The ABC7 regimen: a new approach to metastatic breast cancer using seven common drugs to inhibit epithelial-to-mesenchymal transition and augment capecitabine efficacy

Figures & data

Figure 1 The basic biochemical, intracellular, and receptor pathways relating to interventions of the ABC7 regimen for advanced breast cancer.

Notes: This is the basic breast cancer intracellular circuitry that the ABC7 regimen attempts to address. The two major controllers or stimuli for eIF4E activation are indicated by yellow arrows, the p-mTOR and the MNK paths.

Table 1 The drugs of ABC7, their targets during treatment of breast cancer, and suggested doses

Drug	Target in breast cancer treatment	Starting dose	Target dose
Capecitabine	DNA synthesis	600 mg/m^2 twice daily. 7 days on, 7 days off	1250 mg/m^2 twice daily. 7 days on, 7 days off or 14 days on, 7 off
Quetiapine	RANK/RANKL	50 mg once at bedtime	300–600 mg once at bedtime
Pirfenidone	TGF-beta	200 mg three times daily	600 mg three times daily
Rifabutin	BCL-6; beta-catenin	150 mg/day	300 mg/day
Metformin	AMPK*; mTOR; mitochondria oxphos	500 mg once daily	1000 mg twice daily
Propranolol	Beta-adrenergic receptors	10 mg twice daily	Uptitrate as tolerated
Agomelatine	Melatonergic receptors*	25 mg once at bedtime	50 mg once at bedtime
Ribavirin**	eIF4E; MNK; IMPDH	600 mg/day	1200 mg/day

Notes: The drugs are listed in a suggested order of addition. Pace of drug addition is individualized per patient and physician estimations of risk/benefit.

* Note that all entries denote inhibition of named target except for metformin that activates AMPK and agomelatine that stimulates melatonin receptors. All drugs, except capecitabine, are given continuously without interruption. Capecitabine is given on 7 days on, 7 days off, or 14 days on, 7 days off cycles.

** Ribavirin is likely to give unpleasant side effects and depressed mood but is potentially a beneficial enough drug to try.

Table 2 Representative recent trials in metastatic HR+ breast cancer

Intervention	Months survival	Trial
Anastrozole + fulvestrant	48	SWOG
Anastrozole + fulvestrant	38	FACT
Anastrozole + fulvestrant	21	SoFEA
Letrozole + fulvestrant	52	LEA
Everolimus + exemestane	31	BOLERO 2

Table 3 Characteristic protein markers and mediators of EMT in breast cancer

Marker	Epithelial state	Mesenchymal state
E-cadherin	Increased	Decreased
N-cadherin	Decreased	Increased
ZO-1	Increased	Decreased
Occludin	Increased	Decreased
Vimentin	Decreased	Increased
Fibronectin	Decreased	Increased
MMP-2	Decreased	Increased
MMP-9	Decreased	Increased
Phenotype	Epithelial state	Mesenchymal state
Motility	Sessile	Motile
Shape	Elongated	Rounded
Adherence	Adherent to neighbors	Non-adherent to neighbors
Invasion	Noninvasive	Invasive
Proliferation	Higher proliferation	Lower proliferation
Microtentacles	Absent	Present

Abbreviation: EMT, epithelial-to-mesenchymal transition.