CYP2D6 phenotype, tamoxifen, and risk of contralateral breast cancer in the WECARE Study.

BACKGROUND: Tamoxifen treatment greatly reduces a woman's risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. The impact of variation on risk of contralateral breast cancer (CBC) is unknown. METHODS: Germline DNA from 1514 CBC cases and 2203 unilateral breast cancer controls was genotyped for seven single nucleotide polymorphisms, one three-nucleotide insertion-deletion, and a full gene deletion. Each variant has an expected impact on enzyme activity, which in combination allows for the classification of women as extensive, intermediate, and poor metabolizers (EM, IM, and PM respectively). Each woman was assigned one of six possible diplotypes and a corresponding CYP2D6 activity score (AS): EM/EM (AS = 2), EM/IM (AS = 1.5), EM/PM (AS = 1), IM/IM (AS = 0.75), IM/PM (AS = 0.5), and PM/PM (AS = 0). We also collapsed categories of the AS to generate an overall phenotype (EM, AS ≥ 1; IM, AS = 0.5-0.75; PM, AS = 0). Rate ratios (RRs) and 95% confidence intervals (CIs) for the association between tamoxifen treatment and risk of CBC in our study population were estimated using conditional logistic regression, stratified by AS. RESULTS: Among women with AS ≥ 1 (i.e., EM), tamoxifen treatment was associated with a 20-55% reduced RR of CBC (AS = 2, RR = - 0.81, 95% CI 0.62-1.06; AS = 1.5, RR = 0.45, 95% CI 0.30-0.68; and AS = 1, RR = 0.55, 95% CI 0.40-0.74). Among women with no EM alleles and at least one PM allele (i.e., IM and PM), tamoxifen did not appear to impact the RR of CBC in this population (AS = 0.5, RR = 1.08, 95% CI 0.59-1.96; and AS = 0, RR = 1.17, 95% CI 0.58-2.35) (p for homogeneity = - 0.02). CONCLUSION: This study suggests that the CYP2D6 phenotype may contribute to some of the observed variability in the impact of tamoxifen treatment for a first breast cancer on risk of developing CBC

Underlying Causes and Therapeutic Targeting of the Inflammatory Tumor Microenvironment

Historically, the link between chronic inflammation and cancer has long been speculated. Only more recently, pre-clinical and epidemiologic data as well as clinical evidence all point to the role of the tumor microenvironment as inextricably connected to the neoplastic process. The tumor microenvironment (TME), a complex mix of vasculature, inflammatory cells, and stromal cells is the essential “soil” helping to modulate tumor potential. Increasingly, evidence suggests that chronic inflammation modifies the tumor microenvironment, via a host of mechanisms, including the production of cytokines, pro-inflammatory mediators, angiogenesis, and tissue remodeling. Inflammation can be triggered by a variety of different pressures, such as carcinogen exposure, immune dysfunction, dietary habits, and obesity, as well as genetic alterations leading to oncogene activation or loss of tumor suppressors. In this review, we examine the concept of the tumor microenvironment as related to both extrinsic and intrinsic stimuli that promote chronic inflammation and in turn tumorigenesis. Understanding the common pathways inherent in an inflammatory response and the tumor microenvironment may shed light on new therapies for both primary and metastatic disease. The concept of personalized medicine has pushed the field of oncology to drill down on the genetic changes of a cancer, in the hopes of identifying individually targeted agents. Given the complexities of the tumor microenvironment, it is clear that effective oncologic therapies will necessitate targeting not only the cancer cells, but their dynamic relationship to the tumor microenvironment as well

MicroRNA-335 inhibits tumor reinitiation and is silenced through genetic and epigenetic mechanisms in human breast cancer

Post-transcriptional regulators have emerged as robust effectors of metastasis and display deregulated expression through unknown mechanisms. Here, we reveal that the human microRNA-335 locus undergoes genetic deletion and epigenetic promoter hypermethylation in every metastatic derivative obtained from independent patients’ malignant cell populations. Genetic deletion of miR-335 is a common event in human breast cancer, is enriched for in breast cancer metastases, and also correlates with ovarian cancer recurrence. We furthermore identify miR-335 as a robust inhibitor of tumor reinitiation. We thus implicate the miR-335 locus on 7q32.2 as the first selective metastasis suppressor and tumor initiation suppressor locus in human breast cancer

Evaluating Clonal Hematopoiesis in Tumor-Infiltrating Leukocytes in Breast Cancer and Secondary Hematologic Malignancies

Chemotherapy and radiation therapy are the foundations of adjuvant therapy for early-stage breast cancer. As a complication of cytotoxic regimens, breast cancer patients are at risk for therapy-related myeloid neoplasms (t-MNs). These t-MNs are commonly refractory to antileukemic therapies and result in poor patient outcomes. We previously demonstrated that somatic mutations in leukemia-related genes are present in the tumor-infiltrating leukocytes (TILeuks) of a subset of early breast cancers. Here, we performed genomic analysis of microdissected breast cancer tumor cells and TILeuks from seven breast cancer patients who subsequently developed leukemia. In four patients, mutations present in the leukemia were detected in breast cancer TILeuks. This finding suggests that TILeuks in the primary breast cancer may harbor the ancestor of the future leukemogenic clone. Additional research is warranted to ascertain whether infiltrating mutant TILeuks could constitute a biomarker for the development of t-MN and to determine the functional consequences of mutant TILeuks

CYP2D6 phenotype, tamoxifen, and risk of contralateral breast cancer in the WECARE Study

Abstract Background Tamoxifen treatment greatly reduces a woman’s risk of developing a second primary breast cancer. There is, however, substantial variability in treatment response, some of which may be attributed to germline genetic variation. CYP2D6 is a key enzyme in the metabolism of tamoxifen to its active metabolites, and variants in this gene have been associated with reduced tamoxifen metabolism. The impact of variation on risk of contralateral breast cancer (CBC) is unknown. Methods Germline DNA from 1514 CBC cases and 2203 unilateral breast cancer controls was genotyped for seven single nucleotide polymorphisms, one three-nucleotide insertion-deletion, and a full gene deletion. Each variant has an expected impact on enzyme activity, which in combination allows for the classification of women as extensive, intermediate, and poor metabolizers (EM, IM, and PM respectively). Each woman was assigned one of six possible diplotypes and a corresponding CYP2D6 activity score (AS): EM/EM (AS = 2), EM/IM (AS = 1.5), EM/PM (AS = 1), IM/IM (AS = 0.75), IM/PM (AS = 0.5), and PM/PM (AS = 0). We also collapsed categories of the AS to generate an overall phenotype (EM, AS ≥ 1; IM, AS = 0.5–0.75; PM, AS = 0). Rate ratios (RRs) and 95% confidence intervals (CIs) for the association between tamoxifen treatment and risk of CBC in our study population were estimated using conditional logistic regression, stratified by AS. Results Among women with AS ≥ 1 (i.e., EM), tamoxifen treatment was associated with a 20–55% reduced RR of CBC (AS = 2, RR = – 0.81, 95% CI 0.62–1.06; AS = 1.5, RR = 0.45, 95% CI 0.30–0.68; and AS = 1, RR = 0.55, 95% CI 0.40–0.74). Among women with no EM alleles and at least one PM allele (i.e., IM and PM), tamoxifen did not appear to impact the RR of CBC in this population (AS = 0.5, RR = 1.08, 95% CI 0.59–1.96; and AS = 0, RR = 1.17, 95% CI 0.58–2.35) (p for homogeneity = – 0.02). Conclusion This study suggests that the CYP2D6 phenotype may contribute to some of the observed variability in the impact of tamoxifen treatment for a first breast cancer on risk of developing CBC