In 1957, cyclic adenosine monophosphate (cAMP) was identified as the first secondary messenger, and the first signaling cascade discovered was the cAMP-protein kinase A (PKA) pathway. Since then, cAMP has received increasing attention given its multitude of actions. Not long ago, a new cAMP effector named exchange protein directly activated by cAMP (Epac) emerged as a critical mediator of cAMP's actions. Epac mediates a plethora of pathophysiologic processes and contributes to the pathogenesis of several diseases such as cancer, cardiovascular disease, diabetes, lung fibrosis, neurological disorders, and others. These findings strongly underscore the potential of Epac as a tractable therapeutic target. In this context, Epac modulators seem to possess unique characteristics and advantages and hold the promise of providing more efficacious treatments for a wide array of diseases. This paper provides an in-depth dissection and analysis of Epac structure, distribution, subcellular compartmentalization, and signaling mechanisms. We elaborate on how these characteristics can be utilized to design specific, efficient, and safe Epac agonists and antagonists that can be incorporated into future pharmacotherapeutics. In addition, we provide a detailed portfolio for specific Epac modulators highlighting their discovery, advantages, potential concerns, and utilization in the context of clinical disease entities.

Background: Despite evidence discouraging contralateral prophylactic mastectomy (CPM) in average-risk patients, its use is increasing globally. While well-studied in Western settings, little is known about the factors influencing CPM decisions in the Middle East and North Africa (MENA) region. This study explores clinical, psychosocial, and communication-related factors associated with CPM choices among women with early-stage breast cancer. Methods: We conducted a retrospective study of 253 early-stage breast cancer patients who underwent mastectomy, with or without CPM, at the American University of Beirut Medical Center. Clinical and demographic data were extracted from medical records, and decision-making factors were assessed through tailored patient questionnaires. Associations were analyzed using chi-square tests and multivariable logistic regression. Results: Of the 253 women included in the study, 37 underwent CPM, while 216 had unilateral mastectomy (UM). Compared to the UM group, women who chose CPM were more likely to have a college education (96.9% vs. 57.6%, p < 0.001), be employed (69.7% vs. 41.3%, p = 0.002), and report a family history of breast cancer (55.6% vs. 30.2%, p = 0.003). Immediate reconstruction was significantly more common among CPM patients (67.6% vs. 16.4%, p < 0.001), and the 30-day rehospitalization rate was also higher (16.2% vs. 6.1%, p = 0.031). Women in the CPM group were more likely to prioritize extending life (84.6% vs. 56.7%, p = 0.007) and achieving peace of mind (80.8% vs. 49.3%, p = 0.003). Although all CPM patients cited risk reduction as a primary motivator, only 46.2% believed they had a lower recurrence risk than their peers (vs. 20% of UM patients, p < 0.001). Decisions to undergo UM were more frequently influenced by physicians’ recommendations (95.3% vs. 53.8%, p < 0.001), whereas CPM decisions appeared to be more patient-driven. Additionally, CPM patients reported more negative expectations and higher dissatisfaction with pain (57.7% vs. 32.0%, p = 0.012) and reconstructive outcomes (54.5% vs. 27.5%, p = 0.035). Conclusions: In this first study from the MENA region exploring CPM decision-making, choices were largely driven by personal preferences rather than clinical risk. These findings highlight the need for improved risk communication, shared decision-making, and broader integration of genetic counseling in surgical planning.