Talazoparib versus chemotherapy in patients with germline BRCA1/2-mutated HER2-negative advanced breast cancer: final overall survival results from the EMBRACA trial.

BACKGROUND: In EMBRACA, talazoparib prolonged progression-free survival versus chemotherapy (hazard ratio [HR] 0.542 [95% confidence interval (CI) 0.413-0.711]; P < 0.0001) and improved patient-reported outcomes (PRO) in germline BRCA1/2 (gBRCA1/2)-mutated advanced breast cancer (ABC). We report final overall survival (OS). PATIENTS AND METHODS: This randomized phase III trial enrolled patients with gBRCA1/2-mutated HER2-negative ABC. Patients received talazoparib or physician's choice of chemotherapy. OS was analyzed using stratified HR and log-rank test and prespecified rank-preserving structural failure time model to account for subsequent treatments. RESULTS: A total of 431 patients were entered in a randomized study (287 talazoparib/144 chemotherapy) with 412 patients treated (286 talazoparib/126 chemotherapy). By 30 September 2019, 216 deaths (75.3%) occurred for talazoparib and 108 (75.0%) chemotherapy; median follow-up was 44.9 and 36.8 months, respectively. HR for OS with talazoparib versus chemotherapy was 0.848 (95% CI 0.670-1.073; P = 0.17); median (95% CI) 19.3 months (16.6-22.5 months) versus 19.5 months (17.4-22.4 months). Kaplan-Meier survival percentages (95% CI) for talazoparib versus chemotherapy: month 12, 71% (66% to 76%)/74% (66% to 81%); month 24, 42% (36% to 47%)/38% (30% to 47%); month 36, 27% (22% to 33%)/21% (14% to 29%). Most patients received subsequent treatments: for talazoparib and chemotherapy, 46.3%/41.7% received platinum and 4.5%/32.6% received a poly(ADP-ribose) polymerase (PARP) inhibitor, respectively. Adjusting for subsequent PARP and/or platinum use, HR for OS was 0.756 (95% bootstrap CI 0.503-1.029). Grade 3-4 adverse events occurred in 69.6% (talazoparib) and 64.3% (chemotherapy) patients, consistent with previous reports. Extended follow-up showed significant overall improvement and delay in time to definitive clinically meaningful deterioration in global health status/quality of life and breast symptoms favoring talazoparib versus chemotherapy (P < 0.01 for all), consistent with initial analyses. CONCLUSIONS: In gBRCA1/2-mutated HER2-negative ABC, talazoparib did not significantly improve OS over chemotherapy; subsequent treatments may have impacted analysis. Safety was consistent with previous observations. PRO continued to favor talazoparib.

Author Correction: Chemotherapy with radiotherapy influences time-to-development of radiation-induced sarcomas: a multicenter study.

Since the publication of this paper, the authors noticed an error in Fig. 1. The X-axis on all the figure panels should read 'Time (years)', not 'Time (months)'. The corrected Fig. 1 is shown below.

Quality of life with talazoparib versus physician's choice of chemotherapy in patients with advanced breast cancer and germline BRCA1/2 mutation: patient-reported outcomes from the EMBRACA phase III trial.

Background: In the EMBRACA phase III trial, talazoparib (1 mg daily, orally) demonstrated a statistically significant improvement in PFS versus physician's choice of chemotherapy (PCT; capecitabine, eribulin, gemcitabine, or vinorelbine) in patients with HER2-negative advanced breast cancer carrying a germline BRCA1/2 mutation; we evaluated patient-reported outcomes (PROs). Patients and methods: Patients were randomized 2 : 1 to receive talazoparib or PCT. PROs were assessed at day 1 (baseline), the start of each treatment cycle (every 3 weeks), and at the end of treatment, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-30) and its breast cancer module, QLQ-BR23. Prespecified exploratory analyses included a longitudinal mixed-effect model comparing treatment arms and a time to definitive clinically meaningful deterioration (TTD) analysis carried out in the global health status/quality of life (GHS/QoL), and all functional and symptom scales from the EORTC QLQ-C30 and -BR23 questionnaires. Between-arm TTD comparisons were made using a stratified log-rank test and a Cox proportional hazards model. Results: Baseline scores were similar between arms. Statistically significant estimated overall improvement from baseline in GHS/QoL was seen for talazoparib compared with statistically significant deterioration for PCT {3.0 [95% confidence interval (CI) 1.2, 4.8] versus -5.4 [95% CI -8.8, -2.0]; between arms, P < 0.0001}. A statistically significant greater delay was observed in TTD in GHS/QoL, favoring talazoparib over PCT [hazard ratio, 0.38 (95% CI 0.26, 0.55; median, 24.3 versus 6.3 months, respectively; P < 0.0001)]. A statistically significant overall change and a statistically significant delay in TTD, all favoring talazoparib, were also observed in multiple functions and symptoms. Conclusion: Patients who received talazoparib had significant overall improvements and significant delay in TTD in multiple cancer-related and breast cancer-specific symptoms, functions, and GHS/QoL. ClinicalTrials.gov: NCT01945775.

Chemotherapy with radiotherapy influences time-to-development of radiation-induced sarcomas: a multicenter study.

BACKGROUND: An increasing number and proportion of cancer patients with apparently localised disease are treated with chemotherapy and radiation therapy in contemporary oncology practice. In a pilot study of radiation-induced sarcoma (RIS) patients, we demonstrated that chemotherapy was associated with a reduced time to development of RIS. We now present a multi-centre collaborative study to validate this association. METHODS: This was a retrospective cohort study of RIS cases across five large international sarcoma centres between 1 January 2000 to 31 December 2014. The primary endpoint was time to development of RIS. RESULTS: We identified 419 patients with RIS. Chemotherapy for the first malignancy was associated with a shorter time to RIS development (HR 1.37; 95% CI: 1.08-1.72; P=0.009). In the multi-variable model, older age (HR 2.11; 95% CI 1.83-2.43; P<0.001) and chemotherapy for the first malignancy (HR 1.61; 95% CI 1.26-2.05; P<0·001) were independently associated with a shorter time to RIS. Anthracyclines and alkylating agents significantly contribute to the effect. CONCLUSIONS: This study confirms an association between chemotherapy given for the first malignancy and a shorter time to development of RIS.

[Criteria for admitting patients with anorexia nervosa as inpatients to a general hospital; survey among internists]. / Criteria voor opname van volwassenen met anorexia nervosa op een interne afdeling van een algemeen ziekenhuis; enquête onder internisten.

BACKGROUND: Anorexia nervosa (an) is associated with a number of life-threatening complications. Sometimes there are good reasons for admitting an anorexia nervosa patient to a general hospital for treatment as an inpatient. Therefore, there needs to be optimal collaboration between psychiatrists treating the patient and the medical staff at the general hospital. AIM: To obtain insight into the admission criteria and other possible factors that play a role in the physician's decision to admit a patient with anorexia nervosa for inpatient treatment in a general hospital. METHOD: Internists and residents-internal medicine completed a questionnaire about admission criteria and, where applicable, about threshold values for these criteria. The physicians were also asked to judge two case vignettes. In addition, they were questioned about other factors that influenced their views on the admission of patients with anorexia nervosa to a general hospital and about their attitude to this patient-group, their experience of treating patients with anorexia nervosa and their awareness of a need for a guideline. The data were collected at the annual Dutch congress for internists at Maastricht. RESULTS: In total 78 congress attendees responded to the questionnaire; 47% were internist and 53% were resident-in-training. Agreement was greatest with regard to the following admission criteria (top 5): 1. serum potassium (threshold value <2.5 mmol/l was the criterion selected most); 2. arrhythmia; 3. hypoglycemia; 4. heart rate (threshold value <40 bpm was chosen most); 5. prolonged qt interval on an ECG. According to the two fictitious cases, the reason for admitting a patient with anorexia nervosa with milder symptoms was influenced by 'attitude'. Half of the respondents pointed out that the patient's cooperation plays a role in the decision to admit a patient with an eating disorder. CONCLUSION: Respondents reached a consensus regarding several admission criteria but the threshold values they gave varied substantially. Attitude towards the patient-group can sometimes influence the decision to admit a patient with anorexia nervosa to a general hospital. Internists and residents-in-training indicated they require detailed, carefully compiled guidelines which take into consideration the expected results and which emphasise the importance of obtaining the patient's cooperation.

300 million years apart: the extreme case of macromorphological skeletal convergence between deltocyathids and a turbinoliid coral (Anthozoa, Scleractinia).

The integration of morphological and molecular lines of evidence has enabled the family Deltocyathidae to be erected to accommodate Deltocyathus species that were previously ascribed to the family Caryophylliidae. However, although displaying the same morphological characteristics as other species of Deltocyathus , molecular data suggested that D. magnificus was phylogenetically distant from Deltocyathidae, falling within the family Turbinoliidae instead. To elucidate the enigmatic evolutionary history of this species and skeletal microstructural features, the phylogenetic relationships of Deltocyathidae and Turbinoliidae were investigated using nuclear ultraconserved and exon loci and complete mitochondrial genomes. Both nuclear and mitochondrial phylogenomic reconstructions confirmed the position of D. magnificus within turbinolids. Furthermore, a novel mitochondrial gene order was uncovered for Deltocyathidae species. This gene order was not present in Turbinoliidae or in D. magnificus that both have the scleractinian canonical gene order, further indicating the taxonomic utility of mitochondrial gene order. D. magnificus is therefore formally moved to the family Turbinoliidae and accommodated in a new genus (Dennantotrochus Kitahara, Vaga & Stolarski, gen. nov.). Surprisingly, turbinolids and deltocyathids do not differ in microstructural organisation of the skeleton that consists of densely packed, individualised rapid accretion deposits and thickening deposits composed of fibres perpendicular to the skeleton surface. Therefore, although both families are clearly evolutionarily divergent, macromorphological features indicate a case of skeletal convergence while these may still share conservative biomineralisation mechanisms. ZooBank: urn:lsid:zoobank.org:pub:5F1C0E25-3CC6-4D1F-B1F0-CD9D0014678E.

Central nervous system (CNS) relapse in diffuse large B cell lymphoma (DLBCL): pre- and post-rituximab.

Central nervous system (CNS)-directed prophylactic intrathecal (IT) therapy is indicated in patients with Burkitt and acute lymphoblastic lymphoma. Its role in diffuse large B cell lymphoma (DLBCL), a heterogeneous subtype, is less well defined. While addition of rituximab to standard cyclophosphamide-hydroxydaunorubicin-oncovin-prednisone (CHOP) chemotherapy (R-CHOP) has improved the outcomes of DLBCL patients, its role in reducing CNS relapse is unclear. We aim to (1) evaluate the clinical risk factors predictive of CNS relapse, (2) the role of rituximab in influencing CNS relapse, and (3) role of intrathecal prophylaxis. Four hundred ninety-nine patients with DLBCL from 2000 to 2008 were included (CHOP 179 vs. R-CHOP 320). IT prophylaxis was administered to 82 patients based on our institution's guidelines. Baseline characteristics between CHOP- and R-CHOP-treated patients were similar. Although R-CHOP significantly increased the complete remission rate from 71% to 81% (P < 0.01), CNS relapse rates remained unchanged (R-CHOP 6% vs. CHOP 5.1%). On multivariate analysis, poor performance status (Eastern Cooperative Oncology Group >1; hazard ratio (HR) = 2.01, 95% confidence interval (CI) 1.29-3.14), failure to attain remission (non-complete response (CR) vs. CR: HR = 2.39, 95% CI = 1.03 to 5.51), testicular (HR = 6.67, 95% CI = 1.62 to 27.53), kidney (HR = 20.14, 95% CI = 5.23 to 77.46), and breast involvement (HR = 6.14, 95% CI = 1.61 to 23.37) were each independently predictive of CNS relapse. Use of IT prophylaxis did not appear to decrease CNS relapse. Median survival after CNS relapse was 3.2 months. CNS relapse, a fatal event, remains a challenge in R-CHOP-treated patients. IT prophylaxis may not be sufficient to reduce CNS relapse, and strategies including systemic agents with high CNS penetration should be evaluated in high-risk patients identified in this study.

High SUV uptake on FDG-PET/CT predicts for an aggressive B-cell lymphoma in a prospective study of primary FDG-PET/CT staging in lymphoma.

BACKGROUND: Data assessing the role of positron emission tomography (PET)/computed tomography (CT) imaging in lymphoma staging is still being accumulated and current staging is based primarily on CT. This study aims to compare the value of PET/CT over conventional CT and bone marrow biopsy (BMB) in the initial evaluation of patients with lymphoma. METHODS: Data on 122 patients with PET/CT scans as part of their initial staging were prospectively collected and reviewed. All patients had complete staging, including BMB. RESULTS: Among the 122 patients, 101 had non-Hodgkin's lymphoma (NHL) and 21 had Hodgkin's lymphoma (HL). Compared with conventional CT, PET/CT upstaged 21 (17%) cases [B-cell non-Hodgkin's lymphoma (B-NHL), 12; T-cell non-Hodgkin's lymphoma (T-NHL), 3; HL, 6]. Of significance, in 13 patients with 2-[fluorine-18]fluoro-2-deoxy-D-glucose (FDG)-avid splenic lesions, four had normal CT findings. A maximum FDG uptake of >10 standardized uptake value (SUV) seems to significantly correlate with an aggressive B-cell lineage (odds ratio 2.47, 95% confidence interval 2.23-2.70). Overall, PET scan was concordant with BMB results in 108 (89%) and discordant in 14 (11%) cases. In HL, our data show that PET scan and marrow results agreed in 19 of the cases (90%), being concordantly negative in 18 cases and concordantly positive in one, giving a negative predictive value (NPV) of 100%, sensitivity of 100% and specificity of 90%. Of note, all 13 with early-stage HL had negative PET/CT scan and BMB. In NHL, all 17 cases of T-NHL had concordant PET and BMB results. In patients with aggressive B-NHL, BMB and PET/CT agreed in 58 patients (92%) and disagreed in five (8%), while the corresponding rates in indolent B-cell lymphoma were 14 (67%) and seven patients (33%), respectively. All seven were falsely negative. CONCLUSIONS: PET/CT upstages 17% of cases and detects occult splenic involvement. This may have potential therapeutic and prognostic implications. SUV >10 may predict for an aggressive histology. Except for indolent B-NHL, our data show that PET scans have a good overall NPV in excluding lymphomatous bone marrow involvement. This is particularly true of early-stage HL, suggesting that BMB may be safely omitted in this group.

Quality of life with talazoparib after platinum or multiple cytotoxic non-platinum regimens in patients with advanced breast cancer and germline BRCA1/2 mutations: patient-reported outcomes from the ABRAZO phase 2 trial.

BACKGROUND: Talazoparib (1 mg/day) exhibited promising efficacy and safety in patients with advanced breast cancer during ABRAZO (NCT02034916); this study evaluated patient-reported outcomes (PROs). PATIENTS AND METHODS: ABRAZO is a two-cohort, two-stage, phase 2 study of talazoparib in patients with advanced breast cancer after a response to prior platinum-based therapy (cohort 1 [C1], n = 49) or ≥3 platinum-free cytotoxic-based regimens (cohort 2 [C2], n = 35). PROs were assessed on day 1 (baseline), every 6 weeks for an initial 24 weeks, and every 12 weeks thereafter until progression, using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (QLQ-C30) and its breast cancer module, QLQ-BR23. RESULTS: Global health status/quality of life (GHS/QoL) was maintained from baseline across all time points for both C1 and C2. For C1 and C2, median time to deterioration (TTD) of GHS/QoL (95% confidence interval [CI]) was 2.8 (2.1, 3.0) and 5.5 (4.2, 5.7) months, respectively. Median TTD for all QLQ-C30 functional scales for C1 and C2 ranged 2.1-3.1 months and 4.2-5.6 months, respectively; median TTD for all QLQ-BR23 symptom scales ranged 2.6-4.0 months and 4.2-5.6 months, respectively. There were no statistically significant differences in estimated overall change from baseline in the GHS/QoL scale for both cohorts (C1: -2.6 [95% CI, -7.8, 2.5]; C2: 1.2 [95% CI, -5.5, 8.0]). Significant overall improvements in the breast symptoms and arm symptoms and the future perspective of patients in C1 and C2 were observed, despite the statistically significant and clinically meaningful overall deterioration among patients regarding their role functioning (in C1) and dyspnoea symptoms (in C2). CONCLUSION: Despite the statistically significant and clinically meaningful overall deterioration among patients regarding their role functioning (in C1) and dyspnoea symptoms (in C2), patients in both C1 and C2 reported significant overall improvements in their breast symptoms, arm symptoms and future perspective, and their GHS/QoL was maintained from baseline.

JAK-STAT and G-protein-coupled receptor signaling pathways are frequently altered in epitheliotropic intestinal T-cell lymphoma.

Epitheliotropic intestinal T-cell lymphoma (EITL, also known as type II enteropathy-associated T-cell lymphoma) is an aggressive intestinal disease with poor prognosis and its molecular alterations have not been comprehensively characterized. We aimed to identify actionable easy-to-screen alterations that would allow better diagnostics and/or treatment of this deadly disease. By performing whole-exome sequencing of four EITL tumor-normal pairs, followed by amplicon deep sequencing of 42 tumor samples, frequent alterations of the JAK-STAT and G-protein-coupled receptor (GPCR) signaling pathways were discovered in a large portion of samples. Specifically, STAT5B was mutated in a remarkable 63% of cases, JAK3 in 35% and GNAI2 in 24%, with the majority occurring at known activating hotspots in key functional domains. Moreover, STAT5B locus carried copy-neutral loss of heterozygosity resulting in the duplication of the mutant copy, suggesting the importance of mutant STAT5B dosage for the development of EITL. Dysregulation of the JAK-STAT and GPCR pathways was also supported by gene expression profiling and further verified in patient tumor samples. In vitro overexpression of GNAI2 mutants led to the upregulation of pERK1/2, a member of MEK-ERK pathway. Notably, inhibitors of both JAK-STAT and MEK-ERK pathways effectively reduced viability of patient-derived primary EITL cells, indicating potential therapeutic strategies for this neoplasm with no effective treatment currently available.