High Protein Oral Nutritional Supplements Enable the Majority of Cancer Patients to Meet Protein Intake Recommendations during Systemic Anti-Cancer Treatment:A Randomised Controlled Parallel-Group Study

ESPEN guidelines recommend a minimum protein intake of 1.0 g/kg body weight (BW) per day to maintain or restore lean body mass in patients with cancer. During anti-cancer treatment, optimal protein intake is difficult to achieve. We investigated whether a high-protein, low-volume oral nutritional supplement (ONS) supports patients in meeting recommendations. A multi-centre, randomised, controlled, open-label, parallel-group study was carried out in nine hospitals (five countries) between January 2019 and July 2021 in colorectal and lung cancer patients undergoing first-line systemic treatment with chemo(radio-) or immunotherapy. Subjects were randomised (2:1) to receive Fortimel Compact Protein® or standard care. Protein intake was assessed with a 3-day food diary (primary outcome). BW was a secondary outcome. Due to challenges in recruitment, the study was terminated prematurely with 42 patients randomised (intervention group (IG) 28; control group (CG) 14). At T1 and T2, protein intake was statistically significantly higher in the IG compared to the CG (1.40 vs. 1.07 g/kg/day at T1, p = 0.008; 1.32 vs. 0.94 g/kg/day at T2, p = 0.002). At baseline, only 65% (IG) and 45% (CG) of patients met ESPEN minimum protein intake recommendations. However, at T1 and T2 in the IG, a higher proportion of patients met recommendations than in the CG (88% vs. 55% and 40%). No statistically significant difference between study groups was observed for BW. Mean compliance to the ONS was 73.4%. A high-protein, low-volume ONS consumed twice daily enables the majority of patients to reach minimal ESPEN protein recommendations.</p

Proposal of early CT morphological criteria for response of liver metastases to systemic treatments in gastroenteropancreatic neuroendocrine tumors:Alternatives to RECIST

RECIST 1.1 criteria are commonly used with computed tomography (CT) to evaluate the efficacy of systemic treatments in patients with neuroendocrine tumors (NETs) and liver metastases (LMs), but their relevance is questioned in this setting. We aimed to explore alternative criteria using different numbers of measured LMs and thresholds of size and density variation. We retrospectively studied patients with advanced pancreatic or small intestine NETs with LMs, treated with systemic treatment in the first-and/or second-line, without early progression, in 14 European expert centers. We compared time to treatment failure (TTF) between responders and non-responders according to various criteria defined by 0%, 10%, 20% or 30% decrease in the sum of LM size, and/or by 10%, 15% or 20% decrease in LM density, measured on two, three or five LMs, on baseline (≤1 month before treatment initiation) and first revaluation (≤6 months) contrast-enhanced CT scans. Multivariable Cox proportional hazard models were performed to adjust the association between response criteria and TTF on prognostic factors. We included 129 systemic treatments (long-acting somatostatin analogs 41.9%, chemotherapy 26.4%, targeted therapies 31.8%), administered as first-line (53.5%) or second-line therapies (46.5%) in 91 patients. A decrease ≥10% in the size of three LMs was the response criterion that best predicted prolonged TTF, with significance at multivariable analysis (HR 1.90; 95% CI: 1.06–3.40; p =.03). Conversely, response defined by RECIST 1.1 did not predict prolonged TTF (p =.91), and neither did criteria based on changes in LM density. A ≥10% decrease in size of three LMs could be a more clinically relevant criterion than the current 30% threshold utilized by RECIST 1.1 for the evaluation of treatment efficacy in patients with advanced NETs. Its implementation in clinical trials is mandatory for prospective validation. Criteria based on changes in LM density were not predictive of treatment efficacy. Clinical Trial Registration: Registered at CNIL-CERB, Assistance publique hopitaux de Paris as “E-NETNET-L-E-CT” July 2018. No number was assigned. Approved by the Medical Ethics Review Board of University Medical Center Groningen.</p

TP53 outperforms other androgen receptor biomarkers to predict abiraterone or enzalutamide outcome in metastatic castration-resistant prostate cancer

Purpose: To infer the prognostic value of simultaneous androgen receptor (AR) and TP53 profiling in liquid biopsies from patients with metastatic castration-resistant prostate cancer (mCRPC) starting a new line of AR signaling inhibitors (ARSi). Experimental Design: Between March 2014 and April 2017, we recruited patients with mCRPC (n = 168) prior to ARSi in a cohort study encompassing 10 European centers. Blood samples were collected for comprehensive profiling of Cell Search-enriched circulating tumor cells (CTC) and circulating tumor DNA (ctDNA). Targeted CTC RNA sequencing (RNA-seq) allowed the detection of eight AR splice variants (ARV). Low-pass whole-genome and targeted gene-body sequencing of AR and TP53 was applied to identify amplifications, loss of heterozygosity, mutations, and structural rearrangements in ctDNA. Clinical or radiologic progression-free survival (PFS) was estimated by Kaplan-Meier analysis, and independent associations were determined using multivariable Cox regression models. Results: Overall, no single AR perturbation remained associated with adverse prognosis after multivariable analysis. Instead, tumor burden estimates (CTC counts, ctDNA fraction, and visceral metastases) were significantly associated with PFS. TP53 inactivation harbored independent prognostic value [HR 1.88; 95% confidence interval (CI), 1.18-3.00; P = 0.008], and outperformed ARV expression and detection of genomic AR alterations. Using Cox coefficient analysis of clinical parameters and TP53 status, we identified three prognostic groups with differing PFS estimates (median, 14.7 vs. 7.51 vs. 2.62 months; P < 0.0001), which was validated in an independent mCRPC cohort (n = 202) starting first-line ARSi (median, 14.3 vs. 6.39 vs. 2.23 months; P < 0.0001). Conclusions: In an all-comer cohort, tumor burden estimates and TP53 outperform any AR perturbation to infer prognosis. See related commentary by Rebello et al., p. 169

Cell-free DNA profiling of metastatic prostate cancer reveals microsatellite instability, structural rearrangements and clonal hematopoiesis.

This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.BACKGROUND: There are multiple existing and emerging therapeutic avenues for metastatic prostate cancer, with a common denominator, which is the need for predictive biomarkers. Circulating tumor DNA (ctDNA) has the potential to cost-efficiently accelerate precision medicine trials to improve clinical efficacy and diminish costs and toxicity. However, comprehensive ctDNA profiling in metastatic prostate cancer to date has been limited. METHODS: A combination of targeted and low-pass whole genome sequencing was performed on plasma cell-free DNA and matched white blood cell germline DNA in 364 blood samples from 217 metastatic prostate cancer patients. RESULTS: ctDNA was detected in 85.9% of baseline samples, correlated to line of therapy and was mirrored by circulating tumor cell enumeration of synchronous blood samples. Comprehensive profiling of the androgen receptor (AR) revealed a continuous increase in the fraction of patients with intra-AR structural variation, from 15.4% during first-line metastatic castration-resistant prostate cancer therapy to 45.2% in fourth line, indicating a continuous evolution of AR during the course of the disease. Patients displayed frequent alterations in DNA repair deficiency genes (18.0%). Additionally, the microsatellite instability phenotype was identified in 3.81% of eligible samples (≥ 0.1 ctDNA fraction). Sequencing of non-repetitive intronic and exonic regions of PTEN, RB1, and TP53 detected biallelic inactivation in 47.5%, 20.3%, and 44.1% of samples with ≥ 0.2 ctDNA fraction, respectively. Only one patient carried a clonal high-impact variant without a detectable second hit. Intronic high-impact structural variation was twice as common as exonic mutations in PTEN and RB1. Finally, 14.6% of patients presented false positive variants due to clonal hematopoiesis, commonly ignored in commercially available assays. CONCLUSIONS: ctDNA profiles appear to mirror the genomic landscape of metastatic prostate cancer tissue and may cost-efficiently provide somatic information in clinical trials designed to identify predictive biomarkers. However, intronic sequencing of the interrogated tumor suppressors challenges the ubiquitous focus on coding regions and is vital, together with profiling of synchronous white blood cells, to minimize erroneous assignments which in turn may confound results and impede true associations in clinical trials.The Belgian Foundation Against Cancer (grant number C/2014/227); Kom op tegen Kanker (Stand up to Cancer), the Flemish Cancer Society (grant number 00000000116000000206); Royal College of Surgeons/Cancer Research UK (C19198/A1533); The Cancer Research Funds of Radiumhemmet, through the PCM program at KI (grant number 163012); The Erling-Persson family foundation (grant number 4-2689-2016); the Swedish Research Council (grant number K2010-70X-20430-04-3), and the Swedish Cancer Foundation (grant number 09-0677)

The Use of Lanreotide Autogel® in the Treatment of Intestinal Obstruction in a Patient with Adenocarcinoma

Intestinal obstruction is a common complication in patients with advanced abdominal or pelvic cancer. The synthetic somatostatin analogue octreotide can help relieve nausea, vomiting and pain in patients with inoperable obstruction. Here, we report a case of recurrent intestinal obstruction in a patient with adenocarcinoma. Although the obstruction was resolved after 3 days of treatment with octreotide, new episodes of obstruction occurred, resulting in a delay of the chemotherapy treatment. After 3 episodes of obstruction, we initiated treatment with a longer-acting somatostatin analogue, lanreotide Autogel® 120 mg, administered once every 4 weeks. The treatment with lanreotide Autogel is being continued, allowing for continuation of the chemotherapy without further episodes of intestinal subocclusion or obstruction. Until November 2013, the patient received eighteen 4-weekly injections of lanreotide Autogel and did not report side effects. This case report demonstrates the successful treatment of intestinal obstruction with lanreotide Autogel in a patient with adenocarcinoma

Long-Term Disease Control of a Pancreatic Neuroendocrine Tumor with Lanreotide Autogel®: A Case Report

The CLARINET study (ClinicalTrials.gov: NCT00353496) showed that somatostatin analogs are able to stabilize tumor growth in patients with intestinal and pancreatic neuroendocrine tumors (NETs). Here, we present a case of NET originating from the pancreatic tail that was treated with lanreotide Autogel®. A 60-year-old patient underwent resection of a pancreatic NET with splenectomy and distal pancreatectomy. Four months after surgery, there was an increase in chromogranin A levels, along with a hypercaptating lesion of approximately 3.5 cm at the residual part of the pancreatic corpus. Treatment with 30 mg monthly-administered octreotide long-acting release (LAR) was initiated. After 3 months of treatment, a control CT scan revealed diffuse metastases in the liver, although the patient presented no symptoms and liver tests were normal. Due to difficulties with the administration of octreotide LAR, treatment was switched to lanreotide Autogel® 120 mg, administered as monthly deep-subcutaneous injections. Progression-free survival, as shown by 3-monthly CT scans, was obtained for 2 years without the need to increase the lanreotide Autogel® dose, and the patient reported no side effects. After these 2 years, deterioration of the patient's clinical status and weight loss were observed, along with increased size of the liver lesions and appearance of peritoneal metastases. Chemotherapy treatment with cisplatinum-etoposide was initiated, while the lanreotide Autogel® injections were continued. After three chemotherapy cycles, a rapid decline in the patient's quality of life was noted, and she requested discontinuation of the chemotherapy and lanreotide injections. One month later, the patient died due to clinical progressive disease

Not just a 'usual' Li-Fraumeni syndrome

The Li-Fraumeni syndrome (LFS) is characterised clinically by the appearance of tumours in multiple organs, generally at an early age. This hereditary condition is caused by germinal mutations in the TP53 gene, which codifies for the tumour suppressor gene p53. We present here the case of a patient aged 40 with the diagnosis of LFS who presented with premenopausal breast cancer. She had a positive family history of cancer. As a consequence, she was referred to genetic counselling. Genetic analysis revealed a TP53 germline mutation, which is diagnostic for LFS. However, further genetic analysis of different tissues showed a genetic mosaicism in our patient. Patients with LFS have a high risk for a broad spectrum of tumours. The diagnosis and management of Li-Fraumeni syndrome should be performed by a multidisciplinary team, and genetic counselling should be offered to patients and their relatives. Targeted next-generation sequencing represents an efficient approach for the identification of mutations in families with a heterogeneous phenotype. Theoretically, since mosaics do not have mutations in all of their cells, the cells that do not have mutant p53 are less likely to undergo malignant transformation or have the same risk of everyone else