Contralateral breast cancer (CBC) is the most common second primary cancer diagnosed in breast cancer survivors, yet the understanding of the genetic susceptibility of CBC, particularly with respect ...to common variants, remains incomplete. This study aimed to investigate the genetic basis of CBC to better understand this malignancy.
We performed a genome-wide association analysis in the Women's Environmental Cancer and Radiation Epidemiology (WECARE) Study of women with first breast cancer diagnosed at age < 55 years including 1161 with CBC who served as cases and 1668 with unilateral breast cancer (UBC) who served as controls. We observed two loci (rs59657211, 9q32, SLC31A2/FAM225A and rs3815096, 6p22.1, TRIM31) with suggestive genome-wide significant associations (P < 1 × 10
). We also found an increased risk of CBC associated with a breast cancer-specific polygenic risk score (PRS) comprised of 239 known breast cancer susceptibility single nucleotide polymorphisms (SNPs) (rate ratio per 1-SD change: 1.25; 95% confidence interval 1.14-1.36, P < 0.0001). The protective effect of chemotherapy on CBC risk was statistically significant only among patients with an elevated PRS (P
= 0.04). The AUC that included the PRS and known breast cancer risk factors was significantly elevated.
The present GWAS identified two previously unreported loci with suggestive genome-wide significance. We also confirm that an elevated risk of CBC is associated with a comprehensive breast cancer susceptibility PRS that is independent of known breast cancer risk factors. These findings advance our understanding of genetic risk factors involved in CBC etiology.
•Treatment-naive and relapsed/refractory MDS patients receiving venetoclax and HMAs have an ORR of 59% with 63% of responders proceeding to transplant.•Allogeneic stem cell transplantation after ...treatment with venetoclax in combination with HMA is associated with prolonged survival.
Display omitted
Full text
Available for:
GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
B-cell-maturation-antigen (BCMA)-directed therapies are highly active for multiple myeloma, but infections are emerging as a major challenge. In this retrospective, single-center analysis we ...evaluated infectious complications after BCMA-targeted chimeric-antigen-receptor T-cell therapy (CAR-T), bispecific-antibodies (BsAb) and antibody-drug-conjugates (ADC). The primary endpoint was severe (grade ≥3) infection incidence. Amongst 256 patients, 92 received CAR-T, 55 BsAb and 109 ADC. The incidence of severe infections was higher with BsAb (40%) than CAR-T (26%) or ADC (8%), including grade 5 infections (7% vs 0% vs 0%, respectively). Comparing T-cell redirecting therapies, the incidence rate of severe infections was significantly lower with CAR-T compared to BsAb at 1-year (incidence-rate-ratio IRR = 0.43, 95%CI 0.25-0.76, P = 0.004). During periods of treatment-emergent hypogammaglobulinemia, BsAb recipients had higher infection rates (IRR:2.27, 1.31-3.98, P = 0.004) and time to severe infection (HR 2.04, 1.05-3.96, P = 0.036) than their CAR-T counterparts. During periods of non-neutropenia, CAR-T recipients had a lower risk (HR 0.44, 95%CI 0.21-0.93, P = 0.032) and incidence rate (IRR:0.32, 95% 0.17-0.59, P < 0.001) of severe infections than BsAb. In conclusion, we observed an overall higher and more persistent risk of severe infections with BsAb. Our results also suggest a higher infection risk during periods of hypogammaglobulinemia with BsAb, and with neutropenia in CAR-T recipients.
Lenalidomide and dexamethasone with bortezomib (VRd) or carfilzomib (KRd) are commonly used induction regimens in the U.S. This single-center, retrospective study evaluated outcomes and safety of VRd ...and KRd. Primary endpoint was progression-free survival (PFS). Of 389 patients with newly diagnosed multiple myeloma, 198 received VRd and 191 received KRd. Median PFS was not reached (NR) in both groups; 5-year PFS was 56% (95%CI, 48-64%) for VRd and 67% (60-75%) for KRd (P = 0.027). Estimated 5-year EFS was 34% (95%CI, 27-42%) for VRd and 52% (45-60%) for KRd (P < 0.001) with corresponding 5-year OS of 80% (95%CI, 75-87%) and 90% (85-95%), respectively (P = 0.053). For standard-risk patients, 5-year PFS was 68% (95%CI, 60-78%) for VRd and 75% (65-85%) for KRd (P = 0.20) with 5-year OS of 87% (95%CI, 81-94%) and 93% (87-99%), respectively (P = 0.13). For high-risk patients, median PFS was 41 months (95%CI, 32.8-61.1) for VRd and 70.9 months (58.2-NR) for KRd (P = 0.016). Respective 5-year PFS and OS were 35% (95%CI, 24-51%) and 69% (58-82%) for VRd and 58% (47-71%) and 88% (80-97%, P = 0.044) for KRd. Overall, KRd resulted in improved PFS and EFS with a trend toward improved OS compared to VRd with associations primarily driven by improvements in outcome for high-risk patients.
Clinical performance status is designed to be a measure of overall health, reflecting a patient's physiological reserve and ability to tolerate various forms of therapy. Currently, it is measured by ...a combination of subjective clinician assessment and patient-reported exercise tolerance in the context of daily living activities. In this study, we assess the feasibility of combining objective data sources and patient-generated health data (PGHD) to improve the accuracy of performance status assessment during routine cancer care. Patients undergoing routine chemotherapy for solid tumors, routine chemotherapy for hematologic malignancies, or hematopoietic stem cell transplant (HCT) at one of four sites in a cancer clinical trials cooperative group were consented to a six-week prospective observational clinical trial (NCT02786628). Baseline data acquisition included cardiopulmonary exercise testing (CPET) and a six-minute walk test (6MWT). Weekly PGHD included patient-reported physical function and symptom burden. Continuous data capture included use of a Fitbit Charge HR (sensor). Baseline CPET and 6MWT could only be obtained in 68% of study patients, suggesting low feasibility during routine cancer treatment. In contrast, 84% of patients had usable fitness tracker data, 93% completed baseline patient-reported surveys, and overall, 73% of patients had overlapping sensor and survey data that could be used for modeling. A linear model with repeated measures was constructed to predict the patient-reported physical function. Sensor-derived daily activity, sensor-derived median heart rate, and patient-reported symptom burden emerged as strong predictors of physical function (marginal R2 0.429-0.433, conditional R2 0.816-0.822). Trial Registration: Clinicaltrials.gov Id NCT02786628.
Terminal duct lobular units (TDLUs) are the predominant anatomical structures where breast cancers originate. Having lesser degrees of age-related TDLU involution, measured as higher TDLUs counts or ...more epithelial TDLU substructures (acini), is related to increased breast cancer risk among women with benign breast disease (BBD). We evaluated whether a recently developed polygenic risk score (PRS) based on 313-common variants for breast cancer prediction is related to TDLU involution in the background, normal breast tissue, as this could provide mechanistic clues on the genetic predisposition to breast cancer. Among 1398 women without breast cancer, higher values of the PRS were significantly associated with higher TDLU counts (
= 0.004), but not with acini counts (
= 0.808), in histologically normal tissue samples from donors and diagnostic BBD biopsies. Mediation analysis indicated that TDLU counts may explain a modest proportion (≤10%) of the association of the 313-variant PRS with breast cancer risk. These findings suggest that TDLU involution might be an intermediate step in the association between common genetic variation and breast cancer risk.
Abstract
Motivation
Genome-wide association studies are now shifting focus from analysis of common to rare variants. As power for association testing for individual rare variants may often be low, ...various aggregate level association tests have been proposed to detect genetic loci. Typically, power calculations for such tests require specification of large number of parameters, including effect sizes and allele frequencies of individual variants, making them difficult to use in practice. We propose to approximate power to a varying degree of accuracy using a smaller number of key parameters, including the total genetic variance explained by multiple variants within a locus.
Results
We perform extensive simulation studies to assess the accuracy of the proposed approximations in realistic settings. Using these simplified power calculations, we develop an analytic framework to obtain bounds on genetic architecture of an underlying trait given results from genome-wide association studies with rare variants. Finally, we provide insights into the required quality of annotation/functional information for identification of likely causal variants to make meaningful improvement in power.
Availability and implementation
A shiny application that allows a variety of Power Analysis of GEnetic AssociatioN Tests (PAGEANT), in R is made publicly available at https://andrewhaoyu.shinyapps.io/PAGEANT/.
Supplementary information
Supplementary data are available at Bioinformatics online.
BACKGROUND Romiplostim, a thrombopoietin receptor agonist, has been shown in a phase 2 trial to increase platelet count and facilitate chemotherapy administration in the setting of chemotherapy ...induced thrombocytopenia (CIT). The off-label use of romiplostim for this indication is common and is now a Category 2B recommendation by the National Comprehensive Cancer Network. Whether the administration of romiplostim improves clinical outcomes is not established. There are theoretical deleterious effects of platelet stimulation in cancer including the potential release of tumor stimulatory factors and blunting immune response to tumor cells. The goal of this retrospective study was to assess overall survival in patients with cancer treated with romiplostim compared to a cohort who received chemotherapy and granulocyte-colony stimulating factor (GCSF). The rationale for comparison of GCSF-treated arm was to address potential confounders related to chemotherapy dose reductions, delays, and abbreviated treatment courses due to cytopenias. METHODS To minimize cohort differences, we conducted an exact matched case-control analysis of patients with solid tumor malignancies receiving romiplostim with up to four patients receiving GCSF (without romiplostim). Patients were exact-matched based on a) primary cancer site, b) presence or absence of metastatic disease at the time of drug exposure, c) age (within 5 years), d) time from cancer diagnosis to treatment with romiplostim or G-CSF, 5) number of prior lines of antineoplastic therapy, and 6) comorbidities using the Charleston Comorbidity Illness index (<=6,7-10,>10). Overall survival (OS) was calculated from date of first dose of GCSF or romiplostim administration until death or last contact. Patient characteristics were summarized by frequency (percentage) and medians for categorical and continuous characteristics. OS was evaluated by Kaplan-Meier method and the difference between two treatment groups was determined by log-rank test. All statistical analyses were performed using R. RESULTS A total of 130 patients with solid tumor malignancy were identified as receiving romiplostim for CIT. Following strict exact-matching criteria, the analysis cohorts consisted of 58 patients in the romiplostim cohort and 138 patients in the GCSF cohort. The most common malignancies were Colorectal (18%), Non-Small Cell Lung Cancer (15%), Pancreas (13%). There was a median of 13 months between cancer diagnosis to romiplostim or and 16 months to GCSF and the mean number of prior lines of therapy was 2 in romiplostim and 1.8 in GCSF cohorts. The median comorbidity indices were similar in both groups (9 vs 9) and most patients had metastatic disease at the time of drug exposure (83%). The median overall survival in G-CSF treated patients was 18 months compared with romiplostim 10 months (Log rank P=0.014), Figure 1. In the stratified analysis by number of prior lines (1,2,>2), association with romiplostim remained statistically significant (Log rank P=0.012). Further restricting the analysis to patients who received romiplostim or GCSF during first or second lines of therapy, median overall survival in the romiplostim cohort (N=40) was 12 compared 21 months in the GCSF (N=109) cohort (log rank P=0.057), Figure 2. CONCLUSION In this retrospective exact-matched cohort analysis of patients treated with romiplostim for CIT, survival was inferior compared to patients receiving G-CSF alone. We acknowledge the limitations of single-center retrospective cohort analysis, but these findings highlight the urgent need to establish clinical benefit of thrombopoietin receptor agonists in the management of CIT.
Full text
Available for:
IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZRSKP
PDF
