Palbociclib: an evidence-based review of its potential in the treatment of breast cancer

Figures & data

Video abstract

Figure 1 The cell cycle and regulatory process.

Notes: Cell division and the cell cycle are tightly controlled by a number of positive and negative regulators. Mitogenic signals upregulate and activate cyclin D, resulting in the complexing of cyclin D with CDK4 or -6. These complexes facilitate the addition of phosphate groups (P) to RB leading ultimately to the release of bound E2F transcription factors and allowing the cell to divide. The CDKs and their cyclin partners are positive regulators of the cell cycle, while RB, other tumor suppressors (p16^INK4, p15^INK4b, p18^INK4c, and p19^INK4d), and the CDK-interacting protein/kinase inhibitory protein (Cip/Kip) family negatively regulate.
Abbreviations: AR, androgen receptor; CDK, cyclin-dependent kinase; ER, estrogen receptor; NF-κB, nuclear factor κB; PR, progesterone receptor; RB, retinoblastoma; R, restriction point; P, phosphate.

Table 1 RB pathway alterations by breast cancer subtype

Subtype	Luminal A	Luminal B	Basal-like	HER2 enriched
ER+/HER− (%)	87	82	10	20
HER2+ (%)	7	15	2	68
TNBC (%)	2	1	80	9
RB pathway	Cyclin D1 amplification (29%)	Cyclin D1 amplification (58%)	RB mutation/loss (20%)	Cyclin D1 amplification (38%)
	CDK4 gain (14%)	CDK4 gain (25%)	Cyclin E amplification (9%)	CDK4 gain (24%)
	Low expression CDKN2C		High expression CDKN2C
	High expression RB1		Low expression RB1

Note: Adapted by permission from Macmillan Publishers Ltd: Nature. Cancer Genome Atlas Network. Comprehensive molecular portraits of human breast tumours. Nature. 2012;490(7418):61–70, copyright © (2012).²¹

Abbreviations: ER, estrogen receptor; TNBC, triple-negative breast cancer; RB, retinoblastoma.

Figure 2 Palbociclib, or PD-0332991, a CDK4/6 inhibitor from Pfizer, Inc. (New York, NY, USA).

Figure 3 Inhibitory concentration and cell type.

Notes: Bar graph of IC₅₀ values (nM) and cell type. Cell lines are color coded by subtype: light blue, luminal; dark blue bars or stripes, HER2 amplified; yellow, non-luminal/undergone an epithelial-to-mesenchymal transition; red, non-luminal; and turquoise, immortalized. Reproduced from Finn RS, Dering J, Conklin D, et al. PD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitro. Breast Cancer Res. 2009;11(5):R77.³³
Abbreviation: IC₅₀, half maximal inhibitory concentration.

Table 2 Clinical studies of Palbociclib in breast cancer

	Study
	DeMichele et al^Citation42		Slamon et al^Citation43	Finn et al^Citation46
Meeting	ASCO 2013 Annual Meeting (updated presentation)		ASCO 2010 Annual Meeting	AACR Annual Meeting 2014*
Phase	II		Ib	II
N	37		12	165
Primary endpoint	Safety and efficacy (response rate and PFS)		Safety and tolerability	PFS
Therapy	Palbociclib		Palbociclib + letrozole	Palbociclib + letrozole	Versus letrozole
Breast cancer subtype	ER+ HER2−	29/37
	ER+ HER2+ TNBC	2/37 6/37	ER+ HER2−	ER+ HER2−
					Palbociclib + letrozole***	Letrozole***
Prior chemotherapy for advanced disease	34/37 (92%)		8 (67%)	34 (40%)	37 (46%)
Response rate	2/36 (1%) PR 18/36 (50%) SD**		3/12 (25%) PR 9/12 (75%) SD	NR	NR
PFS	ER+ TNBC	3.8 months 1.9 months	NR	20.2 months	10.2 months

Notes:

* This study was also presented at IMPAKT 2012⁴⁴ and SABCS 2012,⁴⁵ as discussed in the text. For simplicity, data presented in the table represent the updated presentation at AACR 2014;⁴⁶

** one patient (1/6) with TNBC had stable disease, (5/6) had progression of disease;

*** demographic data obtained from SABCS 2012⁴⁵ presentation; however, the updated report at AACR represents the same patient population. Palbociclib (Pfizer, Inc., New York, NY, USA).

Abbreviations: AACR, American Association for Cancer Research; ASCO, American Society of Clinical Oncology; ER, estrogen receptor; NR, not reported in abstract; PFS, progression-free survival; PR, partial response; SABCS, San Antonio Breast Cancer Symposium; SD, stable disease; TNBC, triple-negative breast cancer.

Cancer Genome Atlas NetworkComprehensive molecular portraits of human breast tumoursNature20124907418617023000897

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FinnRSDeringJConklinDPD 0332991, a selective cyclin D kinase 4/6 inhibitor, preferentially inhibits proliferation of luminal estrogen receptor-positive human breast cancer cell lines in vitroBreast Cancer Res2009115R7719874578

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FinnRSCrownJPLangIFinal results of a randomized Phase II study of PD 0332991, a cyclin-dependent kinase (CDK)-4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2− advanced breast cancer (PALOMA-1; TRIO-18)Paper presented at: AACR Annual Meeting 2014April 6, 2014San Diego, CA

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FinnRSCrownJPLangIResults of a randomized Phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2− advanced breast cancer (BC)Paper presented at: IMPAKT Breast Cancer Conference 2012May 5; 2012Belgium

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FinnRSCrownJPLangIResults of a randomized phase 2 study of PD 0332991, a cyclin-dependent kinase (CDK) 4/6 inhibitor, in combination with letrozole vs letrozole alone for first-line treatment of ER+/HER2− advanced breast cancer (BC)Paper presented at: Thirty-Fifth Annual CTRC-AACR San Antonio Breast Cancer SymposiumDecember 4–8, 2012San Antonio, TX

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