A 62-year-old woman comes to the office due to a month of progressive right chest and back pain. The patient also noticed a right breast lump several months ago, which has grown over time. She has no prior medical issues, has not seen a physician for many years, and has had no cancer screenings. Physical examination reveals a hard, 5-cm right breast mass, enlarged axillary lymph nodes, and point tenderness along the right-sided ribs and 10th thoracic vertebra. Biopsy of the breast mass shows hormone receptor-positive, HER2-negative, invasive ductal carcinoma. Skeletal survey demonstrates lytic lesions of the ribs and thoracic vertebrae. As part of the treatment regimen, the patient receives a medication that is a potent inhibitor of cyclin-dependent kinase. Which of the following is the most likely dose-limiting toxicity of this medication?

Question

A 62-year-old woman comes to the office due to a month of progressive right chest and back pain.  The patient also noticed a right breast lump several months ago, which has grown over time.  She has no prior medical issues, has not seen a physician for many years, and has had no cancer screenings.  Physical examination reveals a hard, 5-cm right breast mass, enlarged axillary lymph nodes, and point tenderness along the right-sided ribs and 10th thoracic vertebra.  Biopsy of the breast mass shows hormone receptor-positive, HER2-negative, invasive ductal carcinoma.  Skeletal survey demonstrates lytic lesions of the ribs and thoracic vertebrae.  As part of the treatment regimen, the patient receives a medication that is a potent inhibitor of cyclin-dependent kinase.  Which of the following is the most likely dose-limiting toxicity of this medication?

Quizplus · Accepted Answer

11ec160b_3bde_04c4_9249_8d37fa683507_MD0001_00 The cellular growth cycle consists of 4 distinct phases: G₁, S, G₂, and M. Progression through the phases is controlled by surveillance systems (checkpoints) that interrupt the cell cycle and/or induce apoptosis if cells do not meet the requirements to progress forward: Cyclin-dependent kinases (CDKs) 4 and 6 control cell cycle progression from G₁→S. These CDKs are activated by cyclin D and subsequently inhibit the retinoblastoma tumor suppressor protein, leading to the upregulation of transcriptional factors that progress the cell cycle to S phase. Many cancers exploit this crucial checkpoint and achieve unregulated cellular growth via cyclin D amplification (or inactivating mutations to retinoblastoma gene). CDK 4/6 inhibitors (eg, palbociclib) can be used to block the cyclin D binding site on CDK, which results in decreased CDK 4/6 activation, increased activity of the retinoblastoma tumor suppressor protein, and cell cycle arrest. Although CDK 4/6 inhibitors are generally well tolerated, they often inhibit cellular replication in other rapidly dividing cells, particularly hematologic cells in the bone marrow. This can result in treatment-limiting hematologic side effects such as neutropenia, leukopenia, and anemia. (Choice C) Immunotherapy that targets PD-1, PD-L1, and CTLA-4 enhances the immune response against cancer and is often used in the treatment of malignant melanoma. The major side effects of these medications are autoimmune-related adverse events, including skin, liver, gastrointestinal, and endocrine inflammation. (Choices B, D, and E) CDK 4/6 inhibitors do not generally cause adverse side effects in cells that are arrested in G₀, such as myocytes, cochlear hair cells, or neurons. Cardiomyopathy is a common side effect of anthracyclines (eg, doxorubicin) and HER2 antibodies (eg, trastuzumab). Sensorineural hearing loss can be seen with platinum-based chemotherapy (eg, cisplatin). Peripheral neuropathy is a common side effect of vincristine and bortezomib. Educational objective: Cyclin-dependent kinases (CDKs) 4/6 regulate the movement of cells from G₁→S phase. Cancers often have mutations that enhance the activity or downstream effects of CDK 4/6, which contribute to unregulated cellular growth. Inhibitors to CDK 4/6 can be used to treat certain forms of cancer. However, they can inhibit cellular replication in other rapidly dividing cells such as the hematologic cells in the bone marrow (eg, neutropenia, anemia, or thrombocytopenia). __________ References: Palbociclib in hormone-receptor-positive advanced breast cancer. (http://www.ncbi.nlm.nih.gov/pubmed/26030518)

A 62-Year-Old Woman Comes to the Office Due to a Month