Cyclin-dependent kinase pathway aberrations in diverse malignancies: clinical and molecular characteristics

Figures & data

Table 1. Clinical characteristics of 347 patients with CDK4/6, CDKN2A/B aberrations (univariate analysis)

Patient characteristics (N = 347)	Aberrant CDK4/6, DKN2A/B N = 79 (%)	Normal CDK4/6, CDKN2A/B N = 268 (%)	P-value*
Gender			0.026
Women (N = 196)	36 (18.4%)	160 (81.6%)
Men (N = 151)	43 (28.5%)	108 (71.5%)
Age at diagnosis			0.13
Age ≥ 50 y (N = 212)	54 (25.5%)	158 (74.5%)
Age <50 y (N = 135)	25 (18.5%)	110 (81.5%)
Types of cancer diagnosis§
Breast (N = 74)	7 (9.5%)	67 (90.5%)	0.0021
Glioblastoma (N = 26)	21 (80.8%)	5 (19.2%)	< 0.0001
Colorectal (N = 26)	0 (0%)	26 (100%)	0.004
Lung (N = 23)	6 (26.1%)	17 (73.9%)	0.69
Melanoma (N = 23)	8 (34.8%)	15 (65.2%)	0.16
Appendix (N = 20)	1 (5.0%)	19 (95.0%)	0.27
Site of metastasis (N = 280)	Aberrant CDK4/6, DKN2A/B N = 50 (%)	Normal CDK4/6, CDKN2A/B N = 230 (%)
Lymph node metastasis			0.73
Yes (N = 145)	27 (18.6%)	118 (81.4%)
No (N = 135)	23 (17.0%)	112 (83.0%)
Liver metastasis			0.74
Yes (N = 101)	17 (16.8%)	84 (83.2%)
No (N = 179)	33 (18.4%)	146 (81.6%)
Bone metastasis			0.36
Yes (N = 82)	12 (14.6%)	70 (85.4%)
No (N = 198)	38 (19.2%)	160 (80.8%)
Lung metastasis			0.23
Yes (N = 81)	11 (13.6%)	70 (86.4%)
No (N = 199)	39 (19.6%)	160 (80.4%)
Omentum/Peritoneum metastasis			0.92
Yes (N = 49)	9 (18.4%)	40 (81.6%)
No (N = 231)	41(17.8%)	190 (82.2%)
Brain metastasis			0.16
Yes (N = 34)	9 (26.5%)	25 (73.5%)
No (N = 246)	41(16.7%)	205 (83.3%)
Soft tissue metastasis			0.21
Yes (N = 31)	3 (9.7%)	28 (90.3%)
No (N = 249)	47 (18.9%)	202 (81.1%)
Adrenal metastasis			0.51
Yes (N = 12)	3 (25.0%)	9 (75.0%)
No (N = 268)	47 (17.5%)	221 (82.5%)
Site of biopsies			0.83
Primary (N = 125)	23 (18.4%)	102 (81.6%)
Metastases (N = 155)	27 (17.4%)	128 (82.6%)

^* P-values are from Fisher's exact test.

^§ Included characteristics with N ≥ 20 of primary cancer diagnosis. See Table S1 for complete list of characteristics with N < 20.

^¶ Excluded patients with hematological malignancy (N = 21) and CNS tumors (N = 46). Reported here with site of metastasis with N ≥ 10.

Figure 1. Frequency of CDK-associated genetic aberrations in 347 patients with diverse malignancies. Of 347 patients with diverse malignancies, 23% (N = 79) had an aberration in either CDK4 (N = 13 [3.7% of 347 patients]), CDK6 (N = 8 [2.3%]), CDKN2A (N = 62 [17.9%]) and/or CDKN2B (N = 37 [10.7%]). All cases with CDKN2B aberrations (N = 37) also had aberrant CDKN2A (but the opposite was not true). One case of CDK4 amplification had a co-existing CDKN2A/B aberration. CDK6 amplification occasionally co-existed with CDKN2A/B aberration (N = 2) or a CDKN2A aberration (N = 1).

Table 2. CDK4/6 or CDKN2A/B abnormality and types of co-existing genetic aberrations (univariate analysis)

Patient characteristics (N = 347)	Aberrant CDK4/6, CDKN2A/B N = 79 (%)	Normal CDK4/6, CDKN2A/B N = 268 (%)	P-value*
Types of co-existing genetic aberrations§
TP53			0.28
Wild-type (N = 194)	40 (20.6%)	154 (79.4%)
Aberrant (N = 153)	39 (25.5%)	114 (74.5%)
KRAS			0.02
Wild-type (N = 292)	73 (25.0%)	219 (75.0%)
Aberrant (N = 55)	6 (10.9%)	49 (89.1%)
FGFR/FGF			0.11
Wild-type (N = 296)	63 (21.3%)	233 (78.7%)
Aberrant (N = 51)	16 (31.4%)	35 (68.6%)
PIK3CA			0.01
Wild-type (N = 307)	76 (24.8%)	231 (75.2%)
Aberrant (N = 40)	3 (7.5%)	37 (92.5%)
PTEN			0.96
Wild-type (N = 308)	70 (22.7%)	238 (77.3%)
Aberrant (N = 39)	9 (23.1%)	30 (76.9%)
MYC			0.24
Wild-type (N = 311)	68 (21.9%)	243 (78.1%)
Aberrant (N = 36)	11 (30.6%)	25 (69.4%)
EGFR			< 0.0001
Wild-type (N = 321)	59 (18.4%)	262 (81.6%)
Aberrant (N = 26)	20 (76.9%)	6 (23.1%)
CCND1			0.52
Wild-type (N = 322)	72 (22.4%)	250 (77.6%)
Aberrant (N = 25)	7 (28.0%)	18 (72.0%)
APC			0.03
Wild-type (N = 324)	78 (24.1%)	246 (75.9%)
Aberrant (N = 23)	1 (4.4%)	22 (95.7%)
MCL1			1.00
Wild-type (N = 325)	74 (22.8%)	251 (77.2%)
Aberrant (N = 22)	5 (22.7%)	17 (77.3%)
NF1			1.00
Wild-type (N = 325)	74 (22.8%)	251 (77.2%)
Aberrant (N = 22)	5 (22.7%)	17 (77.3%)
ARID1A			0.06
Wild-type (N = 327)	71 (21.7%)	256 (78.3%)
Aberrant (N = 20)	8 (40.0%)	12 (60.0%)
BRCA2			0.39
Wild-type (N = 327)	76 (23.2%)	251 (77.2%)
Aberrant (N = 20)	3 (15.0%)	17 (85.0%)

^* P-values are from Fisher's exact test.

^§ Included characteristics with N ≥ 20 of genetic aberration. See Table S1 for complete list of characteristics with N < 20.

Table 3. Multivariate analysis of patient characteristics (N = 347) associated with CDK4/6, CDKN2A/B aberrations

Characteristics	Odds ratio (95% CI)	P-value*
Women	0.92 (0.48–1.76)	0.80
Breast	0.39 (0.15–1.02)	0.057
Glioblastoma	11.2 (3.7–34.5)	< 0.0001
Colorectal	0.28 (0.03–2.53)	0.26
KRAS aberrant	0.59 (0.22–1.57)	0.29
PIK3CA aberrant	0.56 (0.16–1.96)	0.36
EGFR aberrant	11.9 (3.92–35.7)	< 0.0001
APC aberrant	0.19 (0.02–1.83)	0.15
ARID1A aberrant	3.98 (1.36–11.8)	0.01

Characteristics selected from Table 1 and 2 with P-value < 0.1.

^* P-values are from multivariate logistic regression analysis. P < 0.05 was considered to be statistically significant.

Table 4. Clinical outcomes of patients with CDK4/6, CDKN2A/B aberrations (univariate analysis)

Clinical outcomes	Aberrant CDK4/6, CDKN2A/B Month (range)	Normal CDK4/6, CDKN2A/B Month (range)	P-value*	Comment
Median time from diagnosis to metastasis (N = 280)	17.0 (0–256.7) N = 50	24.2 (0–415.1) N = 230	0.20	(a)
PFS for first line Therapy
Median PFS for all first line therapy (N = 189)	3.3 (0.6–39.0) N = 41	5.0 (0.5–61.0) N = 148	0.32	(b)
Subgroup analysis of median PFS for first line therapy
Platinum-containing regimen (N = 62)	3.5 (0.6–11.0) N = 15	5.0 (1.0–34.0) N = 47	0.13	(c)
5-FU or capecitabine- containing regimen (N = 50)	5.0 (0.6–11.0) N = 11	5.0 (0.8–21.0) N = 39	0.3	(d)
Bevacizumab-containing regimen (N = 33)	6.5 (2.0–39.0) N = 6	6.5 (1.0–34.0) N = 27	0.43
Taxane-containing regimen (N = 32)	3.0 (0.6–39.0) N = 7	9.1 (1.0–38.7) N = 25	0.88	(e)

^* P-values are from log-rank test.

(a) Excluded patients with hematological malignancy (N = 21) and CNS tumors (N = 46).

(b) First line therapy referred to first line after metastatic or recurrent disease (N = 189). Excluded patients with hematological malignancy (N = 21). Neoadjuvant/adjuvant therapy was not included (N = 56). Chemotherapy was not initiated on 33 patients and 48 patients were not assessable for accurate PFS for first line therapy.

(c) Platinum-containing regimen (N = 62): Cisplatin (N = 20), carboplatin (N = 21) and oxaliplatin (N = 21).

(d) 5-FU or capecitabine-containing regimen (N = 50): 5-FU (N = 30) and capecitabine (N = 20)

(e) Taxane-containing regimen (N = 32): Paclitaxel (N = 22), docetaxel (N = 5) and abraxane (N = 5).

Table 5. Univariate and multivariate Cox's regression models predicting duration of overall survival in 347 patients with malignancies

Characteristics¶ (N = 347)	Hazard Ratio	95% CI	P-value*
Gender and age
Women (N = 196)	0.65	0.38–1.04	0.08
Age ≥ 50 y (N = 212)	1.21	0.77–1.97	0.41
Types of cancer
Breast (N = 74)	0.64	0.39–1.08	0.11
Glioblastoma (N = 26)	3.01	1.73–26.7	0.006
Colorectal (N = 26)	1.73	0.71–5.93	0.19
Lung (N = 23)	1.16	0.40–3.46	0.77
Melanoma (N = 23)	0.55	0.25–1.48	0.29
Appendix (N = 20)	0.89	0.30–2.67	0.84
Types of genetic aberration
TP53 aberrant (N = 153)	2	1.27–3.31	0.004
CDK4/6, CDKN2A/B aberrant (N = 79)	2.09	1.35–4.70	0.004
KRAS aberrant (N = 55)	1.24	0.63–2.53	0.51
FGFR/FGF aberrant (N = 51)	0.67	0.39–1.26	0.24
PIK3CA aberrant (N = 40)	0.76	0.39–1.57	0.49
PTEN aberrant (N = 39)	4.02	5.02–31.9	<0.0001
MYC aberrant (N = 36)	1.45	0.71–3.33	0.27
EGFR aberrant (N = 26)	2.23	1.07–9.71	0.04
CCND1 aberrant (N = 25)	0.48	0.27–1.21	0.15
APC (N = 23)	1.75	0.65–6.69	0.22
MCL1 aberrant (N = 22)	0.49	0.25–1.35	0.21
NF1 aberrant (N = 22)	0.74	0.28–2.10	0.61
ARID1A aberrant (N = 20)	0.61	0.26–1.65	0.38
BRCA2 aberrant (N = 20)	1.09	0.38–3.12	0.87
Multivariate Cox's regression model (N = 347)
Women	0.6	0.35–1.02	0.06
Glioblastoma	1.43	0.55–3.72	0.46
TP53 aberrant	1.92	1.17–3.14	0.01
CDK4/6, CDKN2A/B aberrant	1.67	0.92–3.04	0.09
PTEN aberrant	4.83	2.63–8.87	<0.0001
EGFR aberrant	1.31	0.54–3.16	0.55

^¶ Included characteristics with N ≥ 20.

^* P-values (univariate) and hazard ratios with 95% CI are from log-rank test or multivariate Cox's regression model as appropriate. P <0.1 from univariate analysis were included for multivariate analysis.