Common variation in a long non-coding RNA gene modulates variation of circulating TGF-ß2 levels in metastatic colorectal cancer patients (Alliance).

BACKGROUND: Herein, we report results from a genome-wide study conducted to identify protein quantitative trait loci (pQTL) for circulating angiogenic and inflammatory protein markers in patients with metastatic colorectal cancer (mCRC). The study was conducted using genotype, protein marker, and baseline clinical and demographic data from CALGB/SWOG 80405 (Alliance), a randomized phase III study designed to assess outcomes of adding VEGF or EGFR inhibitors to systemic chemotherapy in mCRC patients. Germline DNA derived from blood was genotyped on whole-genome array platforms. The abundance of protein markers was quantified using a multiplex enzyme-linked immunosorbent assay from plasma derived from peripheral venous blood collected at baseline. A robust rank-based method was used to assess the statistical significance of each variant and protein pair against a strict genome-wide level. A given pQTL was tested for validation in two external datasets of prostate (CALGB 90401) and pancreatic cancer (CALGB 80303) patients. Bioinformatics analyses were conducted to further establish biological bases for these findings. RESULTS: The final analysis was carried out based on data from 540,021 common typed genetic variants and 23 protein markers from 869 genetically estimated European patients with mCRC. Correcting for multiple testing, the analysis discovered a novel cis-pQTL in LINC02869, a long non-coding RNA gene, for circulating TGF-ß2 levels (rs11118119; AAF = 0.11; P-value < 1.4e-14). This finding was validated in a cohort of 538 prostate cancer patients from CALGB 90401 (AAF = 0.10, P-value < 3.3e-25). The analysis also validated a cis-pQTL we had previously reported for VEGF-A in advanced pancreatic cancer, and additionally identified trans-pQTLs for VEGF-R3, and cis-pQTLs for CD73. CONCLUSIONS: This study has provided evidence of a novel cis germline genetic variant that regulates circulating TGF-ß2 levels in plasma of patients with advanced mCRC and prostate cancer. Moreover, the validation of previously identified pQTLs for VEGF-A, CD73, and VEGF-R3, potentiates the validity of these associations.

Venous Thromboembolism in Peritoneal Mesothelioma: Uncovering the Hidden Risk.

INTRODUCTION: Venous thromboembolism (VTE) is a common complication in patients with abdominal malignancies. Despite known associations between pleural mesothelioma and increased VTE risk, the characteristics of VTE in patients with peritoneal mesothelioma (PeM) remain undescribed. METHODS: Patients treated for PeM were retrospectively identified from our institutional database. The frequency of VTE was assessed and logistic regression modeling was employed to assess VTE risk factors. The association between VTE and overall survival was also ascertained. Recommended thromboprophylaxis for patients who underwent surgery at our institution comprised a single preoperative dose of prophylactic anticoagulation, followed by daily dosing for four weeks postoperatively. RESULTS: Among 120 PeM patients, 26 (21.7%) experienced VTE, including 19/91 (20.9%) surgical patients, 4/23 (17.4%) patients who received systemic therapy, and 3/6 (50%) patients who underwent observation (p = 0.21). Most events were symptomatic (n = 16, 62%) and were attributable to pulmonary emboli (n = 16, 62%). The 90-day postoperative VTE rate was 4.4% (4/91), including 1 of 60 patients who underwent index surgical intervention at our institution and 3 patients with surgery elsewhere. A low serum albumin concentration was associated with VTE in non-surgical patients (odds ratio 0.12, confidence interval [CI] 0.02-0.72; p = 0.03). No significant difference in overall survival was observed between patients with and without VTE (median 46.0 months [CI 24.9-67.0] vs. 55.0 months [CI 27.5-82.5]; hazard ratio 0.98 [CI 0.54-1.81], p = 0.98). CONCLUSIONS: A high risk of VTE was observed in PeM patients, warranting suspicion throughout the disease trajectory. Postoperative VTE rates were within acceptable limits with 4-week thromboprophylaxis.

Mesothelioma in situ of the peritoneum: report of three cases and review of the literature.

AIM: Diagnosis of mesothelioma in situ (MIS) is historically controversial and, until recently, specific features defining the entity have not been well characterized. Most reported cases of MIS occurred in the pleura; peritoneal MIS is very rare. This study investigates the morphologic features and results of ancillary testing in peritoneal MIS. METHODS: We present three patients with peritoneal MIS, as defined by a single layer of mesothelial cells with loss of nuclear BRCA-1-associated protein-1 (BAP1) immunostaining and without evidence of invasive tumour by microscopic evaluation, imaging, or direct examination of the peritoneum. Histology and immunostains were reviewed by three expert thoracic pathologists with multidisciplinary input. Next-generation sequencing (NGS) was performed in all three cases. A literature review was conducted to characterize this rare precursor lesion. RESULTS: BAP1 was lost in all three lesions, while methylthioadenosine phosphorylase (MTAP) was retained in two (not performed in the third). NGS revealed BAP1 pathogenic alterations in all three cases as well as mutations of SMO, ERCC3, TET2, and U2AF1. Progression to invasive mesothelioma occurred in one patient at 13 months postdiagnosis (case 1). One patient was diagnosed at age 24 and was later found to harbour a BAP1 germline mutation (case 3). CONCLUSION: This work describes the histologic features and clinicopathologic characteristics of peritoneal MIS in three cases, highlights BAP1 somatic and germline mutations in peritoneal MIS, and strengthens the importance of ancillary studies (including immunohistochemical and molecular studies) in the diagnosis of MIS.

Patient-centered outcomes in the POLO study of active maintenance olaparib for germline BRCA-mutated metastatic pancreatic cancer.

BACKGROUND: The phase 3 POLO study demonstrated a significant progression-free survival (PFS) benefit and preserved health-related quality of life (HRQOL) for active maintenance treatment with olaparib vs placebo in patients with metastatic pancreatic cancer and a germline BRCA mutation. Here, we present a post hoc analysis of the patient-centered outcomes: time without significant symptoms of disease progression or toxicity (TWiST) and quality-adjusted TWiST (Q-TWiST). METHODS: Patients were randomized 3:2 to maintenance olaparib (300 mg tablets twice daily) or placebo. Overall survival time was divided into TWiST, toxicity (TOX; time before disease progression with significant symptoms of toxicity), and relapse (REL; time after disease progression until death or censoring). Q-TWiST was the sum of TWiST, TOX, and REL, each weighted by HRQOL utility scores during the relevant health-state period. A base-case and three sensitivity analyses were performed using differing definitions of TOX. RESULTS: In total, 154 patients were randomized (olaparib, n = 92; placebo, n = 62). TWiST was significantly longer for olaparib than placebo in the base-case analysis (14.6 vs 7.1 months; 95% CI, 2.9-12.0; p = .001) and all sensitivity analyses. No statistically significant benefit for Q-TWiST was observed in the base-case analysis (18.4 vs 15.9 months; 95% CI, -1.1 to 6.1; p = .171) or the sensitivity analyses. CONCLUSION: These results support the previous findings that maintenance olaparib significantly improves PFS relative to placebo without compromising HRQOL and demonstrate that the clinically meaningful benefits of olaparib persist even when symptoms of toxicity are considered.

Surgical phenotype of patients with peritoneal mesothelioma and a germline mutation.

BACKGROUND: This study aimed to investigate if peritoneal mesothelioma (PM) patients with germline mutations (GM) have distinct surgical characteristics when compared to those without GM. METHODS: PM patients were selected from an ongoing prospective study that conducts germline testing of 82 susceptibility genes. Germline status was correlated with surgical data obtained from a prospectively collected database using univariate, multivariate, and receiver operating characteristic (ROC) analyses. RESULTS: Out of 88 PM patients enrolled between 2009 and 2019, 18 GMs (20.5%) were identified in BRCA1-associated protein 1 (BAP1) (n = 11, 12.5% of all patients), SDHA (n = 2) and WT1, CDKN2A, CHEK2, ATM, and BRCA2 (n = 1 patient each). Surgical procedures were performed in 71 patients, the most common of which were cytoreductive surgeries with hyperthermic intraperitoneal chemotherapy (n = 61). Patients with GM presented with a higher prevalence of other prior cancers (61.1% vs. 31.4%, p = .02) and lower platelet count (251 [160-413] vs. 367 [196-780] K/µL, p = .005) compared to those without GM (n = 70). Survival outcomes did not differ significantly between the groups. Patients with BAP1 GMs were more likely to develop bicavitary disease and to present with lower platelet count and mitotic count score, and higher peritoneal cancer index (PCI, all p ≤ .04) compared with those without GM. On ROC analysis, the combination of PCI, platelet count and mitotic score yielded an area under the curve of 0.96 (95% CI, 0.91-1.0) for BAP1 GM detection among operated PM patients. CONCLUSION: Higher intraoperative tumor burden and lower platelet count and mitotic score are suggestive of BAP1 GMs in surgical PM patients and should prompt germline testing.

Management of Patients With Pancreatic Cancer Using the "Right Track" Model.

Pancreatic cancer is one of the few cancer types in the US with incidence and death rates continuing to rise. As the disease threatens to become the second leading cause of cancer-related deaths in the country, it is imperative to review the best practices currently available to extend and improve patient lives. To provide a roadmap for healthcare professionals detecting, diagnosing, and caring for patients with pancreatic cancer as a supplement to national guidelines focused on recommended treatment regimens, the Pancreatic Cancer Action Network (PanCAN)'s Scientific and Medical Affairs staff and expert Scientific and Medical Advisory Board have created a series of position statements. The statements are based upon scientific evidence and clinical observations published in the literature and research conducted through PanCAN's internal programs and initiatives. This review summarizes the rationale and sources for these position statements related to diagnosis, treatment, and care for pancreatic cancer and provides information about resources to make these recommendations accessible to patients and their medical teams. Pancreatic cancer is a complex and extremely challenging disease. Beyond treatment recommendations outlined in national guidelines, steps can be taken to help patients feel better and live longer. Under the framework of the "Right Track" model-right team, right tests, right treatments, data sharing-PanCAN's position statements can provide supplementary guidance to healthcare professionals for the short- and long-term management of patients with the disease.

Anetumab ravtansine versus vinorelbine in patients with relapsed, mesothelin-positive malignant pleural mesothelioma (ARCS-M): a randomised, open-label phase 2 trial.

BACKGROUND: Few treatment options exist for second-line treatment of malignant pleural mesothelioma. We aimed to assess the antibody-drug conjugate anetumab ravtansine versus vinorelbine in patients with unresectable locally advanced or metastatic disease overexpressing mesothelin who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. METHODS: In this phase 2, randomised, open-label study, done at 76 hospitals in 14 countries, we enrolled adults (aged ≥18 years) with unresectable locally advanced or metastatic malignant pleural mesothelioma, an Eastern Cooperative Oncology Group performance status of 0-1, and who had progressed on first-line platinum-pemetrexed chemotherapy with or without bevacizumab. Participants were prospectively screened for mesothelin overexpression (defined as 2+ or 3+ mesothelin membrane staining intensity on at least 30% of viable tumour cells by immunohistochemistry) and were randomly assigned (2:1), using an interactive voice and web response system provided by the sponsor, to receive intravenous anetumab ravtansine (6·5 mg/kg on day 1 of each 21-day cycle) or intravenous vinorelbine (30 mg/m2 once every week) until progression, toxicity, or death. The primary endpoint was progression-free survival according to blinded central radiology review, assessed in the intention-to-treat population, with safety assessed in all participants who received any study treatment. This study is registered with ClinicalTrials.gov, NCT02610140, and is now completed. FINDINGS: Between Dec 3, 2015, and May 31, 2017, 589 patients were enrolled and 248 mesothelin-overexpressing patients were randomly allocated to the two treatment groups (166 patients were randomly assigned to receive anetumab ravtansine and 82 patients were randomly assigned to receive vinorelbine). 105 (63%) of 166 patients treated with anetumab ravtansine (median follow-up 4·0 months [IQR 1·4-5·5]) versus 43 (52%) of 82 patients treated with vinorelbine (3·9 months [1·4-5·4]) had disease progression or died (median progression-free survival 4·3 months [95% CI 4·1-5·2] vs 4·5 months [4·1-5·8]; hazard ratio 1·22 [0·85-1·74]; log-rank p=0·86). The most common grade 3 or worse adverse events were neutropenia (one [1%] of 163 patients for anetumab ravtansine vs 28 [39%] of 72 patients for vinorelbine), pneumonia (seven [4%] vs five [7%]), neutrophil count decrease (two [1%] vs 12 [17%]), and dyspnoea (nine [6%] vs three [4%]). Serious drug-related treatment-emergent adverse events occurred in 12 (7%) patients treated with anetumab ravtansine and 11 (15%) patients treated with vinorelbine. Ten (6%) treatment-emergent deaths occurred with anetumab ravtansine: pneumonia (three [2%]), dyspnoea (two [1%]), sepsis (two [1%]), atrial fibrillation (one [1%]), physical deterioration (one [1%]), hepatic failure (one [1%]), mesothelioma (one [1%]), and renal failure (one [1%]; one patient had 3 events). One (1%) treatment-emergent death occurred in the vinorelbine group (pneumonia). INTERPRETATION: Anetumab ravtansine showed a manageable safety profile and was not superior to vinorelbine. Further studies are needed to define active treatments in relapsed mesothelin-expressing malignant pleural mesothelioma. FUNDING: Bayer Healthcare Pharmaceuticals.

Genome-wide association studies of survival in 1520 cancer patients treated with bevacizumab-containing regimens.

Germline variants might predict cancer progression. Bevacizumab improves overall survival (OS) in patients with advanced cancers. No biomarkers are available to identify patients that benefit from bevacizumab. A meta-analysis of genome-wide association studies (GWAS) was conducted in 1,520 patients from Phase III trials (CALGB 80303, 40503, 80405 and ICON7), where bevacizumab was randomized to treatment without bevacizumab. We aimed to identify genes and single nucleotide polymorphisms (SNPs) associated with survival independently of bevacizumab treatment or through interaction with bevacizumab. A cause-specific Cox model was used to test the SNP-OS association in both arms combined (prognostic), and the effect of SNPs-bevacizumab interaction on OS (predictive) in each study. The SNP effects across studies were combined using inverse variance. Findings were tested for replication in advanced colorectal and ovarian cancer patients from The Cancer Genome Atlas (TGCA). In the GWAS meta-analysis, patients with rs680949 in PRUNE2 experienced shorter OS compared to patients without it (P = 1.02 × 10-7 , hazard ratio [HR] = 1.57, 95% confidence interval [CI] 1.33-1.86), as well as in TCGA (P = .0219, HR = 1.58, 95% CI 1.07-2.35). In the GWAS meta-analysis, patients with rs16852804 in BARD1 experienced shorter OS compared to patients without it (P = 1.40 × 10-5 , HR = 1.51, 95% CI 1.25-1.82) as well as in TCGA (P = 1.39 × 10-4 , HR = 3.09, 95% CI 1.73-5.51). Patients with rs3795897 in AGAP1 experienced shorter OS in the bevacizumab arm compared to the nonbevacizumab arm (P = 1.43 × 10-5 ). The largest GWAS meta-analysis of bevacizumab treated patients identified PRUNE2 and BARD1 (tumor suppressor genes) as prognostic genes of colorectal and ovarian cancer, respectively, and AGAP1 as a potentially predictive gene that interacts with bevacizumab with respect to patient survival.

Plasma levels of angiopoietin-2, VEGF-A, and VCAM-1 as markers of bevacizumab-induced hypertension: CALGB 80303 and 90401 (Alliance).

Hypertension is a common toxicity induced by bevacizumab and other antiangiogenic drugs. There are no biomarkers to predict the risk of bevacizumab-induced hypertension. This study aimed to identify plasma proteins related to the function of the vasculature to predict the risk of severe bevacizumab-induced hypertension. Using pretreated plasma samples from 398 bevacizumab-treated patients in two clinical trials (CALGB 80303 and 90401), the levels of 17 proteins were measured via ELISA. The association between proteins and grade 3 bevacizumab-induced hypertension was performed by calculating the odds ratio (OR) from logistic regression adjusting for age, sex, and clinical trial. Using the optimal cut-point of each protein, sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) for hypertension were estimated. Five proteins showed no difference in levels between clinical trials and were used for analyses. Lower levels of angiopoietin-2 (p = 0.0013, OR 3.41, 95% CI 1.67-7.55), VEGF-A (p = 0.0008, OR 4.25, 95% CI 1.93-10.72), and VCAM-1 (p = 0.0067, OR 2.68, 95% CI 1.34-5.63) were associated with an increased risk of grade 3 hypertension. The multivariable model suggests independent effects of angiopoietin-2 (p = 0.0111, OR 2.71, 95% CI 1.29-6.10), VEGF-A (p = 0.0051, OR 3.66, 95% CI 1.54-9.73), and VCAM-1 (p = 0.0308, OR 2.27, 95% CI 1.10-4.92). The presence of low levels of 2-3 proteins had an OR of 10.06 (95% CI 3.92-34.18, p = 1.80 × 10-5) for the risk of hypertension, with sensitivity of 89.7%, specificity of 53.5%, PPV of 17.3%, and NPV of 97.9%. This is the first study providing evidence of plasma proteins with potential value to predict patients at risk of developing bevacizumab-induced hypertension.Clinical trial registration: ClinicalTrials.gov Identifier: NCT00088894 (CALGB 80303); and NCT00110214 (CALGB 90401).

Bevacizumab-induced hypertension and proteinuria: a genome-wide study of more than 1000 patients.

BACKGROUND: Hypertension and proteinuria are common bevacizumab-induced toxicities. No validated biomarkers are available for identifying patients at risk of these toxicities. METHODS: A genome-wide association study (GWAS) meta-analysis was performed in 1039 bevacizumab-treated patients of European ancestry in four clinical trials (CALGB 40502, 40503, 80303, 90401). Grade ≥2 hypertension and proteinuria were recorded (CTCAE v.3.0). Single-nucleotide polymorphism (SNP)-toxicity associations were determined using a cause-specific Cox model adjusting for age and sex. RESULTS: The most significant SNP associated with hypertension with concordant effect in three out of the four studies (p-value <0.05 for each study) was rs6770663 (A > G) in KCNAB1, with the G allele increasing the risk of hypertension (p-value = 4.16 × 10-6). The effect of the G allele was replicated in ECOG-ACRIN E5103 in 582 patients (p-value = 0.005). The meta-analysis of all five studies for rs6770663 led to p-value = 7.73 × 10-8, close to genome-wide significance. The most significant SNP associated with proteinuria was rs339947 (C > A, between DNAH5 and TRIO), with the A allele increasing the risk of proteinuria (p-value = 1.58 × 10-7). CONCLUSIONS: The results from the largest study of bevacizumab toxicity provide new markers of drug safety for further evaluations. SNP in KCNAB1 validated in an independent dataset provides evidence toward its clinical applicability to predict bevacizumab-induced hypertension. ClinicalTrials.gov Identifier: NCT00785291 (CALGB 40502); NCT00601900 (CALGB 40503); NCT00088894 (CALGB 80303) and NCT00110214 (CALGB 90401).

Marital Status, Living Arrangement, and Cancer Recurrence and Survival in Patients with Stage III Colon Cancer: Findings from CALGB 89803 (Alliance).

BACKGROUND: Limited and conflicting findings have been reported regarding the association between social support and colorectal cancer (CRC) outcomes. We sought to assess the influences of marital status and living arrangement on survival outcomes among patients with stage III colon cancer. PATIENTS AND METHODS: We conducted a secondary analysis of 1082 patients with stage III colon cancer prospectively followed in the CALGB 89803 randomized adjuvant chemotherapy trial. Marital status and living arrangement were both self-reported at the time of enrollment as, respectively, married, divorced, separated, widowed, or never-married, and living alone, with a spouse or partner, with other family, in a nursing home, or other. RESULTS: Over a median follow-up of 7.6 years, divorced/separated/widowed patients experienced worse outcomes relative to those married regarding disease free-survival (DFS) (hazards ratio (HR), 1.44 (95% CI, 1.14-1.81); P =.002), recurrence-free survival (RFS) (HR, 1.35 (95% CI, 1.05-1.73); P = .02), and overall survival (OS) (HR, 1.40 (95% CI, 1.08-1.82); P =.01); outcomes were not significantly different for never-married patients. Compared to patients living with a spouse/partner, those living with other family experienced a DFS of 1.47 (95% CI, 1.02-2.11; P = .04), RFS of 1.34 (95% CI, 0.91-1.98; P = .14), and OS of 1.50 (95% CI, 1.00-2.25; P =.05); patients living alone did not experience significantly different outcomes. CONCLUSION: Among patients with stage III colon cancer who received uniform treatment and follow-up within a nationwide randomized clinical trial, being divorced/separated/widowed and living with other family were significantly associated with greater colon cancer mortality. Interventions enhancing social support services may be clinically relevant for this patient population. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT00003835.

Maintenance Olaparib for Germline BRCA-Mutated Metastatic Pancreatic Cancer.

BACKGROUND: Patients with a germline BRCA1 or BRCA2 mutation make up a small subgroup of those with metastatic pancreatic cancer. The poly(adenosine diphosphate-ribose) polymerase (PARP) inhibitor olaparib has had antitumor activity in this population. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 3 trial to evaluate the efficacy of olaparib as maintenance therapy in patients who had a germline BRCA1 or BRCA2 mutation and metastatic pancreatic cancer and disease that had not progressed during first-line platinum-based chemotherapy. Patients were randomly assigned, in a 3:2 ratio, to receive maintenance olaparib tablets (300 mg twice daily) or placebo. The primary end point was progression-free survival, which was assessed by blinded independent central review. RESULTS: Of the 3315 patients who underwent screening, 154 underwent randomization and were assigned to a trial intervention (92 to receive olaparib and 62 to receive placebo). The median progression-free survival was significantly longer in the olaparib group than in the placebo group (7.4 months vs. 3.8 months; hazard ratio for disease progression or death, 0.53; 95% confidence interval [CI], 0.35 to 0.82; P = 0.004). An interim analysis of overall survival, at a data maturity of 46%, showed no difference between the olaparib and placebo groups (median, 18.9 months vs. 18.1 months; hazard ratio for death, 0.91; 95% CI, 0.56 to 1.46; P = 0.68). There was no significant between-group difference in health-related quality of life, as indicated by the overall change from baseline in the global quality-of-life score (on a 100-point scale, with higher scores indicating better quality of life) based on the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (between-group difference, -2.47 points; 95% CI, -7.27 to 2.33). The incidence of grade 3 or higher adverse events was 40% in the olaparib group and 23% in the placebo group (between-group difference, 16 percentage points; 95% CI, -0.02 to 31); 5% and 2% of the patients, respectively, discontinued the trial intervention because of an adverse event. CONCLUSIONS: Among patients with a germline BRCA mutation and metastatic pancreatic cancer, progression-free survival was longer with maintenance olaparib than with placebo. (Funded by AstraZeneca and others; POLO ClinicalTrials.gov number, NCT02184195.).

Phase II Prospective, Open-Label Randomized Controlled Trial Comparing Standard of Care Chemotherapy With and Without Sequential Cytoreductive Interventions for Patients with Oligometastatic Foregut Adenocarcinoma and Undetectable Circulating Tumor Deoxyribose Nucleic Acid (ctDNA) Levels.

BACKGROUND: Metastatic adenocarcinomas of foregut origin are aggressive and have limited treatment options, poor quality of life, and a dismal prognosis. A subset of such patients with limited metastatic disease might have favorable outcomes with locoregional metastasis-directed therapies. This study investigates the role of sequential cytoreductive interventions in addition to the standard of care chemotherapy in patients with oligometastatic foregut adenocarcinoma. METHODS: This is a single-center, phase II, open-label randomized clinical trial. Eligible patients include adults with synchronous or metachronous oligometastatic (metastasis limited to two sites and amenable for curative/ablative treatment) adenocarcinoma of the foregut without progression after induction chemotherapy and having undetectable ctDNA. These patients will undergo induction chemotherapy and will then be randomized (1:1) to either sequential curative intervention followed by maintenance chemotherapy versus routine continued chemotherapy. The primary endpoint is progression-free survival (PFS), and a total of 48 patients will be enrolled to detect an improvement in the median PFS in the intervention arm with a hazard ratio (HR) of 0.5 with 80% power and a one-sided alpha of 0.1. Secondary endpoints include disease-free survival (DFS) in the intervention arm, overall survival (OS), ctDNA conversion rate pre/post-induction chemotherapy, ctDNA PFS, PFS2, adverse events, quality of life, and financial toxicity. DISCUSSION: This is the first randomized study that aims to prospectively evaluate the efficacy and safety of surgical/ablative interventions in patients with ctDNA-negative oligometastatic adenocarcinoma of foregut origin post-induction chemotherapy. The results from this study will likely develop pertinent, timely, and relevant knowledge in oncology.

Inherited predisposition to malignant mesothelioma and overall survival following platinum chemotherapy.

Survival from malignant mesothelioma, particularly pleural mesothelioma, is very poor. For patients with breast, ovarian, or prostate cancers, overall survival is associated with increased sensitivity to platinum chemotherapy due to loss-of-function mutations in DNA repair genes. The goal of this project was to evaluate, in patients with malignant mesothelioma, the relationship between inherited loss-of-function mutations in DNA repair and other tumor suppressor genes and overall survival following platinum chemotherapy. Patients with histologically confirmed malignant mesothelioma were evaluated for inherited mutations in tumor suppressor genes. Survival was evaluated with respect to genotype and site of mesothelioma. Among 385 patients treated with platinum chemotherapy, median overall survival was significantly longer for patients with loss-of-function mutations in any of the targeted genes compared with patients with no such mutation (P = 0.0006). The effect of genotype was highly significant for patients with pleural mesothelioma (median survival 7.9 y versus 2.4 y, P = 0.0012), but not for patients with peritoneal mesothelioma (median survival 8.2 y versus 5.4 y, P = 0.47). Effect of patient genotype on overall survival, measured at 3 y, remained independently significant after adjusting for gender and age at diagnosis, two other known prognostic factors. Patients with pleural mesothelioma with inherited mutations in DNA repair and other tumor suppressor genes appear to particularly benefit from platinum chemotherapy compared with patients without inherited mutations. These patients may also benefit from other DNA repair targeted therapies such as poly-ADP ribose polymerase (PARP) inhibitors.

Heterogeneity in PD-L1 expression in malignant peritoneal mesothelioma with systemic or intraperitoneal chemotherapy.

Programmed death-ligand 1 (PD-L1) expression has been described in patients with malignant peritoneal mesothelioma (MPM), but treatment strategies utilising immune checkpoint inhibition are yet to be defined. Here, we examine levels of PD-L1 expression in MPM patients treated with systemic and/or intraperitoneal chemotherapy using tissue from patient tumour biopsies or resections at multiple time points. We found the mean PD-L1 expression was higher in those with a germline mutation and/or those with a higher somatic mutation burden. Moreover, PD-L1 expression was lower in patients who had received prior chemotherapy as compared to the treatment-naive cohort. Twenty patients who received chemotherapy, either systemic and/or peritoneal, between PD-L1 measurements showed marked heterogeneity. Six (30%) patients demonstrated upregulation of PD-L1, while eight (40%) demonstrated downregulation. Heterogeneity in PD-L1 expression in MPM before and after cytotoxic therapies may present an additional consideration when initiating immune checkpoint inhibition in this rare and challenging disease.

Malignant peritoneal mesothelioma: prognostic significance of clinical and pathologic parameters and validation of a nuclear-grading system in a multi-institutional series of 225 cases.

Malignant peritoneal mesothelioma historically carried a grim prognosis, but outcomes have improved substantially in recent decades. The prognostic significance of clinical, morphologic, and immunophenotypic features remains ill-defined. This multi-institutional cohort comprises 225 malignant peritoneal mesotheliomas, which were assessed for 21 clinical, morphologic, and immunohistochemical parameters. For epithelioid mesotheliomas, combining nuclear pleomorphism and mitotic index yielded a composite nuclear grade, using a previously standardized grading system. Correlation of clinical, morphologic, and immunohistochemical parameters with overall and disease-free survival was examined by univariate and multivariate analyses. On univariate analysis, longer overall survival was significantly associated with diagnosis after 2000 (P = 0.0001), age <60 years (P = 0.0001), ECOG performance status 0 or 1 (P = 0.01), absence of radiographic lymph-node metastasis (P = 0.04), cytoreduction surgery (P < 0.0001), hyperthermic intraperitoneal chemotherapy (P = 0.0001), peritoneal carcinomatosis index <27 (P = 0.01), absence of necrosis (P = 0.007), and epithelioid histotype (P < 0.0001). Among epithelioid malignant mesotheliomas only, longer overall survival was further associated with female sex (P = 0.03), tubulopapillary architecture (P = 0.005), low nuclear pleomorphism (P < 0.0001), low mitotic index (P = 0.0007), and low composite nuclear grade (P < 0.0001). On multivariate analyses, the low composite nuclear grade was independently associated with longer overall and disease-free survival (P < 0.0001). Our data further clarify the interactions of clinical and pathologic features in peritoneal mesothelioma prognosis and validate the prognostic significance of a standardized nuclear-grading system in epithelioid malignant mesothelioma of the peritoneum.

Association of tumour mutational burden with outcomes in patients with advanced solid tumours treated with pembrolizumab: prospective biomarker analysis of the multicohort, open-label, phase 2 KEYNOTE-158 study.

BACKGROUND: Tumour mutational burden (TMB) has been retrospectively correlated with response to immune checkpoint blockade. We prospectively explored the association of high tissue TMB (tTMB-high) with outcomes in ten tumour-type-specific cohorts from the phase 2 KEYNOTE-158 study, which assessed the anti-PD-1 monoclonal antibody pembrolizumab in patients with selected, previously treated, advanced solid tumours. METHODS: In the multi-cohort, open-label, non-randomised, phase 2 KEYNOTE-158 study, patients were enrolled from 81 academic facilities and community-based institutions across 21 countries in Africa, the Americas, Asia, and Europe. Eligible patients were aged 18 years or older, had a histologically or cytologically confirmed advanced (ie, unresectable or metastatic, or both) incurable solid tumour (eligible tumour types were anal, biliary, cervical, endometrial, mesothelioma, neuroendocrine, salivary, small-cell lung, thyroid, and vulvar), progression on or intolerance to one or more lines of standard therapy, had measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1) assessed by independent central radiological review, Eastern Cooperative Oncology Group performance status of 0 or 1, life expectancy of at least 3 months, adequate organ function, and a tumour sample for biomarker analysis. Participants were given pembrolizumab 200 mg intravenously every 3 weeks for up to 35 cycles. Tissue TMB (tTMB) was assessed in formalin-fixed paraffin-embedded tumour samples using the FoundationOne CDx assay (Foundation Medicine, Cambridge, MA, USA). The prespecified definition of tTMB-high status was at least 10 mutations per megabase. The primary endpoint was the proportion of patients with an objective response (complete or partial response) as per Response Evaluation Criteria in Solid Tumours (version 1.1) by independent central review. This prespecified analysis assessed the association between antitumour activity and tTMB in treated patients with evaluable tTMB data. Efficacy was assessed in all participants who received at least one dose of pembrolizumab, had evaluable tTMB data, and were enrolled at least 26 weeks before data cutoff (June 27, 2019), and safety was assessed in all participants who received at least one dose of pembrolizumab and had tTMB-high status. KEYNOTE-158 is registered at ClinicalTrials.gov, NCT02628067, and is ongoing. FINDINGS: Between Jan 15, 2016, and June 25, 2019, 1073 patients were enrolled. 1066 participants were treated as of data cutoff (June 27, 2019), of whom 805 (76%) were evaluable for TMB, and 105 (13%) of 805 had tTMB-high status and were assessed for safety. 1050 (98%) of 1066 patients enrolled by at least 26 weeks before data cutoff, of whom 790 (75%) were evaluable for TMB and included in efficacy analyses. 102 (13%) of these 790 patients had tTMB-high status (≥10 mutations per megabase), and 688 (87%) patients had non-tTMB-high status (<10 mutations per megabase). Median study follow-up was 37·1 months (IQR 35·0-38·3). Objective responses were observed in 30 (29%; 95% CI 21-39) of 102 patients in the tTMB-high group and 43 (6%; 5-8) of 688 in the non-tTMB-high group. 11 (10%) of 105 patients had treatment-related serious adverse events. 16 (15%) participants had a grade 3-5 treatment-related adverse event, of which colitis was the only such adverse event that occurred in more than one patient (n=2). One patient had fatal pneumonia that was assessed by the investigator to be treatment related. INTERPRETATION: tTMB-high status identifies a subgroup of patients who could have a robust tumour response to pembrolizumab monotherapy. tTMB could be a novel and useful predictive biomarker for response to pembrolizumab monotherapy in patients with previously treated recurrent or metastatic advanced solid tumours. FUNDING: Merck Sharp & Dohme Corp, a subsidiary of Merck & Co, Inc.

A phase Ib study of GSK3052230, an FGF ligand trap in combination with pemetrexed and cisplatin in patients with malignant pleural mesothelioma.

Background Fibroblast growth factors (FGFs) have a fundamental role in cancer. Sequestering FGFs with GSK3052230 (FP-1039) blocks their ability to activate FGFRs while avoiding toxicities associated with small molecule inhibitors of FGFR, including hyperphosphatemia and retinal, nail, and skin toxicities. Methods A multicenter, open-label, phase Ib study evaluated weekly GSK3052230 added to pemetrexed/cisplatin in patients with treatment-naive, unresectable malignant pleural mesothelioma. Doses were escalated according to a 3 + 3 design, followed by cohort expansion at the maximum tolerated dose (MTD). Endpoints included safety, overall response rate, progression-free survival, and pharmacokinetics. Results 36 patients were dosed at 10, 15, and 20 mg/kg doses of GSK3052230. Three dose-limiting toxicities were observed at 20 mg/kg and one at 15 mg/kg. The MTD was defined as 15 mg/kg and used for cohort expansion. The most common treatment-related adverse events (AEs) were nausea (56%), decreased appetite (36%), infusion reactions (36%), decreased neutrophil counts (36%), and fatigue (33%). The confirmed ORR was 39% (95% CI: 23.1-56.5) (14/36 PRs) and 47% had stable disease (17/36), giving a disease control rate of 86%. At 15 mg/kg GSK3052230 (n = 25), the ORR was 44% (95% CI: 24.4-65.1), and the median PFS was 7.4 months (95% CI: 6.7-13.4). Four patients had disease control for over 1 year, and three were still ongoing. Conclusion At 15 mg/kg weekly, GSK3052230 was well tolerated in combination with pemetrexed/cisplatin and durable responses were observed. Importantly, AEs associated with small molecule inhibitors of FGFR were not observed, as predicted by the unique mechanism of action of this drug.

A UGT1A1 genotype-guided dosing study of modified FOLFIRINOX in previously untreated patients with advanced gastrointestinal malignancies.

BACKGROUND: FOLFIRINOX (5-fluorouracil [5-FU], leucovorin, irinotecan, oxaliplatin) is an effective but toxic therapy for pancreatic cancer. UGT1A1 (UDP glucuronosyltransferase 1A1) eliminates the active metabolite of irinotecan. Polymorphisms reduce UGT1A1 activity, leading to toxicity. The primary objective was to determine the dose-limiting toxicity (DLT) rate in cycle 1 of modified FOLFIRINOX (mFOLFIRINOX) using genotype-guided dosing of irinotecan for the most common UGT1A1 genotypes (*1/*1, *1/*28) in advanced gastrointestinal malignancies, with expansion in pancreatic and biliary tract cancers. METHOD: 5-FU (2400 mg/m2 over 46 hours), leucovorin (400 mg/m2 ), oxaliplatin (85 mg/m2 ), and irinotecan were given every 14 days. Irinotecan doses of 180, 135, and 90 mg/m2 were administered for UGT1A1 genotypes *1/*1, *1/*28, and *28/*28, respectively. Prophylactic pegfilgrastim was omitted in cycle 1 for cohort 1 (tolerability by genotype), but was given in cohort 2 (tolerability by tumor type). Doses were tolerable if the upper limit of a 2-sided 80% confidence interval for DLT rate was ≤33%. RESULTS: In cohort 1, DLTs (most commonly febrile neutropenia, fatigue, diarrhea) occurred in 2/15 (13%), 3/16 (19%), and 4/10 (40%) patients with *1/*1, *1/*28, and *28/*28 genotypes, respectively. In cohort 2, 6/19 (32%) pancreatic and 4/19 (21%) biliary tract cancer patients experienced DLTs (most commonly fatigue, diarrhea, nausea/vomiting). In cohort 2, upper confidence limits of DLT rates exceeded 33%. Response rates were 38% in pancreatic and 21% in biliary tract cancers. CONCLUSION: On the basis of our prespecified criteria, tolerability of UGT1A1 genotype-guided mFOLFIRINOX was not established in pancreatic and biliary tract cancers. However, this regimen was effective.

An initial genetic analysis of gemcitabine-induced high-grade neutropenia in pancreatic cancer patients in CALGB 80303 (Alliance).

OBJECTIVES: One of the standard of care regimens for advanced pancreatic cancer is gemcitabine-based chemotherapy. The efficacy of gemcitabine is limited by dose-limiting hematologic toxicities especially neutropenia. Uncovering the variability of these toxicities attributed to germline DNA variation is of great importance. PATIENTS AND METHODS: CALGB 80303 was a randomized study in advanced pancreatic cancer patients treated with gemcitabine with or without bevacizumab. The study protocol included genotyping of genes of gemcitabine disposition (CDA, DCTD, SLC29A1, SLC28A1, and SLC29A2), as well as a genome-wide analysis. The clinical phenotype was time to early high-grade neutropenia event accounting for progression or death or other treatment-terminating adverse events as competing for informative events. The inference was carried out on the basis of the association between genotype and cause-specific hazard of a neutropenic event. RESULTS: The primary analyses were carried out on the basis of 294 genetically estimated European pancreatic cancer patients. For CDA rs2072671 (A>C), AC and CC patients had a lower risk of neutropenia than AA patients (P=0.01, hazard ratio: 0.61, 95% confidence interval: 0.41-0.89). For SLC28A1 rs3825876 (G>A), AA patients have a higher risk of neutropenia than GA and GG patients (P=0.02, hazard ratio: 1.51, 95% confidence interval: 1.06-2.16). CDA rs2072671 was associated with increased mRNA expression in whole blood in three studies (P=2.7e-14, 6.61e-62, and 9.70e-65). In the genome-wide analysis, variants in TGFB2 were among the top hits (lowest P=1.62e-06) but had no effect in luciferase assays. CONCLUSION: This is the first genetic analysis of gemcitabine-induced neutropenia using a competing risk model in a prospective randomized clinical study has proposed a potentially novel mechanism of the protective effect of the CDA rs2072671 variant. Further confirmation is needed.