Clinical outcomes and ctDNA correlates for CAPOX BETR: a phase II trial of capecitabine, oxaliplatin, bevacizumab, trastuzumab in previously untreated advanced HER2+ gastroesophageal adenocarcinoma.

Preclinical studies suggest that simultaneous HER2/VEGF blockade may have cooperative effects in gastroesophageal adenocarcinomas. In a single-arm investigator initiated clinical trial for patients with untreated advanced HER2+ gastroesophageal adenocarcinoma, bevacizumab was added to standard of care capecitabine, oxaliplatin, and trastuzumab in 36 patients (NCT01191697). Primary endpoint was objective response rate and secondary endpoints included safety, duration of response, progression free survival, and overall survival.

Epigenetic and Oncogenic Inhibitors Cooperatively Drive Differentiation and Kill KRAS-Mutant Colorectal Cancers.

Combined EZH2 and RAS pathway inhibitors kill KRAS-mutant colorectal cancer cells and promote durable tumor regression in vivo. These agents function by cooperatively suppressing the WNT pathway, driving differentiation, and epigenetically reprogramming cells to permit the induction of apoptotic signals, which then kill these more differentiated tumor cells.

Experience and Needs of Patients With Young-Onset Colorectal Cancer and Their Caregivers: A Qualitative Study.

Purpose: The incidence of young-onset colorectal cancer (YOCRC; defined as patients who are diagnosed with CRC before age 50 years) is rising rapidly, and CRC is predicted to be the leading cause of cancer death in this age group by 2030. Yet, there has been limited research into the experiences and needs of patients with YOCRC and their caregivers. The goal of this study was to better understand the experiences and needs of patients with YOCRC and their caregivers.

RAS/RAF Comutation and ERBB2 Copy Number Modulates HER2 Heterogeneity and Responsiveness to HER2-directed Therapy in Colorectal Cancer.

Purpose: ERBB2-amplified colorectal cancer is a distinct molecular subtype with expanding treatments. Implications of concurrent oncogenic RAS/RAF alterations are not known.

Experimental Design: Dana-Farber and Foundation Medicine Inc.

Sotorasib Is a Pan-RASG12C Inhibitor Capable of Driving Clinical Response in NRASG12C Cancers.

Unlabelled: KRASG12C inhibitors, like sotorasib and adagrasib, potently and selectively inhibit KRASG12C through a covalent interaction with the mutant cysteine, driving clinical efficacy in KRASG12C tumors. Because amino acid sequences of the three main RAS isoforms-KRAS, NRAS, and HRAS-are highly similar, we hypothesized that some KRASG12C inhibitors might also target NRASG12C and/or HRASG12C, which are less common but critical oncogenic driver mutations in some tumors. Although some inhibitors, like adagrasib, were highly selective for KRASG12C, others also potently inhibited NRASG12C and/or HRASG12C.

Intertumoral lineage diversity and immunosuppressive transcriptional programs in well-differentiated gastroenteropancreatic neuroendocrine tumors.

Neuroendocrine tumors (NETs) are rare cancers that most often arise in the gastrointestinal tract and pancreas. The fundamental mechanisms driving gastroenteropancreatic (GEP)-NET growth remain incompletely elucidated; however, the heterogeneous clinical behavior of GEP-NETs suggests that both cellular lineage dynamics and tumor microenvironment influence tumor pathophysiology. Here, we investigated the single-cell transcriptomes of tumor and immune cells from patients with gastroenteropancreatic NETs.

Adipose tissue and skeletal muscle wasting precede clinical diagnosis of pancreatic cancer.

Patients with pancreatic cancer commonly develop weight loss and muscle wasting. Whether adipose tissue and skeletal muscle losses begin before diagnosis and the potential utility of such losses for earlier cancer detection are not well understood. We quantify skeletal muscle and adipose tissue areas from computed tomography (CT) imaging obtained 2 months to 5 years before cancer diagnosis in 714 pancreatic cancer cases and 1748 matched controls.

G-CSF rescue of FOLFIRINOX-induced neutropenia leads to systemic immune suppression in mice and humans.

Background: Recombinant granulocyte colony-stimulating factor (G-CSF) is routinely administered for prophylaxis or treatment of chemotherapy-induced neutropenia. Chronic myelopoiesis and granulopoiesis in patients with cancer has been shown to induce immature monocytes and neutrophils that contribute to both systemic and local immunosuppression in the tumor microenvironment. The effect of recombinant G-CSF (pegfilgrastim or filgrastim) on the production of myeloid-derived suppressive cells is unknown.

A deep learning algorithm to predict risk of pancreatic cancer from disease trajectories.

Pancreatic cancer is an aggressive disease that typically presents late with poor outcomes, indicating a pronounced need for early detection. In this study, we applied artificial intelligence methods to clinical data from 6 million patients (24,000 pancreatic cancer cases) in Denmark (Danish National Patient Registry (DNPR)) and from 3 million patients (3,900 cases) in the United States (US Veterans Affairs (US-VA)). We trained machine learning models on the sequence of disease codes in clinical histories and tested prediction of cancer occurrence within incremental time windows (CancerRiskNet).

Phase Ib and Expansion Study of Gemcitabine, Nab-Paclitaxel, and Ficlatuzumab in Patients With Metastatic Pancreatic Cancer.

Background: In preclinical pancreatic ductal adenocarcinoma (PDAC) models, inhibition of hepatocyte growth factor (HGF) signaling using ficlatuzumab, a recombinant humanized anti-HGF antibody, and gemcitabine reduced tumor burden.

Methods: Patients with previously untreated metastatic PDAC enrolled in a phase Ib dose escalation study with 3 + 3 design of 2 dose cohorts of ficlatuzumab 10 and 20 mg/kg administered intravenously every other week with gemcitabine 1000 mg/m2 and albumin-bound paclitaxel 125 mg/m2 given 3 weeks on and 1 week off. This was followed by an expansion phase at the maximally tolerated dose of the combination.

Programmatic Precision Oncology Decision Support for Patients With Gastrointestinal Cancer.

Purpose: With the growing number of available targeted therapeutics and molecular biomarkers, the optimal care of patients with cancer now depends on a comprehensive understanding of the rapidly evolving landscape of precision oncology, which can be challenging for oncologists to navigate alone.

Methods: We developed and implemented a precision oncology decision support system, GI TARGET, (Gastrointestinal Treatment Assistance Regarding Genomic Evaluation of Tumors) within the Gastrointestinal Cancer Center at the Dana-Farber Cancer Institute. With a multidisciplinary team, we systematically reviewed tumor molecular profiling for GI tumors and provided molecularly informed clinical recommendations, which included identifying appropriate clinical trials aided by the computational matching platform MatchMiner, suggesting targeted therapy options on or off the US Food and Drug Administration-approved label, and consideration of additional or orthogonal molecular testing.

Neoadjuvant Chemotherapy Is Associated with Altered Immune Cell Infiltration and an Anti-Tumorigenic Microenvironment in Resected Pancreatic Cancer.

Purpose: Neoadjuvant chemotherapy is increasingly administered to patients with resectable or borderline resectable pancreatic ductal adenocarcinoma (PDAC), yet its impact on the tumor immune microenvironment is incompletely understood.

Design: We employed quantitative, spatially resolved multiplex immunofluorescence and digital image analysis to identify T-cell subpopulations, macrophage polarization states, and myeloid cell subpopulations in a multi-institution cohort of up-front resected primary tumors (n = 299) and in a comparative set of resected tumors after FOLFIRINOX-based neoadjuvant therapy (n = 36) or up-front surgery (n = 30). Multivariable-adjusted Cox proportional hazards models were used to evaluate associations between the immune microenvironment and patient outcomes.

Utility of Normalized Body Composition Areas, Derived From Outpatient Abdominal CT Using a Fully Automated Deep Learning Method, for Predicting Subsequent Cardiovascular Events.

CT-based body composition (BC) measurements have historically been too resource intensive to analyze for widespread use and have lacked robust comparison with traditional weight metrics for predicting cardiovascular risk. The aim of this study was to determine whether BC measurements obtained from routine CT scans by use of a fully automated deep learning algorithm could predict subsequent cardiovascular events independently from weight, BMI, and additional cardiovascular risk factors. This retrospective study included 9752 outpatients (5519 women and 4233 men; mean age, 53.

SDHx mutations and temozolomide in malignant pheochromocytoma and paraganglioma.

Malignant pheochromocytomas (PHEOs)/paragangliomas (PGLs) are rare tumors for which clinical outcomes remain poorly defined and therapeutic options are limited. Approximately 27% carry pathogenic germline succinate dehydrogenase (SDHx) mutations; the presence of such mutations has been correlated with response to temozolomide (TMZ). We aimed to investigate the association between germline mutations in SDHx and response to TMZ.

Serological testing for SARS-CoV-2 antibodies of employees shows low transmission working in a cancer center.

Background: The COVID-19 pandemic led to emergency measures to continue patient care and research at a comprehensive cancer center while protecting both employees and patients. Determining exposure and infection rates with SARS-CoV-2 were important to adjust workplace policies over time.

Methods: Dana-Farber Cancer Institute (DFCI) has over 7,000 employees.

Benefit of Primary Tumor Resection in Stage IV, Grade 1 and 2, Pancreatic Neuroendocrine Tumors: A Propensity-Score Matched Cohort Study.

Objective: To determine the association of primary tumor resection in stage IV pancreatic neuroendocrine tumors (Pan-NET) and survival in a propensity-score matched study.

Background: Pan-NET are often diagnosed with stage IV disease. The oncologic benefit from primary tumor resection in this scenario is debated and previous studies show contradictory results.

Liquid biopsy reveals collateral tissue damage in cancer.

Cancer inflicts damage to surrounding normal tissues, which can culminate in fatal organ failure. Here, we demonstrate that cell death in organs affected by cancer can be detected by tissue-specific methylation patterns of circulating cell-free DNA (cfDNA). We detected elevated levels of hepatocyte-derived cfDNA in the plasma of patients with liver metastases originating from different primary tumors, compared with cancer patients without liver metastases.