Combination of cyclin-dependent kinase 4/6 inhibitors and renin-angiotensin system inhibitors in breast cancer treatment: a promising therapeutic approach

Mutlu, Emel; İnanç, Mevlüde

doi:10.1590/1806-9282.20251164

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Original Article • Rev. Assoc. Med. Bras. 71 (12) • 2025 • https://doi.org/10.1590/1806-9282.20251164 linkcopy

Combination of cyclin-dependent kinase 4/6 inhibitors and renin-angiotensin system inhibitors in breast cancer treatment: a promising therapeutic approach

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OBJECTIVE: The prognosis of metastatic breast cancer has improved with new targeted therapies like cyclin-dependent kinase 4/6 inhibitors. Renin-angiotensin system inhibitors, such as direct renin inhibitors, angiotensin II receptor blockers and angiotensin-converting enzyme inhibitors are frequently used to manage hypertension and heart failure. However, recent research indicates that they may also provide potential benefits in cancer therapy. The combination of renin-angiotensin system inhibitors with cyclin-dependent kinase 4/6 inhibitors is an emerging area of interest in cancer research. Our hypotesis that, by inhibiting angiogenesis, renin-angiotensin system inhibitors may reduce tumor growth and improve the effectiveness of cyclin-dependent kinase 4/6 inhibitors by cutting off the supply of nutrients and oxygen to the tumor.

METHODS: Metastatic breast cancer patients treated with cyclin-dependent kinase 4/6 inhibitors were enrolled and retrospectively divided according to angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker use: angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (+) and angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (-). Progression-free survival and overall survival were defined as primary and secondary endpoints. The effect of categorized data on progression-free survival and overall survival was determined by Cox regression analyses.

RESULTS: Estimated median progression-free survival (HR 0.61, 95%CI 0.34–0.94; p = 0.041) and overall survival (HR 0.71, 95%CI 0.49-0.79; p: 0.01) were statistically significantly longer in the angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (+) group than in the angiotensin-converting enzyme inhibitor/angiotensin II receptor blocker (-) group.

CONCLUSION: Concomitant use of renin-angiotensin system inhibitors and cyclin-dependent kinase 4/6 inhibitors may have beneficial oncological effects in patients with breast cancer beyond their cardiovascular indications.

KEYWORDS:
Breast cancer; Cyclin-dependent kinases; Renin-angiotensin system; Survival

Variables	Categories	Median PFS (months)	Univariate analysis HR 95%Cl	p-value	Multivariate analysis HR 95%Cl	p-value
Age	≤65*	25.5
Age	>65	30.2	2.16 (0.98–4.72)	0.532
CDK 4/6 inh.	Palbociclib*	27.4
CDK 4/6 inh.	Ribociclib	25.2	1.52 (0.92–2.53)	0.100
Endocrine therapy	Fulvestrant*	19.5
Endocrine therapy	Aromatase inhibitors	29.8	0.34 (0.21–0.55)	<0.001	0.42 (0.27–0.63)	<0.001
CDK 4/6 Inh. treatment line	1-2*	28.0
CDK 4/6 Inh. treatment line	≥3	20.7	2.25 (1.35–3.74)	0.002	1.42 (0.91–3.35)	0.082
Tiazide diuretics	No*	25.9
Tiazide diuretics	Yes	28.1	0.58 (0.26–1.28)	0.182
CCB	No*	25.8
CCB	Yes	28.5	0.56 (0.25–1.22)	0.143
ACE-I/ARB	No*	21.9
ACE-I/ARB	Yes	29.9	0.42 (0.25–0.69)	0.001	0.61 (0.34–0.94)	0.041
Group	ACE-I/ARB(-)#CCB(-)*	22.1
	ACE-I/ARB(-)#CCB(+)	20	0.62 (0.14–2.59)	0.514
	ACE-I/ARB(+)#CCB(+)	28.6	0.34 (0.10–1.12)	0.078
	ACE-I/ARB(+)#CCB(-)	29.1	0.49 (0.29–0.82)	0.007	0.63 (0.31–0.77)	0.026
Groups	ACE-I/ARB(-)#Tiazide(-)*	22.5
	ACE-I/ARB(+)#Tiazide(+)	28.2	0.42 (0.19–0.95)	0.039	0.21 (0.01–2.53)	0.321
	ACE-I/ARB(+)#Tiazide(-)	29.2	0.48 (0.28–0.83)	0.009	0.39 (0.08–2.63)	0.252
	ACE-I/ARB(-)#Tiazide(+)	14.6	1.7 (0.40–7.08)	0.461

Variables	Categories	Median OS (months)	Univariate analysis HR 95%Cl	p-value	Multivariate analysis HR 95%Cl	p-value
Age	≤65*	64.1
Age	>65	48.2	0.89 (0.31–2.58)	0.840
CDK 4/6 type	Ribociclib*	79.2
CDK 4/6 type	Palbociclib	72.6	1.13 (0.38–1.80)	0.639
Endocrine therapy	Fulvestrant*	70.9
Endocrine therapy	Aromatase inhibitors	76.9	0.59 (0.29–1.21)	0.155
CDK 4/6 Inh. treatment line	1-2*	79.5
CDK 4/6 Inh. treatment line	≥3	70.1	1.18 (0.54–2.61)	0.141
Tiazide diuretics	No*	76.7
Tiazide diuretics	Yes	77.1	0.55 (0.13–2.33)	0.422
CCB	No*	68.3
CCB	Yes	78.1	0.65 (0.29–2.49)	0.127
ACE-I/ARB	No*	66.5
ACE-I/ARB	Yes	72.2	0.41 (0.20–0.86)	0.019	0.71 (0.49–0.79)	0.01
Group	ACE-I/ARB(-)#CCB(-)*	53.1
	ACE-I/ARB(-)#CCB(+)	45.0	1.41 (0.26–4.83)	0.879
	ACE-I/ARB(+)#CCB(+)	40	1.32 (0.36–3.50)	0.457
	ACE-I/ARB(+)#CCB(-)	79.3	0.42 (0.19–0.90)	0.027	0.79 (0.42–0.82)	0.02
Groups	ACE-I/ARB(-)#Tiazide(-)*	67.1
	ACE-I/ARB(+)#Tiazide(+)	77.2	0.38 (0.09–1.67)	0.200
	ACE-I/ARB(+)#Tiazide(-)	78.4	0.44 (0.20–0.97)	0.044	0.83 (0.38–0.76)	0.04
	ACE-I/ARB(-)#Tiazide(+)	18.6	4.43 (0.56–14.9)	0.158

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[TFN1] Statistically significant values are denoted in bold. CCB: calcium channel blocker; CDK 4/6: cyclin-dependent kinase 4/6; ACE-I: angiotensin-converting enzyme inhibitors; ARB: angiotensin II receptor blockers; PFS: progression free survival; HR: hazard ratio; CI: confidence interval.

[TFN2] ^*
Reference category.