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Anti-CD38 monoclonal antibodies have consistently shown increased efficacy when added to standard of care for patients with multiple myeloma. We aimed to assess the efficacy of isatuximab in addition to lenalidomide, bortezomib, and dexamethasone in patients with newly diagnosed transplantation-eligible multiple myeloma.This open-label, multicentre, randomised, active-controlled, phase 3 trial was done at 67 academic and oncology practice centres in Germany. This study is ongoing and divided into two parts; herein, we report results from part 1. Eligible patients were aged 18-70 years; had a confirmed diagnosis of untreated multiple myeloma requiring systemic treatment and a WHO performance status of 0-2; and were eligible for induction therapy, high-dose melphalan and autologous haematopoietic stem-cell transplantation, and maintenance treatment. Patients were randomly assigned (1:1) to receive three 42-day cycles of induction therapy either with isatuximab plus lenalidomide, bortezomib, and dexamethasone (isatuximab group) or lenalidomide, bortezomib, and dexamethasone alone (control group) using a web-based system and permuted blocks. Patients in both groups received lenalidomide (25 mg orally on days 1-14 and 22-35), bortezomib (1·3 mg/mBetween Oct 23, 2018, and Sep 22, 2020, 660 patients were included in the ITT analysis (331 in the isatuximab group and 329 in the control group). 654 (99%) patients were White, two were African, one was Arabic, and three were Asian. 250 (38%) were women and 410 (62%) were men. The median age was 59 years (IQR 54-64). MRD negativity after induction therapy was reached in 166 (50%) patients in the isatuximab group versus 117 (36%) in the control group (OR 1·82 [95% CI 1·33-2·48]; p=0·00017). Median follow-up time from start to end of induction therapy was 125 days (IQR 125-131) versus 125 days (125-132). At least one grade 3 or 4 adverse event occurred in 208 (63%) of 330 patients versus 199 (61%) of 328 patients. Neutropenia of grade 3 or 4 occurred in 77 (23%) versus 23 (7%) patients and infections of grade 3 or 4 occurred in 40 (12%) versus 32 (10%) patients. Among 12 deaths during induction therapy, one death due to septic shock in the isatuximab group and four deaths (one cardiac decompensation, one hepatic and renal failure, one cardiac arrest, and one drug-induced enteritis) in the control group were considered treatment-related.Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone for induction therapy improved rates of MRD negativity with no new safety signals in patients with newly diagnosed transplantation-eligible multiple myeloma.Sanofi and Bristol Myers Squibb (Celgene).

Background To include the patient perspective in the assessment of adverse events (AE) in oncology, a patient-reported outcomes (PRO) version of the Common Terminology Criteria for Adverse Events (CTCAE) was developed by the NCI, the so called PRO-CTCAE. The objective of this study was the development of disease-specific PRO-CTCAE item sets with high content validity for patients with breast cancer (BC), multiple myeloma (MM) and prostate cancer (PC). Methods A cross-sectional survey was conducted at three German outpatient cancer centers. Prevalence and importance of the 78 PRO-CTCAE symptoms were assessed using a patient questionnaire. To select the most relevant PRO-CTCAE items for each tumor entity, symptoms were ranked based on patient answers. Results 101 patients with BC, 107 with MM, and 66 with PC participated. The final item sets contained 21 symptoms (BC) or 19 symptoms (MM and PC), respectively. Eight symptoms were represented in all three item sets. Fatigue was the symptom with the highest ranking across item sets followed by sleep disorders. Symptoms with the highest rankings represented in only one item set were symptoms affecting the urogenital system in the PC item set, blurred vision in the BC item set and appetite loss in the MM item set. Conclusions Individual PRO-CTCAE item sets with high content validity were developed for three tumor diseases on the basis of patient-reported symptom patterns and perceptions. The quality and psychometric criteria of the newly compiled item sets should be further validated.

Supplementary Data from A Novel Polymorphism in the Promoter Region of ERBB4 Is Associated with Breast and Colorectal Cancer Risk

Purpose: KEAP1 and NFE2L2 mutations are associated with impaired prognosis in a variety of cancers and with squamous cell carcinoma formation in non–small cell lung cancer (NSCLC). However, little is known about frequency, histology dependence, molecular and clinical presentation as well as response to systemic treatment in NSCLC.Experimental Design: Tumor tissue of 1,391 patients with NSCLC was analyzed using next-generation sequencing (NGS). Clinical and pathologic characteristics, survival, and treatment outcome of patients with KEAP1 or NFE2L2 mutations were assessed.Results: KEAP1 mutations occurred with a frequency of 11.3% (n = 157) and NFE2L2 mutations with a frequency of 3.5% (n = 49) in NSCLC patients. In the vast majority of patients, both mutations did not occur simultaneously. KEAP1 mutations were found mainly in adenocarcinoma (AD; 72%), while NFE2L2 mutations were more common in squamous cell carcinoma (LSCC; 59%). KEAP1 mutations were spread over the whole protein, whereas NFE2L2 mutations were clustered in specific hotspot regions. In over 80% of the patients both mutations co-occurred with other cancer-related mutations, among them also targetable aberrations like activating EGFR mutations or MET amplification. Both patient groups showed different patterns of metastases, stage distribution and performance state. No patient with KEAP1 mutation had a response on systemic treatment in first-, second-, or third-line setting. Of NFE2L2-mutated patients, none responded to second- or third-line therapy.Conclusions: KEAP1- and NFE2L2-mutated NSCLC patients represent a highly heterogeneous patient cohort. Both are associated with different histologies and usually are found together with other cancer-related, partly targetable, genetic aberrations. In addition, both markers seem to be predictive for chemotherapy resistance. Clin Cancer Res; 24(13); 3087–96. ©2018 AACR.

Supplemental Table 1-7 Supplemental Table 1: Diagnostic panels used for Next-generation sequencing (NGS) Supplemental Table 2: KEAP1 mutations Supplemental Table 3: NFE2L2 mutations Supplemental Table 4: Co-aberrations of KEAP1 Supplemental Table 5: Co-aberrations of NFE2L2 Supplemental Table 6: Distribution on FISH finding depending on histology Supplemental Table 7: Therapeutic outcome of patients receiving systemic therapy.

Main characteristics of the control group.

Purpose: The receptor tyrosine kinase ERBB4/HER4 plays a role in cell division, migration, differentiation, as well as apoptosis, and is frequently overexpressed in breast and colorectal tumors. To understand the role of genetic variations in the regulation of ERBB4 expression, we identified new polymorphisms and investigated their functional implication and risk association with breast and colorectal cancer.Experimental Design: We screened colorectal tumors from 92 patients for genetic variants at the ERBB4 ATG −1000 bp 5′-regulatory region by denaturing high-performance liquid chromatography and sequencing. Variants were subjected to DNA-protein interaction analyses (electrophoretic mobility shift assay), reporter gene assays in breast cancer cell lines MDA134 and MDA157, and immunohistochemical analyses of breast tumors. We established genotype frequencies within a breast cancer case-control collection (1,021 cases, 1,015 population-based controls) and a colorectal cancer case-control collection (459 cases, 569 blood donors) using matrix-assisted laser desorption ionization/time of flight mass spectrometry. Adjusted odds ratios (OR) and 95% confidence intervals (CI) were assessed by multivariate logistic regression.Results: We identified five new germ line variants −815 A>T, −782 G>T, −638 insTC, −267 C>G, and −219 del10bp. Two variants showed in vitro functional effects. The −782T allele showed lower protein binding affinity and lower promoter activity compared with the −782G allele, however, the −815T allele showed higher protein binding affinity and higher promoter activity. The −782T variant was identified as a risk allele for breast and colorectal cancer (OR, 1.59; 95% CI, 1.06-2.34 and OR, 2.21; 95% CI, 1.22-3.99, respectively).Conclusion: The ERBB4 −782 G>T polymorphism, by virtue of its in vitro functional implication and incidence, is a risk factor for breast and colorectal cancer.

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Background: The aim of this study was to examine the validity of PET/CT scans in the preoperative identification of lymph node metastases (LNM) and compare them with postoperative outcomes. Methods: In this retrospective study, we included 87 patients with a solitary lung nodule or biopsy-proven non-small cell lung cancer treated in our institution from 2009 to 2015. Patients were divided into two groups and four subgroups, depending on pre- and postoperative findings. Results: According to our analysis, PET/CT scan has a sensitivity of 50%, a specificity of 88.89%, a positive predictive value of 63.16%, and a negative predictive value of 82.35%. Among the patients, 13.8% were downstaged in PET-CT, while 8% were upstaged. In 78.2% of cases, the PET/CT evaluation was consistent with the histology. Metastases without extracapsular invasion were seldom recognized on PET/CT. Conclusions: This analysis showed the significance of extracapsular tumor invasion, which causes an inflammatory reaction, on LNM, which is probably responsible for preoperative false-positive findings. In conclusion, PET/CT scans are very effective in identifying patients without tumors. Furthermore, it is highly probable that patients with negative findings are free of disease.

Noninvasive detection of aberrant DNA methylation could provide invaluable biomarkers for earlier detection of triple-negative breast cancer (TNBC) which could help clinicians with easier and more efficient treatment options. We evaluated genome-wide DNA methylation data derived from TNBC and normal breast tissues, peripheral blood of TNBC cases and controls and reference samples of sorted blood and mammary cells. Differentially methylated regions (DMRs) between TNBC and normal breast tissues were stringently selected, verified and externally validated. A machine-learning algorithm was applied to select the top DMRs, which then were evaluated on plasma-derived circulating cell-free DNA (cfDNA) samples of TNBC patients and healthy controls. We identified 23 DMRs accounting for the methylation profile of blood cells and reference mammary cells and then selected six top DMRs for cfDNA analysis. We quantified un-/methylated copies of these DMRs by droplet digital PCR analysis in a plasma test set from TNBC patients and healthy controls and confirmed our findings obtained on tissues. Differential cfDNA methylation was confirmed in an independent validation set of plasma samples. A methylation score combining signatures of the top three DMRs overlapping with the SPAG6, LINC10606 and TBCD/ZNF750 genes had the best capability to discriminate TNBC patients from controls (AUC = 0.78 in the test set and AUC = 0.74 in validation set). Our findings demonstrate the usefulness of cfDNA-based methylation signatures as noninvasive liquid biopsy markers for the diagnosis of TNBC.

Therapeutic decisions in lung cancer critically depend on the determination of histologic types and oncogene mutations. Therefore, tumor samples are subjected to standard histologic and immunohistochemical analyses and examined for relevant mutations using comprehensive molecular diagnostics. In this study, an alternative diagnostic approach for automatic and label-free detection of mutations in lung adenocarcinoma tissue using quantum cascade laser-based infrared imaging is presented. For this purpose, a five-step supervised classification algorithm was developed, which was not only able to detect tissue types and tumor lesions, but also the tumor type and mutation status of adenocarcinomas. Tumor detection was verified on a data set of 214 patient samples with a specificity of 97% and a sensitivity of 95%. Furthermore, histology typing was verified on samples from 203 of the 214 patients with a specificity of 97% and a sensitivity of 94% for adenocarcinoma. The most frequently occurring mutations in adenocarcinoma (KRAS, EGFR, and TP53) were differentiated by this technique. Detection of mutations was verified in 60 patient samples from the data set with a sensitivity and specificity of 95% for each mutation. This demonstrates that quantum cascade laser infrared imaging can be used to analyze morphologic differences as well as molecular changes. Therefore, this single, one-step measurement provides comprehensive diagnostics of lung cancer histology types and most frequent mutations.

Die moderne Systemtherapie mit Chemotherapie, zielgerichteter Therapie und Immuntherapie hat bei vielen Tumorerkrankungen in den letzten 15 Jahren zu einer deutlichen Verbesserung des Gesamtuberlebens gefuhrt. Somit ist die operative Therapie von Lungenmetastasen und Lymphknotenmetastasen nicht nur wertvoll, um eine Heilung bei ausgesuchten Tumoren zu erreichen, sondern sie kann und muss eingesetzt werden, um im Falle einer umschriebenen Progredienz Spitzen des Tumorwachstums zu eliminieren. Diese konnen Ausdruck einer Tumorheterogenitat sein, die von der Systemtherapie nicht erreicht werden. Abhangig von der Dynamik und der Ausdehnung der Metastasierung muss das therapeutische Vorgehen individuell im Tumorboard entschieden werden.

Genome-wide analysis identifies 32 loci associated with breast cancer susceptibility, accounting for estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype(1-3). To identify novel loci, we performed a genome-wide association study including 133,384 breast cancer cases and 113,789 controls, plus 18,908 BRCA1 mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 status and tumor grade. We identified 32 novel susceptibility loci (P < 5.0 x 10(-8)), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate < 0.05). Five loci showed associations (P < 0.05) in opposite directions between luminal and non-luminal subtypes. In silico analyses showed that these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 54.2% for luminal A-like disease and 37.6% for triple-negative disease. The odds ratios of polygenic risk scores, which included 330 variants, for the highest 1% of quantiles compared with middle quantiles were 5.63 and 3.02 for luminal A-like and triple-negative disease, respectively. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.

BACKGROUNDProtein truncating variants in ATM, BRCA1, BRCA2, CHEK2 and PALB2 are associated with increased breast cancer risk, but risks associated with missense variants in these genes are uncertain.METHODSCombining 59,639 breast cancer cases and 53,165 controls, we sampled training (80%) and validation (20%) sets to analyze rare missense variants in ATM (1,146 training variants), BRCA1 (644), BRCA2 (1,425), CHEK2 (325) and PALB2 (472). We evaluated breast cancer risks according to five in-silico prediction-of-deleteriousness algorithms, functional protein domain, and frequency, using logistic regression models and also mixture models in which a subset of variants was assumed to be risk-associated.RESULTSThe most predictive in-silico algorithms were Helix (BRCA1, BRCA2 and CHEK2) and CADD (ATM). Increased risks appeared restricted to functional protein domains for ATM (FAT and PIK domains) and BRCA1 (RING and BRCT domains). For ATM, BRCA1 and BRCA2, data were compatible with small subsets (approximately 7%, 2% and 0.6%, respectively) of rare missense variants giving similar risk to those of protein truncating variants in the same gene. For CHEK2, data were more consistent with a large fraction (approximately 60%) of rare missense variants giving a lower risk (OR 1.75, 95% CI (1.47-2.08)) than CHEK2 protein truncating variants. There was little evidence for an association with risk for missense variants in PALB2. The best fitting models were well calibrated in the validation set.CONCLUSIONSThese results will inform risk prediction models and the selection of candidate variants for functional assays, and could contribute to the clinical reporting of gene panel testing for breast cancer susceptibility.

ObjectIntra-tumoral hemorrhage is considered an imaging characteristic of advanced cancer disease. However, data on the influence of intra-tumoral hemorrhage in patients with brain metastases (BM) remains scarce. We aimed at investigating patients with BM who underwent neurosurgical resection of the metastatic lesion for a potential impact of preoperative hemorrhagic transformation on overall survival (OS).MethodsBetween 2013 and 2018, 357 patients with BM were surgically treated at the authors’ neuro-oncological center. Preoperative magnetic resonance imaging (MRI) examinations were assessed for the occurrence of malignant hemorrhagic transformation.Results122 of 375 patients (34%) with BM revealed preoperative intra-tumoral hemorrhage. Patients with hemorrhagic transformed BM exhibited a median OS of 5 months compared to 12 months for patients without intra-tumoral hemorrhage. Multivariate analysis revealed preoperative hemorrhagic transformation as an independent and significant predictor for worsened OS.ConclusionsThe present study identifies preoperative intra-tumoral hemorrhage as an indicator variable for poor prognosis in patients with BM undergoing neurosurgical treatment.

Background: Brain metastases (BM) indicate advanced states of cancer disease and cranial surgery represents a common treatment modality. In the present study, we aimed to identify the risk factors for a reduced survival in patients receiving a surgical treatment of BM derived from non-small cell lung cancer (NSCLC). Methods: A total of 154 patients with NSCLC that had been surgically treated for BM at the authors’ institution between 2013 and 2018 were included for a further analysis. A multivariate analysis was performed to identify the predictors of a poor overall survival (OS). Results: The median overall survival (mOS) was 11 months (95% CI 8.2–13.8). An age &gt, 65 years, the infratentorial location of BM, elevated preoperative C-reactive protein levels, a perioperative red blood cell transfusion, postoperative prolonged mechanical ventilation (&gt, 48 h) and the occurrence of postoperative adverse events were identified as independent factors of a poor OS. Conclusions: The present study identified several predictors for a worsened OS in patients that underwent surgery for BM of NSCLC. These findings might guide a better risk/benefit assessment in the course of metastatic NSCLC therapy and might help to more sufficiently cope with the challenges of cancer therapy in these advanced stages of disease.

Simple Summary Patients with brain metastasis are at a severe stage of cancer, and brain surgery can prevent neurological morbidity. However, the success of brain surgery might require a patient’s physical integrity prior to the operation. In the present study, we asked whether a preoperative physical decline affects survival in patients with brain metastasis from lung cancer. In order to measure the physical condition, we used a commonly-known index—the so-called frailty index—and additionally measured the thickness of a particular masticatory muscle as muscle loss correlates to physical decline. We found that a decreased muscle thickness was accompanied by worsened survival for patients < 65 years and an increased frailty index correlated to worsened survival for patients ≥ 65 years. These results encourage to use of the frailty index and muscle thickness as easily available parameters in order to more sufficiently estimate individual treatment success in patients with metastatic lung cancer. Abstract Neurosurgical resection represents an important therapeutic pillar in patients with brain metastasis (BM). Such extended treatment modalities require preoperative assessment of patients’ physical status to estimate individual treatment success. The aim of the present study was to analyze the predictive value of frailty and sarcopenia as assessment tools for physiological integrity in patients with non-small cell lung cancer (NSCLC) who had undergone surgery for BM. Between 2013 and 2018, 141 patients were surgically treated for BM from NSCLC at the authors’ institution. The preoperative physical condition was assessed by the temporal muscle thickness (TMT) as a surrogate parameter for sarcopenia and the modified frailty index (mFI). For the ≥65 aged group, median overall survival (mOS) significantly differed between patients classified as ‘frail’ (mFI ≥ 0.27) and ‘least and moderately frail’ (mFI < 0.27) (15 months versus 11 months (p = 0.02)). Sarcopenia revealed significant differences in mOS for the

BackgroundCopy number variants (CNVs) are pervasive in the human genome but potential disease associations with rare CNVs have not been comprehensively assessed in large datasets. We analysed rare CNVs in genes and non-coding regions for 86,788 breast cancer cases and 76,122 controls of European ancestry with genome-wide array data.ResultsGene burden tests detected the strongest association for deletions in BRCA1 (P= 3.7E-18). Nine other genes were associated with a p-value < 0.01 including known susceptibility genes CHEK2 (P= 0.0008), ATM (P= 0.002) and BRCA2 (P= 0.008). Outside the known genes we detected associations with p-values < 0.001 for either overall or subtype-specific breast cancer at nine deletion regions and four duplication regions. Three of the deletion regions were in established common susceptibility loci.ConclusionsThis is the first genome-wide analysis of rare CNVs in a large breast cancer case-control dataset. We detected associations with exonic deletions in established breast cancer susceptibility genes. We also detected suggestive associations with non-coding CNVs in known and novel loci with large effects sizes. Larger sample sizes will be required to reach robust levels of statistical significance.

Surgical resection is highly effective in the treatment of tumor-related epilepsy (TRE) in patients with brain metastases (BM). Nevertheless, some patients suffer from postoperative persistent epilepsy which negatively impacts health-related quality of life. Therefore, early identification of patients with potentially unfavorable seizure outcome after BM resection is important. Patients with TRE that had undergone surgery for BM at the authors’ institution between 2013 and 2018 were analyzed with regard to preoperatively identifiable risk factors for unfavorable seizure outcome. Tumor tissue and tumor necrosis ratios were assessed volumetrically. According to the classification of the International League Against Epilepsy (ILAE), seizure outcome was categorized as favorable (ILAE 1) and unfavorable (ILAE 2–6) after 3 months in order to avoid potential interference with adjuvant cancer treatment. Among all 38 patients undergoing neurosurgical treatment for BM with concomitant TRE, 34 patients achieved a favorable seizure outcome (90%). Unfavorable seizure outcome was significantly associated with larger tumor volumes (p = 0.012), a midline shift > 7 mm (p = 0.025), and a necrosis/tumor volume ratio > 0.2 (p = 0.047). The present study identifies preoperatively collectable risk factors for unfavorable seizure outcome in patients with BM and TRE. This might enable to preselect for highly vulnerable patients with postoperative persistent epilepsy who might benefit from accompanying neuro-oncological expertise during further systemical treatment regimes.

Background: Metastatic melanoma disease is accompanied by highly systemic inflammatory responses. The prognostic value of preoperative laboratory inflammation markers in brain metastatic melanoma patients has not been adequately investigated so far. Methods: Preoperative inflammatory blood parameters were correlated to overall survival (OS) rates in melanoma patients that underwent surgery for brain metastasis (BM) between 2013 and 2019 at the authors’ institution. Receiver operating characteristic (ROC) analyses were used for cutoff determination of routine laboratory parameters. Results: Median OS in the present cohort of 30 melanoma patients with surgically treated BM was 7 months (95% confidence interval (CI) 5.7–8.3). Initial elevated C-reactive protein (CRP) levels (&gt, 10 mg/L), neutrophil-to-lymphocyte ratio (NLR) ≥ 4, platelet-to-lymphocyte ratio (PLR) ≥ 145, and lymphocyte-to-monocyte ratio (LMR) &lt, 2 were associated with significantly reduced OS rates. Conclusions: The present study identifies several preoperative peripheral inflammatory markers as indicators for poor prognosis in melanoma patients with BM undergoing neurosurgical treatment. Elevated initial CRP values, higher NLR and PLR, and lower LMR were associated with reduced OS and, thus, might be incorporated into preoperative interdisciplinary treatment planning and counseling for affected patients.

Author(s): Coignard, Juliette; Lush, Michael; Beesley, Jonathan; O'Mara, Tracy A; Dennis, Joe; Tyrer, Jonathan P; Barnes, Daniel R; McGuffog, Lesley; Leslie, Goska; Bolla, Manjeet K; Adank, Muriel A; Agata, Simona; Ahearn, Thomas; Aittomaki, Kristiina; Andrulis, Irene L; Anton-Culver, Hoda; Arndt, Volker; Arnold, Norbert; Aronson, Kristan J; Arun, Banu K; Augustinsson, Annelie; Azzollini, Jacopo; Barrowdale, Daniel; Baynes, Caroline; Becher, Heko; Bermisheva, Marina; Bernstein, Leslie; Bialkowska, Katarzyna; Blomqvist, Carl; Bojesen, Stig E; Bonanni, Bernardo; Borg, Ake; Brauch, Hiltrud; Brenner, Hermann; Burwinkel, Barbara; Buys, Saundra S; Caldes, Trinidad; Caligo, Maria A; Campa, Daniele; Carter, Brian D; Castelao, Jose E; Chang-Claude, Jenny; Chanock, Stephen J; Chung, Wendy K; Claes, Kathleen BM; Clarke, Christine L; GEMO Study Collaborators; EMBRACE Collaborators; Collee, J Margriet; Conroy, Don M; Czene, Kamila; Daly, Mary B; Devilee, Peter; Diez, Orland; Ding, Yuan Chun; Domchek, Susan M; Dork, Thilo; Dos-Santos-Silva, Isabel; Dunning, Alison M; Dwek, Miriam; Eccles, Diana M; Eliassen, A Heather; Engel, Christoph; Eriksson, Mikael; Evans, D Gareth; Fasching, Peter A; Flyger, Henrik; Fostira, Florentia; Friedman, Eitan; Fritschi, Lin; Frost, Debra; Gago-Dominguez, Manuela; Gapstur, Susan M; Garber, Judy; Garcia-Barberan, Vanesa; Garcia-Closas, Montserrat; Garcia-Saenz, Jose A; Gaudet, Mia M; Gayther, Simon A; Gehrig, Andrea; Georgoulias, Vassilios; Giles, Graham G; Godwin, Andrew K; Goldberg, Mark S; Goldgar, David E | Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-23162-4.

Background: High-risk (HR) multiple myeloma (MM) has an impaired prognostic outcome. Addition of anti-CD38 monoclonal antibodies to standard-of-care regimens improved response rates and depth of response. Here, we report a prespecified interim analysis (IA) following induction therapy with the quadruplet regimen isatuximab, carfilzomib, lenalidomide and dexamethasone (Isa-KRd) in newly diagnosed (ND) HR MM patients (pts) in the phase II multicentric GMMG-CONCEPT trial (NCT03104842). Methods: 153 pts with HR NDMM were enrolled into the trial, the IA reports on the first 50 pts evaluable for IA. Pts receive Isa-KRd in induction, consolidation and Isa-KR maintenance. Transplant eligible pts undergo high-dose therapy. This IA reports on overall response rates (ORR) during induction. Findings: 50 pts were included in the IA population for ORR. HR MM was defined by del17p in 52%, t(4;14) in 38%, t(14;16) in 12% and > 3 copies 1q21 in 42% and ISS stage 2/3 disease. 46/50 pts completed induction treatment. ORR was 100%, with 5 pts (10·0%) showing partial response (PR), 22 (44·0%; including 4 in arm B) very good partial response (VGPR) and 23 (46·0%) complete response (CR). Hematologic grade 3/4 treatment-emergent adverse events (≥ 10%) were neutropenia (34·0%), leukopenia (26·0%) and thrombocytopenia (14·0%). Main non-hematologic toxicities grade 3/4 were hypertension (12·0%) and infection (8·0%). Interpretation: We report for the first time on a trial investigating Isa-KRd quadruplet treatment in solely HR NDMM. Isa-KRd induction induces rapid and deep responses. The overall safety profile is consistent with previous reports. Trial Registration: The trial is registered at clinicaltrials.gov (NCT03104842). Funding Statement: Study drug and financial support by Amgen, Celgene-BMS and Sanofi. Declaration of Interests: Dr. Leypoldt reports grants and non-financial support from Celgene-BMS, grants and non-financial support from Sanofi, grants and non-financial support from Amgen, during the conduct of the study; non-financial support from GSK, non-financial support from Abbvie, outside the submitted work; Dr. Asemissen has nothing to disclose. Dr. Besemer has nothing to disclose. Dr. Hanel reports personal fees from Celgene, personal fees from Novartis, personal fees from Takeda, personal fees from Amgen, during the conduct of the study; Dr. Blau has nothing to disclose. Dr. Gorner has nothing to disclose. Dr. Ko has nothing to disclose. Dr. Reinhardt reports personal fees from Abbvie, grants from Gilead, personal fees from Merck, other from CDL Therapeutics GmbH, outside the submitted work; Dr. Staib reports grants, personal fees, non-financial support and other from Abbvie, grants, personal fees, non-financial support and other from Amgen, grants, personal fees, non-financial support and other from Celgene, grants, personal fees, non-financial support and other from Janssen-Cilag, grants, personal fees, non-financial support and other from Novartis, grants, personal fees, non-financial support and other from Gilead, grants, personal fees, non-financial support and other from Pfizer, grants, personal fees, non-financial support and other from Roche, outside the submitted work; Dr. Mann has nothing to disclose. Dr. Lutz has nothing to disclose. Dr. Munder reports personal fees and non-financial support from Janssen, personal fees and non-financial support from Amgen, grants from Incyte, personal fees and non-financial support from BMS, personal fees from Abbvie, personal fees from Sanofi, personal fees from GSK, personal fees from Takeda, outside the submitted work; Dr. Graeven reports personal fees from Amgen, personal fees and non-financial support from Boehringer Ingelheim, personal fees from Daichi Sankyo, personal fees from Servier, personal fees from Celgene, personal fees from Astra Zeneca, personal fees from Johnson Johnson, non-financial support from Merck, personal fees from MSD, personal fees from BMS, during the conduct of the study; Dr. Peceny reports grants and personal fees from Sanofi Genzyme, grants from Novartis, grants from DRK Blutspendedienst NSTOB, grants from Boehringer Ingelheim Pharma GmbH & Co KG, grants from Celgene, outside the submitted work; Dr. Salwender reports personal fees from Bristol-Myers Squibb/Celgene, personal fees from Janssen Cilag, personal fees from Glaxo Smith Kline, personal fees from Oncopeptides, personal fees from Takeda, personal fees from Sanofi, personal fees from AbbVie, personal fees from Amgen, outside the submitted work; Dr. Jauch has nothing to disclose. Dr. Zago has nothing to disclose. Axel Benner has nothing to disclose. Dr. Tichy has nothing to disclose. Dr. Bokemeyer reports personal fees from Sanofi Aventis, personal fees from Merck KgA, personal fees from Bristol-Myers Squibb, personal fees from Merck Sharp & Dohme, personal fees from Lilly Imclone, personal fees from Bayer Healthcare, personal fees from GSO Contract research, personal fees from AOK-Rheinland-Hamburg, personal fees from Novartis, outside the submitted work; Dr. Goldschmidt reports grants, personal fees, non-financial support and other from Amgen, grants, personal fees, non-financial support and other from BMS, grants, personal fees, non-financial support and other from Celgene, grants, personal fees, and other from Chugai, grants, personal fees, non-financial support and other from Janssen, grants, personal fees, non-financial support and other from Sanofi, other from Incyte, other from Molecular Partners, other from Merck Sharp and Dohme (MSD), other from Mundipharma, grants, personal fees, non-financial support and other from Takeda, personal fees and other from Novartis, personal fees from Adaptive Biotechnology, personal fees from GlaxoSmithKline (GSK), outside the submitted work. Dr. Weisel reports grants from AMGEN, grants from Celgene, grants from Sanofi, during the conduct of the study; grants, personal fees and non-financial support from Amgen, personal fees and non-financial support from BMS, grants, personal fees and non-financial support from Celgene, personal fees from Adaptive Biotech, grants, personal fees and non-financial support from Janssen, personal fees and non-financial support from GSK, personal fees from Karyopharm, grants, personal fees and non-financial support from Sanofi, personal fees and non-financial support from Takeda, personal fees from Oncopeptides, personal fees from Roche, outside the submitted work. Ethics Approval Statement: All patients provided written informed consent. The trial was approved by the competent authorities and the Tuebingen University Ethics Committee.

Previous research has shown that polygenic risk scores (PRSs) can be used to stratify women according to their risk of developing primary invasive breast cancer. This study aimed to evaluate the association between a recently validated PRS of 313 germline variants (PRS313) and contralateral breast cancer (CBC) risk. We included 56,068 women of European ancestry diagnosed with first invasive breast cancer from 1990 onward with follow-up from the Breast Cancer Association Consortium. Metachronous CBC risk (N = 1,027) according to the distribution of PRS313 was quantified using Cox regression analyses. We assessed PRS313 interaction with age at first diagnosis, family history, morphology, ER status, PR status, and HER2 status, and (neo)adjuvant therapy. In studies of Asian women, with limited follow-up, CBC risk associated with PRS313 was assessed using logistic regression for 340 women with CBC compared with 12,133 women with unilateral breast cancer. Higher PRS313 was associated with increased CBC risk: hazard ratio per standard deviation (SD) = 1.25 (95%CI = 1.18-1.33) for Europeans, and an OR per SD = 1.15 (95%CI = 1.02-1.29) for Asians. The absolute lifetime risks of CBC, accounting for death as competing risk, were 12.4% for European women at the 10th percentile and 20.5% at the 90th percentile of PRS313. We found no evidence of confounding by or interaction with individual characteristics, characteristics of the primary tumor, or treatment. The C-index for the PRS313 alone was 0.563 (95%CI = 0.547-0.586). In conclusion, PRS313 is an independent factor associated with CBC risk and can be incorporated into CBC risk prediction models to help improve stratification and optimize surveillance and treatment strategies. ispartof: AMERICAN JOURNAL OF HUMAN GENETICS vol:107 issue:5 pages:837-848 ispartof: location:United States status: published

Surgical resection is a key treatment modality for brain metastasis (BM). However, peri- and postoperative adverse events (PAEs) might be associated with a detrimental impact on postoperative outcome. We retrospectively analyzed our institutional database with regard to patient safety indicators (PSIs), hospital-acquired conditions (HACs) and specific cranial surgery-related complications (CSCs) as high-quality metric profiles for PAEs in patients who had undergone surgery for BM in our department between 2013 and 2018. The comorbidity burden was assessed by means of the Charlson comorbidity index (CCI). A multivariate analysis was performed to identify independent predictors for the development of PAEs after surgical resection of BM. In total, 33 patients (8.5%) suffered from PAEs after surgery for BM. Of those, 17 PSI, 5 HAC and 11 CSC events were identified. Multiple brain metastases (p = 0.02) and a higher comorbidity burden (CCI &gt, 10, p = 0.003) were associated with PAEs. In-hospital mortality of patients suffering from a PAE was significantly higher than that of patients without a PAE (24% vs. 0.6%, p &lt, 0.0001). Awareness of risk factors for postoperative complications enables future prevention and optimal response, particularly in vulnerable oncological patients. The present study identified the presence of multiple brain metastases and increased comorbidity burden associated with PAEs in patients suffering from BM.

Background:\ud State-of-the art therapy for recurrent ovarian cancer suitable for platinum-based re-treatment includes bevacizumab-containing combinations (eg, bevacizumab combined with carboplatin–paclitaxel or carboplatin–gemcitabine) or the most active non-bevacizumab regimen: carboplatin–pegylated liposomal doxorubicin. The aim of this head-to-head trial was to compare a standard bevacizumab-containing regimen versus carboplatin–pegylated liposomal doxorubicin combined with bevacizumab.\ud Methods:\ud This multicentre, open-label, randomised, phase 3 trial, was done in 159 academic centres in Germany, France, Australia, Austria, and the UK. Eligible patients (aged ≥18 years) had histologically confirmed epithelial ovarian, primary peritoneal, or fallopian tube carcinoma with first disease recurrence more than 6 months after first-line platinum-based chemotherapy, and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were stratified by platinum-free interval, residual tumour, previous antiangiogenic therapy, and study group language, and were centrally randomly assigned 1:1 using randomly permuted blocks of size two, four, or six to receive six intravenous cycles of bevacizumab (15 mg/kg, day 1) plus carboplatin (area under the concentration curve [AUC] 4, day 1) plus gemcitabine (1000 mg/m 2, days 1 and 8) every 3 weeks or six cycles of bevacizumab (10 mg/kg, days 1 and 15) plus carboplatin (AUC 5, day 1) plus pegylated liposomal doxorubicin (30 mg/m 2, day 1) every 4 weeks, both followed by maintenance bevacizumab (15 mg/kg every 3 weeks in both groups) until disease progression or unacceptable toxicity. There was no masking in this open-label trial. The primary endpoint was investigator-assessed progression-free survival according to Response Evaluation Criteria in Solid Tumors version 1.1. Efficacy data were analysed in the intention-to-treat population. Safety was analysed in all patients who received at least one dose of study drug. This completed study is registered with ClinicalTrials.gov, NCT01837251.\ud Findings:\ud Between Aug 1, 2013, and July 31, 2015, 682 eligible patients were enrolled, of whom 345 were randomly assigned to receive carboplatin–pegylated liposomal doxorubicin–bevacizumab (experimental group) and 337 were randomly assigned to receive carboplatin–gemcitabine–bevacizumab (standard group). Median follow-up for progression-free survival at data cutoff (July 10, 2018) was 12·4 months (IQR 8·3–21·7) in the experimental group and 11·3 months (8·0–18·4) in the standard group. Median progression-free survival was 13·3 months (95% CI 11·7–14·2) in the experimental group versus 11·6 months (11·0–12·7) in the standard group (hazard ratio 0·81, 95% CI 0·68–0·96; p=0·012). The most common grade 3 or 4 adverse events were hypertension (88 [27%] of 332 patients in the experimental group vs 67 [20%] of 329 patients in the standard group) and neutropenia (40 [12%] vs 73 [22%]). Serious adverse events occurred in 33 (10%) of 332 patients in the experimental group and 28 (9%) of 329 in the standard group. Treatment-related deaths occurred in one patient in the experimental group (

We evaluated the joint associations between a new 313-variant PRS (PRS313) and questionnaire-based breast cancer risk factors for women of European ancestry, using 72 284 cases and 80 354 controls from the Breast Cancer Association Consortium. Interactions were evaluated using standard logistic regression and a newly developed case-only method for breast cancer risk overall and by estrogen receptor status. After accounting for multiple testing, we did not find evidence that per-standard deviation PRS313 odds ratio differed across strata defined by individual risk factors. Goodness-of-fit tests did not reject the assumption of a multiplicative model between PRS313 and each risk factor. Variation in projected absolute lifetime risk of breast cancer associated with classical risk factors was greater for women with higher genetic risk (PRS313 and family history) and, on average, 17.5% higher in the highest vs lowest deciles of genetic risk. These findings have implications for risk prevention for women at increased risk of breast cancer. ispartof: JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE vol:113 issue:3 pages:329-337 ispartof: location:United States status: published