Higher serum PD-L1 level predicts increased overall survival with lapatinib versus trastuzumab in the CCTG MA.31 phase 3 trial.

BACKGROUND: The purpose of this retrospective biomarker study of the Canadian Cancer Trials Group (CCTG) MA.31 randomized phase 3 trial (lapatinib vs trastuzumab) of HER2-positive metastatic breast cancer (MBC) was to evaluate the prognostic and predictive biomarker utility of pretreatment serum programmed death ligand 1 (PD-L1) levels. METHODS: CCTG MA.31 accrued 652 HER2-positive patients; 387 had serum available (185 in the trastuzumab arm and 202 in the lapatinib arm). The Ella immunoassay platform (ProteinSimple, San Jose, California) was used to quantitate serum PD-L1 levels. Stepwise forward Cox multivariable analyses were performed for progression-free survival and overall survival (OS). RESULTS: In the whole trial population, continuous pretreatment serum PD-L1 levels were not associated with OS. However, within the trastuzumab arm, a higher continuous pretreatment serum PD-L1 level was significant for shorter OS (hazard ratio [HR], 3.85; P = .04), but within the lapatinib arm, pretreatment serum PD-L1 was not associated with OS (P = .37). In the whole trial, in a multivariable analysis for OS, serum PD-L1 (median cut point) remained a significant independent covariate (HR, 2.38; P = .001). There was a significant interaction between treatment arm and continuous serum PD-L1 (bootstrap method; P = .0025): at or above 214.2 pg/mL (the 89th percentile), serum PD-L1 was associated with significantly shorter OS with trastuzumab treatment versus lapatinib treatment. CONCLUSIONS: In the CCTG MA.31 trial, serum PD-L1 was a significant predictive factor: a higher pretreatment serum PD-L1 level was associated with shorter OS with trastuzumab treatment but with longer OS with lapatinib treatment. Immune evasion may decrease the effectiveness of trastuzumab therapy. Further evaluation of elevated serum PD-L1 in advanced breast cancer is warranted to identify patients with HER2-positive MBC who may benefit from novel immune-targeted therapies in addition to trastuzumab.

Collagen fragments quantified in serum as measures of desmoplasia associate with survival outcome in patients with advanced pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) patients have poor prognosis and poor response to treatment. This is largely due to PDAC being associated with a dense and active stroma and tumor fibrosis (desmoplasia). Desmoplasia is characterized by excessive degradation and formation of the extracellular matrix (ECM) generating collagen fragments that are released into circulation. We evaluated the association of specific collagen fragments measured in pre-treatment serum with outcome in patients with PDAC. Matrix metalloprotease (MMP)-degraded type I collagen (C1M), type III collagen (C3M), type IV collagen (C4M) and a pro-peptide of type III collagen (PRO-C3) were measured by ELISA in pre-treatment serum from a randomized phase 3 clinical trial of patients with stage III/IV PDAC treated with 5-fluorouracil based therapy (n = 176). The collagen fragments were evaluated for their correlation (r, Spearman) with serum CA19-9 and for their association with overall survival (OS) based on Cox-regression analyses. In this phase 3 PDAC trial, pre-treatment serum collagen fragment levels were above the reference range for 67%-98% of patients, with median values in PDAC approximately two-fold higher than reference levels. Collagen fragment levels did not correlate with CA19-9 (r = 0.049-0.141, p = ns). On a continuous basis, higher levels of all collagen fragments were associated with significantly shorter OS. When evaluating degradation (C3M) and formation (PRO-C3) of type III collagen further, higher PRO-C3 was associated with poor OS (>25th percentile cut-point, HR = 2.01, 95%CI = 1.33-3.05) and higher C3M/PRO-C3 ratio was associated with improved OS (>25th percentile cut-point, HR = 0.53, 95%CI = 0.34-0.80). When adjusting for CA19-9 and clinical covariates, PRO-C3 remained significant (HR = 1.65, 95%CI = 1.09-2.48). In conclusion, collagen remodeling quantified in pre-treatment serum as a surrogate measure of desmoplasia was significantly associated with OS in a phase 3 clinical PDAC trial, supporting the link between desmoplasia, tumorigenesis, and response to treatment. If validated, these biomarkers may have prognostic and/or predictive potential in future PDAC trials.

Hereditary angioedema in children: a review and update.

PURPOSE OF REVIEW: Hereditary angioedema (HAE) most often presents in the first two decades of life. Despite these patients often see multiple doctors and go many years before confirmation of the diagnosis. the impact on quality of life, productivity and risk of anxiety, depression, and posttraumatic stress emphasizes the need for early diagnosis and appropriate treatment. RECENT FINDINGS: Over the past decade, therapy in the USA has emerged from fresh-frozen plasma and androgens to more than seven medications that are specific for bradykinin-induced disease. During the same time, treatment has evolved from intravenous to subcutaneous and the future will be a focus on oral therapy. SUMMARY: Much optimism exists that patients with HAE will live a life with minimal disease and impact on their quality of life making it even more important to diagnose children at an early age.

Effect of Chronic Hematologic Malignancies on In-Hospital Outcomes of Patients With ST-Segment Elevation Myocardial Infarction.

In view of hemorrhagic and prothrombotic tendencies, ST-segment elevation myocardial infarction (STEMI) patients with chronic hematologic malignancies (CHM) are felt to be at a higher risk and hence denied standard reperfusion strategies. In-hospital outcomes of CHM patients presenting with STEMI are unclear. The Nationwide Inpatient Sample data files from 2003 to 2014 were used to extract adult patients who presented with a primary diagnosis of STEMI. Patients who had a diagnosis of CHM defined as chronic myelogenous leukemia, chronic lymphocytic leukemia, essential thrombocythemia, polycythemia vera, chronic monocytic leukemia, and multiple myeloma were identified. The primary study outcome measure was in-hospital mortality. Inverse probability weighting-adjusted binary logistic regression was performed to identify independent predictors of in-hospital mortality. Of 2,715,807 STEMI patients included in the final analyses, 11,974 (0.4%) patients had a diagnosis of CHM. Patients with CHM were significantly older, had a higher prevalence of co-morbidities, and had a significantly higher unadjusted in-hospital mortality (14.9% vs 9.0%; p <0.001). After adjusting for co-morbidities, CHM did not independently predict a higher in-hospital mortality (odds ratio = 1.02, 95% confidence interval = 0.96 to 1.09; p = 0.461). In patients with CHM who presented with STEMI, percutaneous coronary intervention was found to be associated with a significant reduction in in-hospital mortality (odds ratio = 0.22, 95% confidence interval = 0.18 to 0.27; p <0.001) (c-statistic = 0.81). In conclusion, CHM patients presenting with STEMI should be treated with similar treatment strategies as those without CHM, including revascularization if indicated, as there appears to be a sizable outcome advantage with this approach.

Association of clinical outcomes in metastatic breast cancer patients with circulating tumour cell and circulating cell-free DNA.

BACKGROUND: Both circulating tumour cell (CTC) and total circulating cell-free DNA (ccfDNA) predict cancer patient prognosis. However, no study has explored the prognostic value of the combined use of CTC and ccfDNA. We aimed to investigate individual and joint effects of CTC and ccfDNA on clinical outcomes of metastatic breast cancer (MBC) patients. METHODS: We collected 227 blood samples from 117 MBC patients. CTCs were enumerated using the CellSearch System. ccfDNAs were quantified by quantitative real-time polymerase chain reaction and Qubit fluorometer. The individual and joint effects of CTC and ccfDNA levels on patient progression-free survival (PFS) and overall survival (OS) were analysed using Cox proportional hazards models. RESULTS: Compared to patients with <5 CTCs, patients with ≥5 CTCs had a 2.58-fold increased risk of progression and 3.63-fold increased risk of death. High level of ccfDNA was associated with a 2.05-fold increased risk of progression and 3.56-fold increased risk of death. These associations remained significant after adjusting for other important clinical covariates and CTC/ccfDNA levels. CTC and ccfDNA levels had a joint effect on patient outcomes. Compared to patients with low levels of both CTC and ccfDNA, those with high levels of both markers exhibited a >17-fold increased death risk (P < 0.001). Moreover, longitudinal analysis of 132 samples from 22 patients suggested that the inconsistency between CTC level and outcome in some patients could possibly be explained by ccfDNA level. CONCLUSIONS: CTC and total ccfDNA levels were individually and jointly associated with PFS and OS in MBC patients.