Citations

Abstract Women with one or more first-degree female relatives with a history of breast cancer have a two-fold increased risk of developing breast cancer. This risk increases with the number of affected family members, particularly for those diagnosed at a young age or with bilateral disease. Segregation analyses of breast cancer families led to the identification of inactivating mutations in the BRCA1 and BRCA2 breast cancer susceptibility genes. Pathogenic variants resulting in truncation of these proteins, along with a small number of pathogenic missense variants, have been associated with 55% to 65% lifetime risk of breast cancer in the general population and up to 85% lifetime risks among women with a strong family history of the disease. In contrast, the influence on cancer risk of many rare variants of uncertain significance (VUS) is not known. Mutations in several genes in addition to BRCA1 and BRCA2 have been implicated in predisposition to breast cancer through family segregation studies. These include moderate risk mutations (relative risk between 2.0 and 5.0) in CHEK2 and ATM, high-risk mutations (relative risk greater than 5.0) in PALB2, and high-risk mutations in CDH1, PTEN, STK11, and TP53 that are associated with hereditary diffuse gastric cancer, Cowden, Peutz-Jeghers, and Li-Fraumeni syndromes. However, risks of breast and other cancers associated with mutations in these and other genes that have been suggested to predispose to cancer have not been established or have very broad confidence intervals. Despite the absence of accurate risk estimates clinical testing with gene panels for hereditary cancer gene mutations has become an integral component of medical management for high-risk families and individuals with triple negative breast cancer. To estimate breast cancer risks several large studies of breast cancer patients from the general population and from high-risk families are underway. These studies are expected to identify the subset of panel genes that are associated with increased risk of breast cancer or breast cancer subtypes and to establish more accurate risks of breast and other cancers. In addition, classification of the clinical relevance of VUS in BRCA1, BRCA2, and other predisposition genes remains a significant problem, with patients unable to benefit from enhanced risk assessment, prevention, and clinical management. Thousands of VUS in BRCA1 and BRCA2 have already been identified through clinical testing and many more in BRCA1, BRCA2, and other predisposition genes are being identified through panel-based genetic testing and tumor sequencing studies. Efforts to classify VUS as neutral or pathogenic have focused on large case-control studies and quantitative multifactorial models based on family history of cancer and pathology. However, more recent studies have established the utility of validated functional assays for VUS assessment. Hundreds of BRCA1 and BRCA2 VUS have been reclassified by commercial testing laboratories or by the ENIGMA consortium that serves as the expert review panel for variants in these genes for the ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/) and BRCA Exchange (http://brcaexchange.org) publically accessible websites. Common genetic variants associated with breast cancer risk have also been identified through genome-wide association studies (GWAS). The magnitude of these associations have ranged from 1.03 to 1.29 in women of European ancestry. While the majority of the 179 known breast cancer variants are associated with estrogen receptor (ER) positive breast cancer, 21 of these show specific associations with ER negative or triple negative (ER negative, PR negative, HER2 negative) breast cancer. The variants in risk loci account for approximately 19% of the familial relative risk of breast cancer. Several studies have recently established that polygenic risk scores derived from these risk variants improve personalized risk assessment by identifying women at increased or reduced risk of breast cancer in the general population and by modifying risks of breast cancer among BRCA1 and BRCA2 mutation carriers. In summary, germline genetic studies have substantially changed the landscape of breast cancer, identifying mutations associated with moderate and high risks of breast cancer in up to 5% of population-based breast cancer cases and 35% of high-risk families and providing personalization of underlying breast cancer risk for all women. Citation Format: Couch FJ. OI-1 Decoding breast cancer predisposition genes [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr OI-1.

Abstract While it remains unclear whether the immune system naturally evolved to prevent cancer, it is clear that many of its constituent cells and factors can greatly influence the clinical course of the disease in many different cancers, including breast cancer. Generally speaking, the immune system is a double edged sword and produces a broad array of both pro-tumor and anti-tumor factors. Of those which demonstrate anti-tumor activity, antigen-specific T cells (including both cytotoxic and helper T cells) are the most important as several studies have now shown that increased T cell infiltration is generally, and markedly, protective. More recent evidence also suggests that B cells can also be protective, particularly when producing tumor-specific antibodies or associated with intratumoral tertiary lymphoid structures. Thus, newer therapeutics being developed in academia and industry are being designed to directly augment adaptive immunity. The methods to manipulate the numbers of lymphocytes is growing and includes direct clonal expansion approaches such as vaccination and adoptive T cell therapy as well as more indirect methods that modulate cell intrinsic regulatory mechanisms (e.g. checkpoint and co-stimulatory pathways). In contrast, the pro-tumor activity of the immune system is largely mediated by the myeloid compartment of the immune system. While normal myeloid cells are not generally pro-tumorigenic, most tumors impair proper myeloid differentiation inducing intratumoral and systemic accumulation of defective myeloid cells which have profound tumor-promoting activity. This tumor-promoting activity of myeloid cells is mediated either through direct tumor growth-promoting activity (e.g. growth and angiogenic factors) or through blockade of adaptive immune response. Mechanisms by myeloid cells promote tumor growth appear to be diversified and are now only recently becoming understood, but nonetheless represent unique targets for therapeutic manipulation either alone in combination with other therapeutic modalities (e.g. checkpoint blockade). The basic underpinnings of tumor immunology are being rapidly identified and applied clinically to treat a variety of cancers and more recently breast cancer. This educational lecture will be a general overview of tumor immunology focusing on recent basic and therapeutic advances, highlighting those relevant to the field of breast cancer. Citation Format: Knutson KL. Basic science of immunotherapy [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr ES4-1.

Key Points Depletion of CD123-redirected CAR T cells with monoclonal antibodies preserves leukemia remission in human AML xenograft models. AML CAR T-cell depletion enhances feasibility of subsequent allogeneic stem cell transplantation.

Pulmonary nocardiosis is a severe and uncommon opportunistic infection caused by Nocardia species. We present a patient with cryptogenic organizing pneumonia who was receiving long-term immunosuppressive therapy, whose treatment course was complicated by cutaneous and pulmonary nocardiosis. Tissue cultures confirmed Nocardia brasiliensis. Nocardiosis should be a diagnostic consideration for patients treated with long-term immunosuppression who have worsening pulmonary symptoms and relapsing pustular skin lesions.

AbstractPurposeLocal control for Ewing sarcoma (ES) has improved in modern studies. However, it is unclear if these gains have also been achieved for pelvis tumors. The purpose of this study is to evaluate local control and survival in pelvis ES patients treated in the modern era.MethodsAll pelvis ES patients diagnosed from 1990 to 2012 and seen at Mayo Clinic were identified. Factors relevant to survival and local control were analyzed.ResultsThe cohort consisted of 48 patients. Fifty‐two percent had metastatic disease at diagnosis. The 5‐year overall survival and event‐free survival was 73% and 65%, respectively, for localized disease. The 5‐year cumulative incidence of local recurrence was 19%, with a 26% incidence for radiation, 13% for surgery, and 0% for surgery + radiation (P = 0.54). All local failures occurred in‐field. Sacral involvement by tumor trended toward a higher incidence of local recurrence (hazard ratio 3.06, P = 0.09). Patients treated with definitive radiation doses ≥5,600 cGy had a lower incidence of local recurrence (17% vs. 28%, P = 0.61).ConclusionsOur study demonstrates excellent survival for localized tumors in the modern era. Anatomical localization within the pelvis likely correlates with outcomes. Local control remains problematic, especially for patients treated with definitive radiation. Though statistically not significant, surgery + radiation and definitive radiation dose ≥5,600 cGy were associated with the lowest incidence of local failure, suggesting treatment intensification may improve local control for pelvis ES.