Sorafenib is the only systemic therapy to demonstrate a significant survival benefit over supportive care in robust randomised controlled trials for advanced hepatocellular carcinoma (HCC). In the context of an intense search for prognostic and predictive factors for response and efficacy of different systemic therapies (including sorafenib), a number of molecular targets have been identified, paving new avenues for potential therapeutic opportunities. Such molecular targets include somatostatin receptor (SSTR)-related alterations. In this review, we provide an overview of the various considerations relating to SSTRs as potentially novel prognostic and predictive biomarkers for HCC with special emphasis on the therapeutic potential of somatostatin analogues in HCC management.
Omar Abdel-Rahman, Angela Lamarca, Juan W Valle, and Richard A Hubner
Joakim Crona, Angela Lamarca, Suman Ghosal, Staffan Welin, Britt Skogseid, and Karel Pacak
Pheochromocytoma and paraganglioma (PPGL) can be divided into at least four molecular subgroups. Whether such categorizations are independent factors for prognosis or metastatic disease is unknown. We performed a systematic review and individual patient meta-analysis aiming to estimate if driver mutation status can predict metastatic disease and survival. Driver mutations were used to categorize patients according to three different molecular systems: two subgroups (SDHB mutated or wild type), three subgroups (pseudohypoxia, kinase signaling or Wnt/unknown) and four subgroups (tricarboxylic acid cycle, VHL/EPAS1, kinase signaling or Wnt/unknown). Twenty-one studies and 703 patients were analyzed. Multivariate models for association with metastasis showed correlation with SDHB mutation (OR 5.68 (95% CI 1.79–18.06)) as well as norepinephrine (OR 3.01 (95% CI 1.02–8.79)) and dopamine (OR 6.39 (95% CI 1.62–25.24)) but not to PPGL location. Other molecular systems were not associated with metastasis. In multivariate models for association with survival, age (HR 1.04 (95% CI 1.02–1.06)) and metastases (HR 6.13 (95% CI 2.86–13.13)) but neither paraganglioma nor SDHB mutation remained significant. Other molecular subgroups did not correlate with survival. We conclude that molecular categorization accordingly to SDHB provided independent information on the risk of metastasis. Driver mutations status did not correlate independently with survival. These data may ultimately be used to guide current and future risk stratification of PPGL.
Alexa Childs, Amy Kirkwood, Julien Edeline, Tu Vinh Luong, Jennifer Watkins, Angela Lamarca, Doraid Alrifai, Phyllis Nsiah-Sarbeng, Roopinder Gillmore, Astrid Mayer, Christina Thirlwell, Debashis Sarker, Juan W Valle, and Tim Meyer
Chemotherapy (CT) is widely used for neuroendocrine tumours (NETs), but there are no validated biomarkers to predict response. The Ki-67 proliferation index has been proposed as a means of selecting patients for CT, but robust data are lacking. The aim of this study was to investigate the relationship between response to chemotherapy and Ki-67 in NET. We reviewed data from 222 NET patients treated with CT. Tumours were graded according to Ki-67 index: G1 ≤2%, G2 3–20% and G3 >20%. Response was assessed according to RECIST and survival calculated from start of chemotherapy to death. To explore Ki-67 as a marker of response, we calculated the likelihood ratio and performed receiver operating characteristic analysis. Overall, 193 patients had a documented Ki-67 index, of which 173 were also evaluable for radiological response: 10% were G1, 46% G2 and 43% G3; 46% were pancreatic NET (PNET). Median overall survival was 22.1 months. Overall response rate was 30% (39% in PNET vs 22% in non-PNET) and 43% of patients had stable disease. Response rate increased with grade: 6% in G1 tumours, 24% in G2 and 43% in G3. However, maximum likelihood ratio was 2.3 at Ki-67=35%, and the area under the ROC curve was 0.60. As reported previously, a high Ki-67 was an adverse prognostic factor for overall survival. In conclusion, response to CT increases with Ki-67 index, but Ki-67 alone is an unreliable means to select patients for CT. Improved methods to stratify patients for systemic therapy are required.
Louis de Mestier, Angela Lamarca, Jorge Hernando, Wouter Zandee, Teresa Alonso-Gordoa, Marine Perrier, Annemieke M E Walenkamp, Bipasha Chakrabarty, Stefania Landolfi, Marie-Louise F. Van Velthuysen, Gursah Kats-Ugurlu, Alejandra Carminoa, Maxime Ronot, Prakash Manoharan, Alejandro Garcia-Alvarez, Tessa Brabander, María Isabel García Gómez-Muriel, Guillaume Cadiot, Anne Couvelard, Jaume Capdevilla, Marianne E Pavel, and Jerome Cros
There is no standardized treatment for grade 3 neuroendocrine tumors (G3 NETs). We aimed to describe the treatments received in patients with advanced G3 NETs and compare their efficacy. Patients with advanced digestive G3 NETs treated between 2010 and 2018 in seven expert centers were retrospectively studied. Pathological samples were centrally reviewed, and radiological data were locally reviewed. We analyzed RECIST-defined objective response (OR), tumor growth rate (TGR) and progression-free survival (PFS) obtained with first- (L1) or second-line (L2) treatments. We included 74 patients with advanced G3 NETs, mostly from duodenal or pancreatic origin (71.6%), with median Ki-67 of 30%. The 126 treatments (L1=74; L2=52) included alkylating-based (n=32), etoposide-platinum (n=22) or adenocarcinoma-like chemotherapy (n=20), somatostatin analogs (n=21), targeted therapies (n=22) and liver-directed therapies (n=7). Alkylating-based chemotherapy achieved the highest OR rate (37.9%) compared to other treatments (multivariable OR 4.22, 95% CI [1.5-12.2]; p=0.008). Adenocarcinoma-like and alkylating-based chemotherapies showed the highest reductions in 3-month TGR (p<0.001 and p=0.008, respectively). The longest median PFS were obtained with adenocarcinoma-like chemotherapy (16.5 months [9.0-24.0]) and targeted therapies (12.0 months [8.2-15.8]), while the shortest PFS were observed with somatostatin analogues (6.2 months [3.8-8.5]) and etoposide-platinum chemotherapy (7.2 months [5.2-9.1]). Etoposide-platinum CT achieved shorter PFS than adenocarcinoma-like (multivariable HR 3.69 [1.61-8.44], p=0.002) and alkylating-based chemotherapies (multivariable HR 1.95 [1.01-3.78], p=0.049). Overall, adenocarcinoma-like and alkylating-based chemotherapies may be the most effective treatments for patients with advanced G3 NETs regarding OR and PFS. Etoposide-platinum chemotherapy has poor efficacy in this setting.