Current and novel therapeutic opportunities for systemic therapy in biliary cancer

Biliary tract cancers (BTCs) are a group of rare and aggressive malignancies that arise in the biliary tree within and outside the liver. Beyond surgical resection, which is beneficial for only a small proportion of patients, current strategies for treating patients with BTCs include chemotherapy, as a single agent or combination regimens, in the adjuvant and palliative setting. Increased characterisation of the molecular landscape of these tumours has facilitated the identification of molecular vulnerabilities, such as IDH mutations and FGFR fusions, that can be exploited for the treatment of BTC patients. Beyond targeted therapies, active research avenues explore the development of novel therapeutics that target the crosstalk between cancer and stroma, the cellular pathways involved in the regulation of cell death, the chemoresistance phenotype and the dysregulation of RNA. In this review, we discuss the therapeutic opportunities currently available in the management of BTC patients, and explore the strategies that can support the implementation of precision oncology in BTCs, including novel molecular targets, liquid biopsies and patient-derived predictive tools

KRAS and BRAF mutations in circulating tumour DNA from locally advanced rectal cancer

Abstract There are limited data on circulating, cell-free, tumour (ct)DNA analysis in locally advanced rectal cancer (LARC). Digital droplet (dd)PCR was used to investigate KRAS/BRAF mutations in ctDNA from baseline blood samples of 97 LARC patients who were treated with CAPOX followed by chemoradiotherapy, surgery and adjuvant CAPOX ± cetuximab in a randomised phase II trial. KRAS mutation in G12D, G12V or G13D was detected in the ctDNA of 43% and 35% of patients with tumours that were mutant and wild-type for these hotspot mutations, respectively, according to standard PCR-based analyses on tissue. The detection rate in the ctDNA of 10 patients with less common mutations was 50%. In 26 cases ctDNA analysis revealed KRAS mutations that were not previously found in tissue. Twenty-two of these (84.6%) were detected following repeat tissue testing by ddPCR. Overall, the ctDNA detection rate in the KRAS mutant population was 66%. Detection of KRAS mutation in ctDNA failed to predict prognosis or refine patient selection for cetuximab. While this study confirms the feasibility of ctDNA analysis in LARC and the high sensitivity of ddPCR, larger series are needed to better address the role of ctDNA as a prognostic or predictive tool in this setting

91 Circulating lipid profile as a prognostic factor in patients with advanced solid tumors treated with immune checkpoint inhibitors

Background Components of lipid profile seem to impact differently on phenotype and activity of immune cells in cancer.1,2 Their prognostic role in solid cancer patients treated with immune checkpoint inhibitors (ICIs) is still matter of debate. Methods We retrospectively collected baseline clinicopathological characteristics including circulating lipid profile [total cholesterol (TC), triglycerides (TGs), low-density lipoproteins (LDL), high-density lipoproteins (HDL)] of consecutive solid cancer patients treated with ICIs and we investigated their impact on clinical outcomes. Cut-off values showing alteration of plasma lipid profile were ≥200 mg/dl for TC, ≥170 mg/dl for TGs, ≥130 mg/dl for LDL, <40 mg/dl for HDL in males, <45 mg/dl for HDL in females. Results Among 432 patients enrolled, 67% (N=289) were men, 61% (N=266) were diagnosed with advanced non-small cell lung cancer and 86.6% (N=374) of patients were treated with ICIs as monotherapy. Patients’ circulating lipid assessments were described in tables (tables 1–3). At a median follow-up of 46 months, patients with TC≥200 mg/dl showed an improved, although not significant, progression free survival (PFS) (6.61 versus 4.67 months, p=0.4) and longer overall survival (OS) (19.4 versus 10.8 months, p=0.02) compared to those with TC<200 mg/dl. Conversely, patients with TGs≥170 mg/dl showed a shorter PFS (2.8 versus 5.07 months, p=0.006) and OS (5.92 versus 12.99 months, p<0.001) compared to those with TGs<170 mg/dl. Then, we combined TC and TGs in a LIPID-score that identified three subgroups: good risk (GR) (TC≥200 mg/dl and TGs<170 mg/dl), intermediate risk (IR) (TC<200 mg/dl and TGs<170 mg/dl or TC≥200 mg/dl and TGs≥170 mg/dl) and poor risk (PR) (TC<200 mg/dl and TGs≥170 mg/dl). The median PFS of GR, IR and PR groups was 7.76, 4.18 and 2.40 months, respectively (p<0.001). Moreover, median OS of GR, IR and PR was 20.36, 11.18 and 4.14 months, respectively (p<0.001) (figure 1). At multivariate analyses, after adjusting for baseline performance status, histology, treatment line, sex, statin use, number of metastatic sites and body mass index, the impact of LIPID score remained significant for both PFS and OS (table 4). Looking at TC components, HDL and LDL, a significant association was detected only for HDL and OS, with patients characterized by higher HDL levels showing longer OS (15.3 vs 10.1 months, p=0.02). Conclusions LIPID score seems to strongly define subgroups of patients treated with ICIs with different prognosis. Further mechanistic insights are needed to clarify the prognostic and predictive role of lipid profile components in patients treated with ICIs

Retrospective Cohort Study of Caveolin-1 Expression as Prognostic Factor in Unresectable Locally Advanced or Metastatic Pancreatic Cancer Patients

Caveolin-1 (Cav-1) plays a key role in various neoplastic diseases and is upregulated in different cancers, including pancreatic ductal adenocarcinoma (PDAC). Furthermore, Cav-1 is critical for the uptake of albumin as well as nab-paclitaxel in PDAC cells. Here, we investigated the prognostic impact of Cav-1 expression in a cohort of 39 metastatic PDAC patients treated with different first-line chemotherapy regimens. We also assessed the predictive value of Cav-1 in patients treated with gemcitabine and nab-paclitaxel. Cav-1 expression was evaluated by immunohistochemistry staining in neoplastic and stromal cells, using metastatic sites or primary tumor tissue specimens. Higher levels of Cav-1 expression were associated with significantly worse overall survival (OS) and progression-free survival (PFS). No differences in OS were found between patients treated with gemcitabine + nab-paclitaxel vs. other chemotherapy options. Multivariate analysis for OS and PFS confirmed the independent prognostic role of Cav-1 expression. Our study evidenced a negative prognostic role of Cav-1 in patients affected by metastatic/locally advanced unresectable PDAC. Moreover, Cav-1 expression seems not to predict different response rates to different types of first-line treatment. Future prospective trials will be necessary to confirm the prognostic role of Cav-1 and explore Cav-1 specific inhibitors as a therapeutic option for advanced PDAC patients

Prognostic Impact of Blood Lipid Profile in Patients With Advanced Solid Tumors Treated With Immune Checkpoint Inhibitors: A Multicenter Cohort Study

Background: Specific components of lipid profile seem to differently impact on immune activity against cancer and unraveling their prognostic role in patients with solid cancer treated with immune checkpoint inhibitors (ICIs) is needed. Materials and methods: We retrospectively collected baseline clinicopathological characteristics including circulating lipid profile (total cholesterol [TC], triglycerides [TG], low-density lipoproteins [LDL], high-density lipoproteins [HDL]) of patients with consecutive solid cancer treated with ICIs, and we investigated their role in predicting clinical outcomes. Results: At a median follow-up of 32.9 months, among 430 enrolled patients, those with TC ≥ 200 mg/dl showed longer median progression-free survival (mPFS; 6.6 vs. 4.7 months, P = .4), although not reaching statistical significance, and significantly longer median overall survival (mOS; 19.4 vs. 10.8 months, P = .02) compared to those with TC < 200 mg/dl. Conversely, patients with TG ≥150 mg/dl displayed shorter PFS (3.4 vs. 5.1 months, P = .02) and OS (7.1 vs. 12.9 months, P = .009) compared to those with TG <150 mg/dl. TC and TG were then combined in a "LIPID score" identifying three subgroups: good-risk (GR) (TC ≥200 mg/dl and TG <150 mg/dl), intermediate-risk (IR) (TC <200 mg/dl and TG <150 mg/dl or TC ≥200 mg/dl and TG ≥150 mg/dl) and poor-risk (PR) (TC <200 mg/dl and TG ≥150 mg/dl). The mPFS of GR, IR, and PR groups was 7.8, 4.3, and 2.5 months, respectively (P = .005); mOS of GR, IR, and PR was 20.4, 12.4, and 5.3 months, respectively (P < .001). At multivariable analysis, the PR profile represented an independent poor prognostic factor for both PFS and OS. Conclusions: We developed a lipid score that defined subgroups of patients with cancer who differently benefit from ICIs. Further mechanistic insights are warranted to clarify the prognostic and predictive role of lipid profile components in patients treated with ICIs

Alarming Drop in Early Stage Colorectal Cancer Diagnoses After COVID-19 Outbreak: A Real-World Analysis from the Italian COVID-DELAY Study

Background: Coronavirus disease 2019 (COVID-19) has triggered the disruption of health care on a global scale. With Italy tangled up in the pandemic response, oncology care has been largely diverted and cancer screenings suspended. Our multicenter Italian study aimed to evaluate whether COVID-19 has impacted access to diagnosis, staging, and treatment for patients newly diagnosed with colorectal cancer (CRC), compared with pre-pandemic time. Methods: All consecutive new CRC patients referred to 8 Italian oncology institutions between March and December 2020 were included. Access rate and temporal intervals between date of symptoms onset, radiological and cytohistological diagnosis, treatment start and first radiological evaluation were analyzed and compared with the same months of 2019. Results: A reduction (29%) in newly diagnosed CRC cases was seen when compared with 2019 (360 vs 506). New CRC patients in 2020 were less likely to be diagnosed with early stage (stages I-II-III) CRC (63% vs 78%, P < .01). Gender and sidedness were similar regardless of the year. The percentage of tumors with any mutation among BRAF, NRAS, and KRAS genes were significantly different between the 2 years (61% in 2020 vs 50% in 2019, P = .04). Timing of access to cancer diagnosis, staging, and treatment for patients with CRC has not been negatively affected by the pandemic. Significantly shorter temporal intervals were observed between symptom onset and first oncological appointment (69 vs 79 days, P = .01) and between histological diagnosis and first oncological appointment (34 vs 42 days, P < .01) during 2020 compared with 2019. Fewer CRC cases were discussed in multidisciplinary meetings during 2020 (38% vs 50%, P = .01). Conclusions: Our data highlight a significant drop in CRC diagnosis after COVID-19, especially for early stage disease. The study also reveals a remarkable setback in the multidisciplinary management of patients with CRC. Despite this, Italian oncologists were able to ensure diagnostic-therapeutic pathways proper operation after March 2020

Rising incidence of late stage breast cancer after COVID-19 outbreak. Real-world data from the Italian COVID-DELAY study

Purpose: Breast cancer (BC) patients' (pts) management was affected by a global reorganization after Coronavirus disease 2019 (COVID-19). Our multicenter study aimed to assess the impact of COVID-19 on access to diagnosis, staging and treatment for BC pts compared to pre-pandemic. Methods: Medical records of all consecutive newly diagnosed BC pts referred to 6 Italian Institutions between March and December 2020 were assessed. Monthly access rate and temporal intervals between date of symptoms onset, radiological, cytohistological diagnosis and treatment start were analyzed and compared with 2019. Results: A reduction (25%) in newly diagnosed BC was observed compared to 2019 (666 vs 890). New BC pts in 2020 were less likely to be diagnosed with early stage BC (77% vs 83%, p  0 in 2020 vs 16.5% in 2019, p < 0.01) and fewer pts were asymptomatic at diagnosis in 2020 (54% vs 71%,p < 0.01). COVID-19 did not negatively impact in terms of access to diagnosis, staging and treatment. Time intervals between symptom onset and radiological diagnosis, symptom onset and cytohistological diagnosis, cytohistological diagnosis and treatment start were maintained or improved. However, less cases were discussed in multidisciplinary tumor meetings during 2020 (60% vs 73%, p < 0.01). Conclusions: Our data proved an alarming reduction of early stage BC associated with the COVID-19 crisis in 2020. Despite the upheaval generated by the pandemic, our study shed light on the effective performance delivered by Italian Oncology Departments to guarantee diagnostic-therapeutic pathways

The Gustave Roussy Immune (GRIm)-Score Variation Is an Early-on-Treatment Biomarker of Outcome in Advanced Non-Small Cell Lung Cancer (NSCLC) Patients Treated with First-Line Pembrolizumab

Background: The Gustave Roussy Immune (GRIm)-Score takes into account neutrophil-to-lymphocyte ratio (NLR), serum albumin concentration and lactate dehydrogenase (LDH) and its prognostic value has been investigated in patients treated with immune check-point inhibitors (ICIs). To further assess the prognostic and predictive value of baseline GRIm-Score (GRImT0) in advanced non-small cell lung cancer (aNSCLC) patients, we separately investigated two cohorts of patients treated with first-line pembrolizumab or chemotherapy. We also investigated whether GRIm-Score at 45 days since treatment initiation (GRImT1) and GRIm-Score difference between the two timepoints may better predict clinical outcomes (GRIm Delta = GRImT0 - GRImT1). Methods: We retrospectively evaluated 222 aNSCLC patients: 135 treated with pembrolizumab and 87 treated with chemotherapy as the first-line regimen. NLR, serum albumin and LDH concentrations were assessed at T0 and at T1. According to the GRIm-Score, patients were assigned 1 point if they had NLR > 6, LDH > upper limit normal or albumin < 3.5 g/dL. Patients with a GRIm-Score < 2 were considered as having a low Score. Results: In both cohorts, no difference in terms of overall survival (OS) between patients with low and high GRImT0 was found. Otherwise, median OS and progression free survival (PFS) of the low GRImT1 group were significantly longer than those of the high GRImT1 group in pembrolizumab-treated patients, but not in the CHT cohort (pembrolizumab cohort: low vs. high; median OS not reached vs. 9.2 months, p = 0.004; median PFS 10.8 vs. 2.3 months, p = 0.002). Patients receiving pembrolizumab with stable/positive GRIm Delta had better OS (median OS not reached vs. 12.0 months, p < 0.001), PFS (median PFS 20.6 vs. 2.6 months, p < 0.001) and objective response rate (58.2% vs. 7.6%, p = 0.003) compared to patients with negative GRIm Delta. Conclusion: Our data shown that GRImT1 and GRIm Delta are more reliable peripheral blood biomarkers of outcome compared to GRImT0 in aNSCLC patients treated with pembrolizumab and might represent useful biomarkers to drive clinical decisions in this setting

Longitudinal liquid biopsy and mathematical modeling of clonal evolution forecast time to treatment failure in the PROSPECT-C phase II colorectal cancer clinical trial

Sequential profiling of plasma cell-free DNA (cfDNA) holds immense promise for early detection of patient progression. However, how to exploit the predictive power of cfDNA as a liquid biopsy in the clinic remains unclear. RAS pathway aberrations can be tracked in cfDNA to monitor resistance to anti-EGFR monoclonal antibodies in patients with metastatic colorectal cancer. In this prospective phase II clinical trial of single-agent cetuximab in RAS wild-type patients, we combine genomic profiling of serial cfDNA and matched sequential tissue biopsies with imaging and mathematical modeling of cancer evolution. We show that a significant proportion of patients defined as RAS wild-type based on diagnostic tissue analysis harbor aberrations in the RAS pathway in pretreatment cfDNA and, in fact, do not benefit from EGFR inhibition. We demonstrate that primary and acquired resistance to cetuximab are often of polyclonal nature, and these dynamics can be observed in tissue and plasma. Furthermore, evolutionary modeling combined with frequent serial sampling of cfDNA allows prediction of the expected time to treatment failure in individual patients. This study demonstrates how integrating frequently sampled longitudinal liquid biopsies with a mathematical framework of tumor evolution allows individualized quantitative forecasting of progression, providing novel opportunities for adaptive personalized therapies