Background: Preventing breast cancer (BC) in high-risk women relies on both pharmacological and lifestyle-based interventions. Low-dose tamoxifen (LDT) has shown efficacy in reducing BC incidence while maintain a favourable safety profile. Concurrently, lifestyle strategies such as increased physical activity and caloric restriction may modulate metabolic and inflammatory pathways linked to BC risk. Sex Hormone Binding Globulin (SHBG), a key regulator of estradiol bioavailability, represents a promising biomarker for preventive strategies. A combined approach integrating pharmacologic and lifestyle interventions could optimize biomarker modulation and preventive efficacy while minimizing adverse effects.
Objectives: The study aimed to evaluate the effects of LDT and lifestyle interventions, with or without intermittent caloric restriction (ICR), on BC-related biomarkers. The primary objective was to assess changes in SHBG after six months of intervention. Secondary objectives included changes in insulin resistance, inflammatory and adipokine markers, mammographic density, body composition, gut microbiome composition, quality of life (QoL), safety, and tolerability.
Methods: This randomized, phase II biomarker trial was conducted across four Italian centres (Milan, Padua, Genoa and Naples). Participants had a median age of 52 years and 65% were postmenopausal (65%). Overall 62% were classified at increased risk for breast cancer -i.e. carrier of a pathogenic variant in a predisposition gene or according to the Tyrer-Cuzick model - while 38% had a history of surgically treated intraepithelial neoplasia. A total of 110 women were randomized to one of four arms: LDT (10 mg every other day); LDT plus ICR; lifestyle intervention based on step-counter– monitoring (LI); or lifestyle intervention plus ICR (LI-ICR). The ICR followed a "5:2 diet" model, with two days per week at 25% of total energy expenditure. Interventions lasted six months, with clinic visits and blood collection at baseline, at 3 months and study end and interim monitoring. Stools were collected at baseline and at the end of intervention. QoL, safety, and toxicity were also evaluated.
Results: LDT–based interventions significantly modulated the IGF axis, leading to an increase in IGFBP-3 (p=0.0016) and a decrease in IGF-I levels (p=0.0055). ICR primarily affected adipokines profiles, increasing adiponectin (p=0.0054) and reducing leptin (p=0.036). Combining ICR with LDT did not provide additional biomarker benefits. In contrast, the addition of ICR to LI resulted in significant improvement in TNF-α (p=0.04), IGF-I (p=0.04), Leptin (p=0.01), and IL-6 (p=0.01). Additionally, BMI showed a modest reduction across interventions, with the largest decrease observed in the LI + ICR group (median change -1.50 kg, IQR -2.10 to -0.40; p=0.013). LDT was associated with an increase in vasomotor (p<0.001), sexual (p=0.01), and physical (p=0.05) QoL scores, even if clinically negligible.
Conclusions/Implications: The TOLERANT study demonstrates that LDT effectively modulates growth-factor biomarkers, while lifestyle interventions, in particular ICR, primarily influence inflammatory and adipokine pathways. Combining pharmacologic and behavioural strategies can target distinct risk pathways, providing a tailored approach for BC prevention. Ongoing analyses of secondary endpoints will further inform the clinical relevance of these biomarkers.  Future studies should focus on optimizing combination strategies to maximize preventive efficacy while preserving quality of life.