Approximately 70% of invasive breast cancers have some degree of dependence on the estrogen hormone for cell proliferation and growth. These tumors have estrogen and/or progresterone receptors (ER/PR+), or generally referred to as hormone receptor positive (HR+) tumors, as indicated by the presence of positive staining and varying intensity levels of estrogen and/or progesterone receptors on immunohistochemistry. Therapies that inhibit ER signaling pathways, such as aromatase inhibitors (letrozole, anastrazole, exemestane), selective ER modulators (tamoxifen), and ER down-regulators (fulvestrant), are the mainstays of treatment for hormone receptor positive breast cancers. However, de novo or acquired resistance to ER targeted therapies is present in many tumors leading to disease progression. The PI3K/AKT/mTOR pathway is implicated in sustaining endocrine resistance and has become the target of many new drugs for ER + breast cancer. This article will review the function of the phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway and the various classes of PI3K pathway inhibitors that have been developed to disrupt this pathway signaling for the treatment of hormone receptor positive breast cancer. Function of the PI3K/AKT/mTOR pathway and role in tumorigenesisThe PI3K/AKT/mTOR pathway (Figure 1) controls many important cellular functions including metabolism, growth, survival, and proliferation. This pathway transmits a wide variety of extracellular stimuli through a signaling cascade via phosphatidylinositol 3kinases (PI3Ks). 1 PI3Ks are lipid kinases which are divided into three different classes. Class I PI3Ks are heterodimers consisting of a p85 regulatory subunit and a p110 catalytic subunit (p110α, p110β, p110γ or p110δ). This class of PI3Ks is the most studied and is

Alterations in the phosphoinositide 3-kinase (PI3K)/AKT pathway are frequently found in cancer and are especially common in breast cancer, where it is estimated that 70% of tumors have some type of genetic alteration that could lead to pathway hyperactivation. A variety of PI3K pathway inhibitors have been developed in an attempt to target this pathway and improve cancer control. One of the challenges in treating patients with PI3K/AKT pathway inhibitors is the associated toxicity from on-target and off-target effects. Such side-effects are common, but reversible, and include hyperglycemia, rash, stomatitis, diarrhea, nausea, and fatigue. As a result, dose reductions, treatment delays, and treatment discontinuation are frequently reported. This impairs not only patients’ quality of life but also treatment efficacy. Most side-effects are reversible with drug interruption, since these drugs typically have a short half-life and are manageable with early intervention. An interdisciplinary approach with proactive management of patients receiving PI3K pathway inhibitors should include comprehensive education of patients about the range of toxicities, frequent monitoring, early toxicity recognition, active intervention, as well as prophylactic strategies.

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BACKGROUND Hodgkin lymphoma (HL) survivors have significant cardiovascular risk and require long-term surveillance. This study assessed the prevalence of coronary artery disease (CAD) by coronary computed tomographic angiography (CCTA) in adult survivors of childhood HL. METHODS Thirty-one HL survivors, 13 (42%) treated with radiation therapy (RT) only and 18 (58%) with multimodal therapy, underwent CCTA, echocardiography, electrocardiography (ECG), and treadmill stress testing. Obstructive CAD was defined as ≥50% occlusion of the left main (LM) or ≥70% occlusion of the left anterior descending (LAD), left circumflex (LCx), or right coronary (RCA) arteries on CCTA. Echocardiograms with resting wall motion abnormalities or ejection fraction <50%; ECGs with Q waves, ST abnormalities without Q waves, or T-wave abnormalities without Q waves; and ≥1-mm J-point depression with horizontal or down-sloping ST segment on stress testing were considered abnormal. RESULTS Prevalence of disease in participants (median age, 40 years; range, 26–55; median time from cancer diagnosis, 24 years; range, 17–39) was 39%, with 39 plaques detected in 12 survivors. Three participants (10%) treated with RT only had 4 obstructive lesions; 9 (29%; 5 treated with RT only; 4 with multimodal therapy) had nonobstructive lesions. Approximately 15% of lesions involved the LM; 21%, proximal LAD; 18%, proximal RCA; and 13%, proximal LCx arteries. Of the 12 participants with CAD by CCTA, 7 had positive ECG; 1, positive echocardiography; and 1, a positive stress test. CONCLUSIONS CCTA identified CAD in a substantial portion of HL survivors and may be an effective screening modality for this population.

Triple-negative breast cancer (TNBC) is pathologically defined by lack of expression of the estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2 amplification and portends an aggressive clinical course with worse outcomes compared with other breast cancers. Until recently, standard treatment options consisted of sequential cytotoxic chemotherapies for both early and metastatic disease. Advances in sequencing technology have led to the identification of 4 main subtypes of TNBC based on recurrent genetic alterations, transcriptional patterns, and molecular features: basal-like 1 (BL1), basal-like 2 (BL2), mesenchymal (M), and luminal androgen receptor (LAR). Frequent alterations found in DNA damage response pathways, germline and somatic BRCA1/2 genes, PI3K signaling pathways, and the presence of androgen receptors and infiltrating immune cells could serve as actionable targets to optimize treatments and improve outcomes for patients with TNBC. Recent approvals for immune checkpoint inhibitors and the antibody-drug conjugate, sacituzumab govitecan-hziy, for advanced TNBC illustrate the advances in treatment that can result from these molecular discoveries. This review will explore the molecular subtypes of TNBC and their distinct characteristics, as well as highlight the molecular features and potential “drivers” that have been identified as promising targets for new treatment strategies.