A Phase I/II Study of GSK525762 Combined with Fulvestrant in Patients with Hormone Receptor-positive/HER2-negative Advanced or Metastatic Breast Cancer.

PURPOSE: Endocrine-based therapy is the initial primary treatment option for hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) metastatic breast cancer (mBC). However, patients eventually experience disease progression due to resistance to endocrine therapy. Molibresib (GSK525762) is a small-molecule inhibitor of bromodomain and extraterminal (BET) family proteins (BRD2, BRD3, BRD4, and BRDT). Preclinical data suggested that the combination of molibresib with endocrine therapy might overcome endocrine resistance. This study aimed to investigate the safety, tolerability, pharmacokinetics, pharmacodynamics, and efficacy [objective response rate (ORR)] of molibresib combined with fulvestrant in women with HR+/HER2- mBC. PATIENTS AND METHODS: In this phase I/II dose-escalation and dose-expansion study, patients received oral molibresib 60 or 80 mg once daily in combination with intramuscular fulvestrant. Patients enrolled had relapsed/refractory, advanced/metastatic HR+/HER2- breast cancer with disease progression on prior treatment with an aromatase inhibitor, with or without a cyclin-dependent kinase 4/6 inhibitor. RESULTS: The study included 123 patients. The most common treatment-related adverse events (AE) were nausea (52%), dysgeusia (49%), and fatigue (45%). At a 60-mg dosage of molibresib, >90% of patients experienced treatment-related AE. Grade 3 or 4 treatment-related AE were observed in 47% and 48% of patients treated with molibresib 60 mg and molibresib 80 mg, respectively. The ORR was 13% [95% confidence interval (CI), 8-20], not meeting the 25% threshold for proceeding to phase II. Among 82 patients with detected circulating tumor DNA and clinical outcome at study enrollment, a strong association was observed between the detection of copy-number amplification and poor progression-free survival (HR, 2.89; 95% CI, 1.73-4.83; P < 0.0001). CONCLUSIONS: Molibresib in combination with fulvestrant did not demonstrate clinically meaningful activity in this study.

Acute aerobic exercise-conditioned serum reduces colon cancer cell proliferation in vitro through interleukin-6-induced regulation of DNA damage.

Epidemiological evidence shows that regular physical activity is associated with reduced risk of primary and recurrent colon cancer. However, the underlying mechanisms of action are poorly understood. We evaluated the effects of stimulating a human colon cancer cell line (LoVo) with human serum collected before and after an acute exercise bout vs nonexercise control serum on cancer cell proliferation. We also measured exercise-induced changes in serum cytokines and intracellular protein expression to explore potential biological mechanisms. Blood samples were collected from 16 men with lifestyle risk factors for colon cancer (age ≥50 years; body mass index ≥25 kg/m2 ; physically inactive) before and immediately after an acute bout of moderate-intensity aerobic interval exercise (6 × 5 minutes intervals at 60% heart rate reserve) and a nonexercise control condition. Stimulating LoVo cells with serum obtained immediately after exercise reduced cancer cell proliferation compared to control (-5.7%; P = .002). This was accompanied by a decrease in LoVo cell γ-H2AX expression (-24.6%; P = .029), indicating a reduction in DNA damage. Acute exercise also increased serum IL-6 (24.6%, P = .002). Furthermore, stimulating LoVo cells with recombinant IL-6 reduced γ-H2AX expression (ß = -22.7%; P < .001) and cell proliferation (ß = -5.3%; P < .001) in a linear dose-dependent manner, mimicking the effect of exercise. These findings suggest that the systemic responses to acute aerobic exercise inhibit colon cancer cell proliferation in vitro, and this may be driven by IL-6-induced regulation of DNA damage and repair. This mechanism of action may partly underlie epidemiological associations linking regular physical activity with reduced colon cancer risk.

Effectiveness of diet and physical activity interventions amongst adults attending colorectal and breast cancer screening: a systematic review and meta-analysis.

PURPOSE: To estimate the effectiveness of tailored physical activity and dietary interventions amongst adults attending colorectal and breast cancer screening. METHODS: Five literature databases were systematically searched to identify randomised controlled trials (RCTs) of tailored physical activity and/or dietary interventions with follow-up support initiated through colorectal and breast cancer screening programmes. Outcomes included markers of body fatness, physical activity, and dietary intake. Mean differences (MDs) or standardised mean differences (SMDs) with 95% confidence intervals (CIs) were pooled using random effects models. RESULTS: Five RCTs met the inclusion criteria encompassing a total of 722 participants. Diet and physical activity interventions led to statistically significant reductions in body mass (MD - 1.6 kg, 95% CI - 2.7 to - 0.39 kg; I2 = 81%; low quality evidence), body mass index (MD - 0.78 kg/m2, 95% CI - 1.1 to - 0.50 kg/m2; I2 = 21%; moderate quality evidence), and waist circumference (MD - 2.9 cm, 95% CI - 3.8 to - 1.91; I2 = 0%; moderate quality evidence), accompanied by an increase in physical activity (SMD 0.31, 95% CI 0.13 to 0.50; I2 = 0%; low quality evidence) and fruit and vegetable intake (SMD 0.33, 95% CI 0.01 to 0.64; I2 = 51%; low quality evidence). CONCLUSION: There is low quality evidence that lifestyle interventions involving follow-up support lead to modest weight loss and increased physical activity and fruit and vegetable intake. Due to the modest intervention effects, low quality of evidence and small number of studies, further rigorously designed RCTs with long-term follow-up of modifiable risk factors and embedded cost-benefit analyses are warranted (PROSPERO ref: CRD42020179960).