1.98

0.011

1.25

1.06–1.97

3.09 × 10^–3

CDK4/6i (ref: abemaciclib)

Palbociclib

20.27 vs 31.43

1.5

1.11–2.8

4.96 × 10^–8

0.8

0.43–0.9

2.7 × 10^–4

Ribociclib

20.27 vs 25.37

1.9

1.5–2.9

7.59 × 10^–5

0.92

0.62–1.67

0.48

Line of CDK4/6i treatment (ref: first line)

Second line

31.5 vs 26.3

1.84

1.37–2.47

5.29 × 10^–5

1.17

1.08–3.46

2.39 × 10^–3

Third line

31.5 vs 21.27

5.7

4.13–6.86

1.34 × 10^–4

5.38

2.04–7.08

8.06 × 10^–3

Partner drug–endocrine therapy (ref: letrozole)

Fulvestrant

31.4 vs 28.37

1.2

0.9–1.45

0.29

↓ **Table 5.** Univariate and Multivariate Cox-Proportional Hazards Model for mOS of Patients Receiving CDK4/6i
Univariate analysis	Multivariate Analysis
HR: hazard ratio; BC: breast cancer; CDK4/6i: cyclin-dependent kinase 4 and 6 inhibitors; CI: confidence interval; ECOG: Eastern Cooperative Oncology Group; mOS: median overall survival; ref: reference.
Age at diagnosis (ref: < 65 years)	≥ 65 years	55.23 vs 51.7	1.23	1.03–1.59	0.042	1.58	1.26–2.69	0.034
Menopausal status (ref: postmenopause)	Premenopause	56.8 vs 53.67	0.94	0.44–1.59	0.68	-	-	-
Breast cancer histology at initial diagnosis (ref: ductal carcinoma)	Lobular carcinoma	55.8 vs 53.7	0.78	0.52–1.16	0.22	-	-	-
Breast cancer grade at initial diagnosis (ref: grade 1)	Grade 2	60.32 vs 55.8	1.16	0.59–2.26	0.66	-	-	-
	Grade 3	60.32 vs 51.2	1.73	1.18–3.39	0.02	1.17	1.03–2.79	0.037
Breast cancer stage at initial diagnosis (ref: stage I)	Stage II	58.83 vs 44.43	0.89	0.39–3.06	0.23
	Stage III	58.83 vs 40.08	1.7	0.63–4.78	0.36
	De novo metastatic stage IV	58.83 vs 33.4	1.99	1.34–4.81	2.6 × 10^–4	1.96	1.02–3.4	0.03
Number of metastatic sites at time of CDK4/6i treatment (ref: n = 1)	N = 2	56.73 vs 53.77	1.36	1.11–1.97	0.03	1.28	0.6–1.8	0.73
	N = 3	56.73 vs 50.6	2.42	1.57–3.35	0.6 × 10^–3	2.15	1.13–4.03	0.02
	N = 4	56.73 vs 46.67	4.29	1.4–6.45	4.29 × 10^–5	2.56	1.73–6.81	0.039
Bone metastasis (ref: no)	Yes	55.46 vs 50.28	1.48	0.78–3.85	0.12	-	-	-
Lung metastasis (ref: no)	Yes	58.8 vs 51.72	1.3	0.91–3.6	0.29	-	-	-
Lymph node metastasis (ref: no)	Yes	60.77 vs 50.73	2.29	1.18–2.63	0.003	1.53	1.28–3.06	0.017
Brain metastasis (ref: no)	Yes	57.4 vs 48.67	2.78	1.51–3.22	0.001	2.1	1.34–2.19	0.04
Liver metastasis (ref: no)	Yes	56.8 vs 53.73	2.12	1.69–2.59	1.6 × 10^–3	1.32	0.8–2.94	0.36
ECOG performance at time of CDK4/6i treatment (ref: ECOG 1)	ECOG 2	62.87 vs 54.77	1.3	1.05 – 2.57	0.008	2.07	0.63–4.82	0.39
	ECOG 3	62.87 vs 50.68	1.2	1.08–1.83	0.042	1.39	1.06–1.99	3.1 × 10^–3
CDK4/6i (ref: abemaciclib)	Palbociclib	43.63 vs 59.77	0.57	0.28–0.95	0.01	0.37	0.2–0.8	2.35 × 10^–5
	Ribociclib	43.63 vs 53.73	0.5	0.24–0.94	0.04	0.75	0.46–2.93	0.61
Line of CDK4/6i treatment (ref: first line)	Second line	57.8 vs 47.43	1.21	1.04–2.59	0.0033	2.79	1.98–7.36	0.81 × 10^–3
	Third line	57.8 vs 42.67	3.31	2.66–10.62	2.62 × 10^–4	4.21	2.01–9.08	1.04 × 10^–4
Partner drug–endocrine therapy (ref: letrozole)	Fulvestrant	58.33 vs 52.6	1.11	0.5–1.25	0.37	-	-	-

↓ Table 5. Univariate and Multivariate Cox-Proportional Hazards Model for mOS of Patients Receiving CDK4/6i

Univariate analysis

Multivariate Analysis

Reference

No reference

Median OS (months)

95% CI

P value

95% CI

P value

HR: hazard ratio; BC: breast cancer; CDK4/6i: cyclin-dependent kinase 4 and 6 inhibitors; CI: confidence interval; ECOG: Eastern Cooperative Oncology Group; mOS: median overall survival; ref: reference.

Age at diagnosis (ref: < 65 years)

≥ 65 years

55.23 vs 51.7

1.23

1.03–1.59

0.042

1.58

1.26–2.69

0.034

Menopausal status (ref: postmenopause)

Premenopause

56.8 vs 53.67

0.94

0.44–1.59

0.68

Breast cancer histology at initial diagnosis (ref: ductal carcinoma)

Lobular carcinoma

55.8 vs 53.7

0.78

0.52–1.16

0.22

Breast cancer grade at initial diagnosis (ref: grade 1)

Grade 2

60.32 vs 55.8

1.16

0.59–2.26

0.66

Grade 3

60.32 vs 51.2

1.73

1.18–3.39

0.02

1.17

1.03–2.79

0.037

Breast cancer stage at initial diagnosis (ref: stage I)

Stage II

58.83 vs 44.43

0.89

0.39–3.06

0.23

Stage III

58.83 vs 40.08

1.7

0.63–4.78

0.36

De novo metastatic stage IV

58.83 vs 33.4

1.99

1.34–4.81

2.6 × 10^–4

1.96

1.02–3.4

0.03

Number of metastatic sites at time of CDK4/6i treatment (ref: n = 1)

N = 2

56.73 vs 53.77

1.36

1.11–1.97

0.03

1.28

0.6–1.8

0.73

N = 3

56.73 vs 50.6

2.42

1.57–3.35

0.6 × 10^–3

2.15

1.13–4.03

0.02

N = 4

56.73 vs 46.67

4.29

1.4–6.45

4.29 × 10^–5

2.56

1.73–6.81

0.039

Bone metastasis (ref: no)

Yes

55.46 vs 50.28

1.48

0.78–3.85

0.12

Lung metastasis (ref: no)

Yes

58.8 vs 51.72

1.3

0.91–3.6

0.29

Lymph node metastasis (ref: no)

Yes

60.77 vs 50.73

2.29

1.18–2.63

0.003

1.53

1.28–3.06

0.017

Brain metastasis (ref: no)

Yes

57.4 vs 48.67

2.78

1.51–3.22

0.001

2.1

1.34–2.19

0.04

Liver metastasis (ref: no)

Yes

56.8 vs 53.73

2.12

1.69–2.59

1.6 × 10^–3

1.32

0.8–2.94

0.36

ECOG performance at time of CDK4/6i treatment (ref: ECOG 1)

ECOG 2

62.87 vs 54.77

1.3

1.05 – 2.57

0.008

2.07

0.63–4.82

0.39

ECOG 3

62.87 vs 50.68

1.2

1.08–1.83

0.042

1.39

1.06–1.99

3.1 × 10^–3

CDK4/6i (ref: abemaciclib)

Palbociclib

43.63 vs 59.77

0.57

0.28–0.95

0.01

0.37

0.2–0.8

2.35 × 10^–5

Ribociclib

43.63 vs 53.73

0.5

0.24–0.94

0.04

0.75

0.46–2.93

0.61

Line of CDK4/6i treatment (ref: first line)

Second line

57.8 vs 47.43

1.21

1.04–2.59

0.0033

2.79

1.98–7.36

0.81 × 10^–3

Third line

57.8 vs 42.67

3.31

2.66–10.62

2.62 × 10^–4

4.21

2.01–9.08

1.04 × 10^–4

Partner drug–endocrine therapy (ref: letrozole)

Fulvestrant

58.33 vs 52.6

1.11

0.5–1.25

0.37