Ayca Gucalp

Paclitaxel is one of the first-line treatments for breast, ovarian, and lung cancers. However, its use is limited by the high frequency of hypersensitivity reactions. In this retrospective chart review at Memorial Sloan Kettering Cancer Center, we assess clinical factors associated with immediate and delayed hypersensitivity reactions to paclitaxel and characterize delayed hypersensitivity reactions to paclitaxel in patients with breast cancer. 12,274 patients were treated with paclitaxel. 6,165 had breast cancer and 1,233 were seen by a dermatologist. 734 patients (11.9%) developed an immediate hypersensitivity reaction. Age (p < 0.001), race (p < 0.001), and prior history of allergy (p = 0.05) were associated with immediate hypersensitivity reactions. 147 patients (4.0%) had a rash of interest. The most common phenotypes were maculopapular (52%) and urticaria (36%). Race (p < 0.001) and history of allergy (p < 0.001) were associated with development of a cutaneous reaction. Patients with an immediate hypersensitivity reaction were more likely to have developed a delayed cutaneous reaction (OR = 1.80). Risk factors for development of immediate hypersensitivity reactions in this study were younger age, race, and history of allergy. Patients who developed an immediate hypersensitivity reaction were more likely to develop a delayed hypersensitivity reaction. Risk factors for development of the rash included Asian race and history of allergy. Identification of risk factors is critical to guide care coordination. Awareness of these clinical factors which are associated with development of a rash could guide providers in choosing treatment with paclitaxel or nab-paclitaxel. If the cutaneous reactions are bothersome to the patient, the transition of treatment from paclitaxel to nab-paclitaxel may be warranted, or a consideration of re-challenge or desensitization may be discussed.

Clinicopathologic features stratified by treatment arm (RNA-seq analysis population).

Progression-free survival by subgroup in (A) cohort 1 and (B) cohort 2 HR based on unstratified Cox regression model with <1 favoring enzalutamide arm. Abbreviations: ECOG PS, Eastern Cooperative Oncology Group Performance Status; HR, hazard ratio.

Progression-free survival by subgroup in (A) cohort 1 and (B) cohort 2 HR based on unstratified Cox regression model with <1 favoring enzalutamide arm. Abbreviations: ECOG PS, Eastern Cooperative Oncology Group Performance Status; HR, hazard ratio.

MRNA expression of (A) AR and (B) ESR1 and correlations between AR and ESR1 in (C) cohort 1 (no prior advanced ET) and (D) cohort 2 (1 prior advanced ET) *R calculated using a Pearson correlation. Abbreviation: ET, endocrine therapy

Plasma trough concentrations by week for (A) enzalutamide and (B) exemestane The labeled values denote mean (SD). The open circles denote trough concentration values of individual patients. Solid squares and vertical lines denote mean with error bars by one SD in both directions. Abbreviations: SD, standard deviation.

Progression-free survival by subgroup in (A) cohort 1 and (B) cohort 2 HR based on unstratified Cox regression model with <1 favoring enzalutamide arm. Abbreviations: ECOG PS, Eastern Cooperative Oncology Group Performance Status; HR, hazard ratio.

Purpose:To determine whether the androgen receptor (AR) inhibitor, enzalutamide, improves effectiveness of endocrine therapy (ET) in hormone receptor–positive (HR+) breast cancer.Patients and Methods:In this phase II trial, patients with HR+/HER2 normal advanced/metastatic breast cancer were randomized 1:1 to exemestane 25 mg with placebo or exemestane 50 mg with enzalutamide 160 mg daily (NCT02007512). Two parallel cohorts enrolled patients with 0 (cohort 1) or 1 (cohort 2) prior ET for advanced disease. Progression-free survival (PFS) was the primary endpoint in the intent-to-treat (ITT) population of each cohort. Biomarkers were evaluated in an exploratory analysis.Results:Overall, 247 patients were randomized (cohort 1, n = 127 and cohort 2, n = 120). PFS was not improved in either cohort of the ITT population [HR, 0.82 (95% confidence interval (CI), 0.54–1.26); P = 0.3631 for cohort 1 and HR, 1.02 (95% CI, 0.66–1.59); P = 0.9212 for cohort 2]. In cohort 1, high levels of AR mRNA were associated with greater benefit of enzalutamide (Pinteraction = 0.0048). This effect was particularly apparent in patients with both high levels of AR mRNA and low levels of ESR1 mRNA [HR, 0.24 (95% CI, 0.10–0.60); P = 0.0011]. The most common any grade adverse events in the enzalutamide arms were nausea (39%) in cohort 1 and fatigue (37%) in cohort 2.Conclusions:Enzalutamide with exemestane was well tolerated. While PFS was not improved by the addition of enzalutamide to exemestane in an unselected population, ET-naïve patients with high AR mRNA levels, particularly in combination with low ESR1 mRNA levels, may benefit from enzalutamide with exemestane.