Development of poly(ADP-ribose) polymerase inhibitors in the treatment of BRCA-mutated breast cancer.

The poly(ADP-ribose) polymerases (PARPs) 1 and 2 are DNA-binding enzymes that play a critical role in the repair of DNA. The use of PARP inhibitors is a rational therapeutic approach to selectively killing a subset of cancer cells with deficiencies in DNA repair pathways. PARP inhibitors that have undergone clinical investigation in the treatment of breast cancer include olaparib, talazoparib, veliparib, niraparib, and rucaparib. The antitumor activity of PARP inhibitors as single agents has been demonstrated in BRCA-associated metastatic breast cancer. In 2018, olaparib became the first oral PARP inhibitor to receive approval in the United States for the treatment of advanced BRCA-mutated breast cancer, an approval that represents a major change in the treatment paradigm for this subtype of breast cancer. PARP inhibition plus chemotherapy and PARP inhibition plus immunotherapy are novel approaches undergoing extensive study in breast cancer. This review focuses on the clinical development of PARP inhibitors administered singly or in combination with other agents for early-stage and metastatic BRCA-mutated breast cancer.

Frequency of Germline Mutations in Cancer Susceptibility Genes in Malignant Mesothelioma.

PURPOSE: The aim of the current study was to determine the prevalence and clinical predictors of germline cancer susceptibility mutations in patients with malignant mesothelioma (MM). METHODS: We performed targeted capture and next-generation sequencing of 85 cancer susceptibility genes on germline DNA from 198 patients with pleural, peritoneal, and tunica vaginalis MM. RESULTS: Twenty-four germline mutations were identified in 13 genes in 23 (12%) of 198 patients. BAP1 mutations were the most common (n = 6; 25%). The remaining were in genes involved in DNA damage sensing and repair (n = 14), oxygen sensing (n = 2), endosome trafficking (n = 1), and cell growth (n = 1). Pleural site (odds ratio [OR], 0.23; 95% CI, 0.10 to 0.58; P < .01), asbestos exposure (OR, 0.28; 95% CI, 0.11 to 0.72; P < .01), and older age (OR, 0.95; 95% CI, 0.92 to 0.99; P = .01) were associated with decreased odds of carrying a germline mutation, whereas having a second cancer diagnosis (OR, 3.33; 95% CI, 1.22 to 9.07; P = .02) significantly increased the odds. The odds of carrying a mutation in BAP1 (OR, 1,658; 95% CI, 199 to 76,224; P < .001), BRCA2 (OR, 5; 95% CI, 1.0 to 14.7; P = .03), CDKN2A (OR, 53; 95% CI, 6 to 249; P < .001), TMEM127 (OR, 88; 95% CI, 1.7 to 1,105; P = .01), VHL (OR, 51; 95% CI, 1.1 to 453; P = .02), and WT1 (OR, 20; 95% CI, 0.5 to 135; P = .049) were significantly higher in MM cases than in a noncancer control population. Tumor sequencing identified mutations in a homologous recombination pathway gene in 52% (n = 29 of 54). CONCLUSION: A significant proportion of patients with MM carry germline mutations in cancer susceptibility genes, especially those with peritoneal MM, minimal asbestos exposure, young age, and a second cancer diagnosis. These data support clinical germline genetic testing for patients with MM and provide a rationale for additional investigation of the homologous recombination pathway in MM.

Impact of Alemtuzumab Therapy and Route of Administration in T-Prolymphocytic Leukemia: A Single-Center Experience.

OBJECTIVE: We conducted a single-center retrospective analysis to determine the impact of the anti-CD52 monoclonal antibody alemtuzumab including route of administration compared to non-alemtuzumab-containing regimens in T-prolymphocytic leukemia (T-PLL). PATIENTS AND METHODS: The study was a retrospective analysis of a consecutive cohort of adult patients diagnosed with T-PLL at Mayo Clinic Rochester from January 1, 1997, through September 30, 2014. RESULTS: A total of 41 patients were diagnosed with T-PLL per the World Health Organization 2008 classification. The median age was 66 years, and 23 (56%) were male. After a median follow-up of 18 months (range, 0.4-66.1 months), 32 patients (78%) had died, with a median overall survival of 16.9 months. Approximately half the cohort was treated with alemtuzumab, almost exclusively after 2004. Median survival for patients receiving intravenous alemtuzumab-based therapy was 40.5 versus 10.3 months for all other therapies (P = .0004). A significant survival difference between intravenous versus subcutaneous alemtuzumab administration of 40.5 versus 13.7 months was noted (P = .0014). Only 4 (14%) of 28 patients aged < 70 years underwent hematopoietic stem cell transplantation, with a median survival after transplantation of 4 months. CONCLUSION: In this large series of T-PLL patients treated at a single tertiary-care center, we confirmed the prior observation of the superiority of intravenous alemtuzumab over other therapies. Hematopoietic stem cell transplantation was feasible in a minority of potentially eligible patients. Early transplant referral should be considered for all eligible patients.

Prognostic irrelevance of ring sideroblast percentage in World Health Organization-defined myelodysplastic syndromes without excess blasts.

The presence of ≥ 15% bone marrow (BM) ring sideroblasts (RS) and < 5% blasts is required for a diagnosis of refractory anemia with ring sideroblasts. We examined the phenotypic and prognostic relevance of this "15%" RS threshold in 200 patients with myelodysplastic syndromes (MDS) without excess blasts and with ≥ 1% RS. The impact of RS% was assessed both as a continuous and categorical variable: < 5% (n = 56), 5%-14% (n = 32), 15%-50% (n = 79), and > 50% (n = 33). RS% correlated (P < .05) directly with age, platelet count, transfusion dependency, BM cellularity, and mutant SF3B1 and inversely with hemoglobin level, multilineage dysplasia, and high-risk karyotype; but did not correlate with IDH mutations. At a median follow-up of 33 months, 156 (73%) deaths and 24 (12%) leukemic transformations were documented. Neither univariate nor multivariable analysis showed significant effect for RS% on overall or leukemia-free survival, suggesting the limited prognostic value of quantifying BM RS in MDS.

Why does my patient have thrombocytosis?

Thrombocytosis is a common clinical problem frequently encountered during routine evaluation. The diagnostic workup entails a step-by-step approach, which allows for an accurate assessment of the underlying cause. A thorough clinical history and physical examination may help differentiate thrombocytosis secondary to a reactive process versus an underlying clonal proliferation process. Once essential thrombocytosis is evident, relevant laboratory evaluation for an ongoing myeloproliferative disorder is paramount. Various treatment modalities have been proven to be beneficial. With further scientific investigation underway, molecular therapies may soon be cornerstones of therapy in essential thrombocytosis.