Colorectal cancer is the second leading cause of cancer-related deaths in the United States and accounts for an estimated 1 million deaths annually worldwide. The liver is the most common site of metastatic spread from colorectal cancer, significantly driving both morbidity and mortality. Although remarkable advances have been made in recent years in the management for patients with colorectal cancer liver metastases, significant challenges remain in early detection, prevention of progression and recurrence, and in the development of more effective therapeutics. In 2017, our group held a multidisciplinary state-of-the-science symposium to discuss the rapidly evolving clinical and scientific advances in the field of colorectal liver metastases, including novel early detection and prognostic liquid biomarkers, identification of high-risk cohorts, advances in tumor-immune therapy, and different regional and systemic therapeutic strategies. Since that time, there have been scientific discoveries translating into therapeutic innovations addressing the current management challenges. These innovations are currently reshaping the treatment paradigms and spurring further scientific discovery. Herein, we present an updated discussion of both the scientific and clinical advances and future directions in the management of colorectal liver metastases, including adoptive T-cell therapies, novel blood-based biomarkers, and the role of the tumor microbiome. In addition, we provide a comprehensive overview detailing the role of modern multidisciplinary clinical approaches used in the management of patients with colorectal liver metastases, including considerations toward specific molecular tumor profiles identified on next generation sequencing, as well as quality of life implications for these innovative treatments.

Cancer remains a significant cause of mortality in developed countries, due in part to difficulties in early detection, understanding disease biology, and assessing treatment response. If effectively harnessed, circulating biomarkers promise to fulfill these needs through non-invasive “liquid” biopsy. While tumors disseminate genetic material and cellular debris into circulation, identifying clinically relevant information from these analytes has proven difficult. In contrast, cell-based circulating biomarkers have multiple advantages, including a source for tumor DNA and protein, and as a cellular reflection of the evolving tumor. While circulating tumor cells (CTCs) have dominated the circulating cell biomarker field, their clinical utility beyond that of prognostication has remained elusive, due to their rarity. Recently, two novel populations of circulating tumor-immune hybrid cells in cancer have been characterized: cancer-associated macrophage-like cells (CAMLs) and circulating hybrid cells (CHCs). CAMLs are macrophage-like cells containing phagocytosed tumor material, while CHCs can result from cell fusion between cancer and immune cells and play a role in the metastatic cascade. Both are detected in higher numbers than CTCs in peripheral blood and demonstrate utility in prognostication and assessing treatment response. Additionally, both cell populations are heterogeneous in their genetic, transcriptomic, and proteomic signatures, and thus have the potential to inform on heterogeneity within tumors. Herein, we review the advances in this exciting field.

Pancreatic ductal adenocarcinoma (PDAC) is among the top causes of cancer-related death. Patients are frequently diagnosed in the more advanced stages when effective treatment options are limited; however, earlier detection of PDAC by liquid biopsy may expand treatment options and improve survival outcomes. Here, we developed a noninvasive detection assay for PDAC based on serum protease activity to leverage the increase in cancer-associated protease activity in the peripheral blood of patients with PDAC. We screened a series of protease-cleavable peptide probes for the discrimination of PDAC samples versus healthy controls and noncancerous pancreatic disease. We identified a single MMP-sensitive probe, which could distinguish PDAC from controls with 79 ± 6% accuracy. We further developed this probe into a rapid magnetic nanosensor assay, termed PAC-MANN, that measures serum protease cleavage of a target-probe nanosensor with a simple fluorescent readout. In a longitudinal cohort of patients undergoing surgical removal of the primary tumor, the probe cleavage signal was reduced by 16 ± 24% after surgery. In a separate blinded retrospective study, the PAC-MANN assay identified PDAC samples with 98% specificity and 73% sensitivity across all stages and distinguished 100% of patients with noncancer pancreatic disease relative to patients with PDAC. The PAC-MANN assay combined with the clinical biomarker CA 19-9 was 85% sensitive for detection of stage I PDAC with 96% specificity. Therefore, the PAC-MANN assay is a rapid, high-throughput method that uses small blood volumes with the potential to enhance early PDAC detection, specifically among individuals at high risk of developing PDAC.

Background/Objectives: Pancreatic ductal adenocarcinoma (PDAC) presents significant diagnostic and prognostic challenges, as current biomarkers frequently fail to accurately stage disease, predict rapid metastatic recurrence (rPDAC), or assess response to neoadjuvant therapy (NAT). We investigated the potential for circulating neoplastic-immune hybrid cells (CHCs) as a non-invasive, multifunctional biomarker for PDAC. Methods: Peripheral blood specimens were obtained from patients diagnosed with PDAC. CHCs were detected by co-expression of pan-cytokeratin and CD45, normalized to 50,000 peripheral blood mononuclear cells. rPDAC was defined as metastatic recurrence within six months of margin-negative pancreatectomy. Cyclic immunofluorescence (CyCIF) analyses compared hybrid phenotypes in blood and tumors. Results: Blood samples were collected from 42 patients with PDAC prior to resection. Those with radiographically occult metastatic disease and rPDAC had higher preoperative CHC numbers compared to patients who did not (65.0 and 74.4, vs. 11.52 CHCs; p < 0.001). Patients with complete or near-complete pathologic responses to NAT had lower preoperative CHC numbers than partial and/or non-responders (1.7 vs. 13.1 CHCs; p = 0.008). When assessed longitudinally, those with partial pathologic response saw CHC levels become undetectable while on treatment but increase in the interval between NAT completion and resection. In contrast, patients with poor responses or development of metastatic disease experienced persistent CHC detection during therapy or rising levels prior to radiographic evidence of metastases. Further, in metastatic PDAC patients, treatment-induced phenotypic changes in hybrid cells mirrored those in paired metastatic tumor samples. Conclusions: CHC enumeration and phenotyping display promise as a real-time indicator of disease burden, recurrence risk, and treatment response in PDAC. CHCs have great potential as tumor-derived biomarkers to optimize therapeutic strategies and improve survival in patients with PDAC.

Existing clinical biomarkers do not reliably predict treatment response or disease progression in patients with advanced intrahepatic cholangiocarcinoma (ICC). Circulating neoplastic-immune hybrid cells (CHCs) have great promise as a blood-based biomarker for patients with advanced ICC. Peripheral blood specimens were longitudinally collected from patients with advanced ICC enrolled in the HELIX-1 phase II clinical trial (NCT04251715). CHCs were identified by co-expression of pan-cytokeratin (CK) and CD45, and levels were correlated to patient clinical disease course. Unsupervised machine learning was then performed to extract their morphological features to compare them across disease courses. Five patients were included in this study, with a median of nine specimens collected per patient. A median of 13.5 CHCs per 50,000 peripheral blood mononuclear cells were identified at baseline, and levels decreased to zero following the initiation of treatment in all patients. Counts remained undetectable in three patients who demonstrated end-of-trial clinical treatment response and conversely increased in two patients with evidence of therapeutic resistance. In the post-trial surveillance period, interval counts increased prior to or at the time of clinical progression in three patients and remain undetectable in one patient with continued long-term disease stability. Using our machine learning platform, treatment-resistant CHCs exhibited upregulation of CK and downregulation of CD45 relative to treatment-responsive CHCs. CHCs represent a promising blood-based biomarker to supplement traditional radiographic and biochemical measures.

BACKGROUND: Synchronous colorectal liver metastases may be managed with primary-first, simultaneous, or liver-first resection. Relative oncologic outcomes based on treatment sequencing are understudied. OBJECTIVE: This study aimed to assess oncologic survival outcomes in patients with synchronous colorectal liver metastases managed with each of the 3 treatment strategies, with respect to early or delayed removal of the primary tumor. DESIGN: Retrospective analysis of the prospectively maintained database, with 1:1 propensity score matching of relevant clinicopathologic variables comparing liver-first to primary-first/simultaneous approaches. SETTINGS: Single-institution, tertiary cancer center. PATIENTS: Patients undergoing curative-intent hepatectomy for synchronous colorectal liver metastases from 2003 to 2019. MAIN OUTCOME MEASURES: Overall and recurrence-free survival. RESULTS: Of 151 patients, 23% (n = 35) had liver-first and 77% (n = 116; primary-first = 93 and simultaneous = 23) had primary-first/simultaneous approaches. The median follow-up was 45 months. Recurrence-free survival was worse for liver-first versus primary-first/simultaneous groups (median 12 versus 16 months, p = 0.02), driven by 3-year extrahepatic recurrence-free survival of 19%, 58%, and 50% for liver-first, primary-first, and simultaneous groups, respectively. Three-year overall survival was not significantly different at 86%, 79%, and 86%, respectively. Oncologic outcomes did not differ significantly between primary-first and simultaneous groups (all p > 0.4). Matching yielded 34 clinicopathologically similar patients per group (liver-first = 34, primary-first = 28, simultaneous = 6). The liver-first approach was associated with shorter recurrence-free survival (median 12 versus 23 months, p = 0.004), driven by extrahepatic recurrence-free survival (3 years: 20% versus 55%, p = 0.04). Overall survival was not significantly different at 3 years (79% versus 80%, p = 0.95) or 5 years (59% versus 59%, p > 0.99). LIMITATIONS: This study has a retrospective design and a limited sample size. CONCLUSIONS: A liver-first approach is associated with worse recurrence-free survival compared to primary-first or simultaneous resection, driven by extrahepatic recurrence. A prospective study of whether oncologic risk is associated with leaving the primary in situ is needed. Multidisciplinary treatment sequencing and enhanced postoperative surveillance for patients receiving liver-first resection are recommended. See Video Abstract. LA RESECCIÓN DEL HÍGADO PRIMERO EN PACIENTES CON METÁSTASIS HEPÁTICAS COLORRECTALES SINCRÓNICAS SE ASOCIA CON UNA SUPERVIVENCIA INFERIOR SIN RECURRENCIA: RECONSIDERACIÓN DE LA IMPORTANCIA DEL CÁNCER PRIMARIO: ANTECEDENTES: Las metástasis hepáticas colorrectales sincrónicas se pueden tratar con resección primaria, simultánea o hepática. Los resultados oncológicos relativos basados en la secuenciación del tratamiento están poco estudiados. OBJETIVO: Este estudio tuvo como objetivo evaluar los resultados de supervivencia oncológica en pacientes con metástasis hepáticas colorrectales sincrónicas tratadas con cada una de las tres estrategias de tratamiento, con respecto a la extirpación temprana o tardía del tumor primario. DISEÑO: Análisis retrospectivo de una base de datos mantenida prospectivamente, con coincidencia de propensión 1:1 de variables clínico-patológicas relevantes que comparan enfoques de hígado primero con enfoques primarios primero/simultáneos. AJUSTES: Centro oncológico terciario de una sola institución. PACIENTES: Pacientes sometidos a hepatectomía con intención curativa por metástasis hepáticas colorrectales sincrónicas entre 2003 y 2019. MEDIDAS PRINCIPALES DE RESULTADOS: Supervivencia general y libre de recurrencia. RESULTADOS: De 151 pacientes, el 23% (n=35) tuvo un abordaje hepático primero y el 77% (n=116; primario primero=93 y simultáneo=23) tuvo un abordaje primario primero/simultáneo. La mediana de seguimiento fue de 45 meses. La supervivencia libre de recurrencia fue peor para los grupos de hígado primero versus primario primero/simultáneo (mediana 12 versus 16 meses, p = 0,02), impulsada por la supervivencia libre de recurrencia extrahepática a tres años del 19%, 58% y 50% para grupos de hígado primero, primario primero y simultáneo, respectivamente. La supervivencia general a tres años no fue significativamente diferente: 86%, 79% y 86%, respectivamente. Los resultados oncológicos no difirieron significativamente entre los grupos primario-primero y simultáneo (todos p > 0,4). El emparejamiento produjo 34 pacientes clínico-patológicamente similares por grupo (hígado primero = 34, primario primero = 28/simultáneo = 6). El enfoque de hígado primero se asoció con una supervivencia libre de recurrencia más corta (mediana de 12 frente a 23 meses, p = 0,004), impulsada por la supervivencia libre de recurrencia extrahepática (3 años: 20 % frente a 55 %, p = 0,04). La supervivencia general no fue significativamente diferente a los 3 años (79% versus 80%, p = 0,95) o a los 5 años (59% versus 59%, p > 0,99). LIMITACIONES: Este estudio tiene un diseño retrospectivo y un tamaño de muestra limitado. CONCLUSIONES: Un enfoque de hígado primero se asocia con una peor supervivencia libre de recurrencia en comparación con la resección primaria o simultánea, impulsada por la recurrencia extrahepática. Es necesario un estudio prospectivo sobre si el riesgo oncológico se asocia con dejar el primario in situ. Se recomienda la secuenciación del tratamiento multidisciplinario y una vigilancia posoperatoria mejorada para los pacientes que reciben una primera resección del hígado. (Traducción—Yesenia Rojas-Khalil)