A 48-year-old woman is evaluated for a painless left breast mass. Physical examination shows a 4-cm mass with dimpling of the overlying skin; left axillary lymphadenopathy also is noted. Breast imaging reveals a spiculated soft tissue mass with microcalcifications. Biopsy of the mass demonstrates invasive ductal carcinoma. Immunohistochemistry of the tissue sample shows the tumor cells are negative for estrogen and progesterone receptors but overexpress the HER2 epidermal growth factor receptor. The patient is treated with systemic chemotherapy and a monoclonal antibody drug that binds the extracellular domain of the growth factor receptor. Repeat evaluation 6 weeks later shows a decrease in the size of the breast mass. Which of the following host factors are primarily responsible for mediating the response to the monoclonal antibody therapy?

Question

A 48-year-old woman is evaluated for a painless left breast mass.  Physical examination shows a 4-cm mass with dimpling of the overlying skin; left axillary lymphadenopathy also is noted.  Breast imaging reveals a spiculated soft tissue mass with microcalcifications.  Biopsy of the mass demonstrates invasive ductal carcinoma.  Immunohistochemistry of the tissue sample shows the tumor cells are negative for estrogen and progesterone receptors but overexpress the HER2 epidermal growth factor receptor.  The patient is treated with systemic chemotherapy and a monoclonal antibody drug that binds the extracellular domain of the growth factor receptor.  Repeat evaluation 6 weeks later shows a decrease in the size of the breast mass.  Which of the following host factors are primarily responsible for mediating the response to the monoclonal antibody therapy?

Quizplus · Accepted Answer

11ec160b_37ce_2263_9249_034fbb7f9e90_MD0001_00 HER2 is an epidermal growth factor receptor overexpressed by aggressive breast cancers. Treatment with a monoclonal antibody (eg, trastuzumab) that targets the HER2 surface receptor often results in tumor regression. Although antibody binding can trigger cancer cell death through a variety of mechanisms (eg, receptor downregulation, complement deposition), much of the response is due to antibody-dependent cellular cytotoxicity (ADCC). ADCC classically involves the following: A naturally occurring or monoclonal IgG binds to a complementary surface antigen on a host or foreign cell. A patrolling natural killer (NK) cell binds the Fc portion of the attached IgG using CD16. Binding triggers the NK cell to release its granules, which contain perforin and granzymes (proteases) that induce apoptosis/osmotic lysis of the antibody-bound cell. Although NK cells are derived from the same lymphocyte lineage as B- and T-cells, they are considered part of the innate immune system because they do not engage with major histocompatibility complexes (MHCs) to differentiate self from nonself. Unlike cytotoxic T-cells, NK cells can often identify neoplasms that have downregulated surface expression of MHC-I molecules. (Choice A) Tumor-infiltrating B cells release inflammatory cytokines, display tumor-associated antigens, and generate tumor-specific immunoglobulin; however, neither B cells nor IgM are involved in mediating responses to exogenously administered monoclonal antibodies. (Choice B) CD8 cells release effector cytokines (eg, interferon gamma, tumor necrosis factor) and cytotoxic granules (eg, perforin, granzymes) that destroy tumor cells. However, they interact with the MHC class I receptors, not monoclonal immunoglobulins. (Choice D) Macrophages and neutrophils also have CD16 and engage in ADCC and CD16-mediated phagocytosis of foreign organisms. However, their role in antitumor activity is unclear. The efficacy of monoclonal antibody therapy is thought to be largely mediated by NK-cell ADCC. Educational objective: Cancer immunotherapy often includes the administration of monoclonal antibodies against a target overexpressed on the cancer cell surface. The Fc portion of the bound antibody is identified by natural killer cells via CD16, leading to antibody-dependent cellular cytotoxicity via the release of granzymes and perforin. __________ References: Trastuzumab: updated mechanisms of action and resistance in breast cancer. (http://www.ncbi.nlm.nih.gov/pubmed/22720269) Natural killer cell mediated antibody-dependent cellular cytotoxicity in tumor immunotherapy with therapeutic antibodies. (http://www.ncbi.nlm.nih.gov/pubmed/23543707)

A 48-Year-Old Woman Is Evaluated for a Painless Left Breast