A B S T R A C T PurposeTo examine the association between beta-blocker (BB) intake, pathologic complete response (pCR) rates, and survival outcomes in patients with breast cancer treated with neoadjuvant chemotherapy. Patients and MethodsWe retrospectively reviewed 1,413 patients with breast cancer who received neoadjuvant chemotherapy between 1995 and 2007. Patients taking BBs at the start of neoadjuvant therapy were compared with patients with no BB intake. Rates of pCR between the groups were compared using a 2 test. Cox proportional hazards models were fitted to determine the association between BB intake, relapse-free survival (RFS), and overall survival (OS). ResultsPatients who used BBs (n ϭ 102) were compared with patients (n ϭ 1,311) who did not. Patients receiving BBs tended to be older and obese (P Ͻ .001). The proportion of pCR was not significantly different between the groups (P ϭ .48). After adjustment for age, race, stage, grade, receptor status, lymphovascular invasion, body mass index, diabetes, hypertension, and angiotensin-converting enzyme inhibitor use, BB intake was associated with a significantly better RFS (hazard ratio [HR], 0.52; 95% CI, 0.31 to 0.88) but not OS (P ϭ .09). Among patients with triple-negative breast cancer (TNBC; n ϭ 377), BB intake was associated with improved RFS (HR, 0.30; 95% CI, 0.10 to 0.87; P ϭ .027) but not OS (HR, 0.35; 95% CI, 0.12 to 1.00; P ϭ .05). ConclusionIn this study, BB intake was associated with improved RFS in all patients with breast cancer and in patients with TNBC. Additional studies evaluating the potential benefits of beta-adrenergic blockade on breast cancer recurrence with a focus on TNBC are warranted.

The electrophysiological and pharmacological properties of nicotinic acetylcholine receptors (nAChRs) were studied in guinea pig small intestinal myenteric neurons maintained in culture or in acutely isolated preparations. Acetylcholine and nicotine caused inward currents that desensitized in ϳ4 s. The current-voltage (I-V) relationship rectified inwardly with a reversal potential near 0 mV. The agonist rank order potency was 1,1-dimethyl-4-phenylpiperazinium Ͼ acetylcholine ϭ nicotine Ͼ Ͼ cytisine. Agonistinduced currents were blocked by nAChR antagonists with a rank order potency of mecamylamine Ͼ hexamethonium Ͼ dihydro-␤-erythroidine (DH␤E); mecamylamine and DH␤E exhibit high potency at ␤4 and ␤2 subunit-containing nAChRs, respectively. ␣-Bungarotoxin (0.1 M) or ␣-methyllycaconitine (0.1 M), antagonists that block nAChRs containing ␣7 subunits, did not affect acetylcholine-induced responses. Immunohistochemical studies revealed that nearly every neuron in culture was labeled by an antibody (mAb35) that recognizes nAChR ␣3 and ␣5 subunits. Antibodies selective for ␣3, ␣5, or ␤2 subunits also stained most neurons, whereas an ␣7 subunit antibody revealed very few neurons. In neurons in the intact myenteric plexus from newborn and adult guinea pigs, local application of acetylcholine (1 mM) and cytisine (1 mM) caused similar amplitude depolarizations, and these responses were blocked by nAChR antagonists with a rank order potency of mecamylamine Ͼ hexamethonium Ͼ DH␤E. These data indicate that myenteric neurons maintained in culture predominately express nAChRs composed of ␣3, ␣5, ␤2, and ␤4 subunits. These subunits may be in a homogenous population of receptors with unique pharmacological properties, or multiple receptors of different subunit composition may be expressed by individual neurons.In the nervous system, nAChRs are ligand-gated cation channels composed of pentameric combinations of 11 subunits (␣2-␣9; ␤2-␤4) (Sargent, 1993;Lukas et al., 1999). The specific subunit composition yields receptors with pharmacological and electrophysiological properties that are unique to that subunit combination (Luetje and Patrick, 1991;Gerzanich et al., 1998). For example, antagonists can discriminate among nAChRs with different subunit compositions. ␣-Methyllycaconitine and ␣-bungarotoxin (␣-BGT) are potent and selective antagonists of ␣7 subunit-containing nAChRs (Couturier et al., 1990;Ward et al., 1990). Receptors composed of the ␣4␤2 or ␣3␤2 subunit combinations are more sensitive to block by dihydro-␤-erythroidine (DH␤E) than receptors composed of other subunit pairs. Alternatively, mecamylamine has high affinity for nAChRs composed of ␣3␤4 subunits (Albuquerque et al., 1997).There are two main classes of neuron in the enteric nervous system: S neurons and AH neurons. S neurons are enteric interneurons or motor neurons (Kunze and Furness, 1999). S neurons receive fast excitatory synaptic input mediated partly by acetylcholine acting at nAChRs (Galligan and Bertrand, 1994). Studies of the pharmacological p...

BACKGROUND: ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may have anti-tumor properties. We investigated whether the use of ACEI/ARBs affects the clinical outcomes of primary breast cancer patients receiving taxane and anthracycline-based neoadjuvant chemotherapy.METHODS: We included 1449 patients with diagnosis of invasive primary breast cancer diagnosed at the MD Anderson Cancer Center between 1995 and 2007 who underwent neoadjuvant chemotherapy. Of them, 160 (11%) patients were identified by review of their medical record, as ACEI/ARBs users. We compared pathologic complete response (pCR) rates, relapse-free survival (RFS), disease-specific survival (DSS) and overall survival (OS) between ACEI/ARB users and non-users. Descriptive statistics and Cox proportional hazards model were used in the analyses.RESULTS: There was no difference in the pCR rates between ACEI/ARB users and non-users (16% vs 18.1%, p-=0.50). After adjustment for important demographic and clinical characteristics, no significant differences between ACEI/ARB users and nonusers were observed in RFS (HR=0.81; 95% CI=0.54-1.21), DSS (HR=0.83; 95% CI=0.52-1.31), or OS (HR=0.91; 95% CI =0.61-1.37). In a subgroup analysis, the 5-year RFS was 82% in ARB only users versus 71% in ACEI/ARB non-users (P=0.03). In the multivariable analysis, ARB use was also associated with a decreased risk of recurrence (HR=0.35; 95% CI=0.14-0.86). No statistically significant differences in DSS or OS were seen.CONCLUSION: No differences in pCR and survival outcomes were seen between ACEI/ARB users and non-users among breast cancer patients receiving neoadjuvant chemotherapy. ARB use may be associated with improved RFS. Further research is needed to validate this finding.

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