Cancer of Unknown Primary
Research topic:
Cancer of Unknown Primary (CUP): the AGNOSTOS PROJECT
Background:
Cancer of Unknown Primary (CUP) is a heterogeneous clinical and pathological syndrome characterized by early tumor metastatic spread without an identifiable, site-specific primary tumor of origin. Despite accounting for 3-5% of all human cancers, CUP represents a still unsolved clinical problem, with a not fully understood biology and paucity of effective therapies. Currently, patients with CUP are given systemic chemotherapy, based on a semi-agnostic approach that considers general histological features rather than organ-derivation. With 25-30% response rate and overall survival ranging from 6 to 16 months, current treatment of CUPs is considered largely suboptimal. Furthermore, because of their innate ability to spread at distant organs early in their natural course, CUPs may represent a valuable clinical and translational model to study the molecular basis of tumor metastatization.
Research Achievements:
We have designed and implemented the AGNOSTOS program, that is aimed at identifying new potential treatments and at conducting systematic translational studies on this rare entity.
The AGNOSTOS program includes two prospective clinical studies.
• The AGNOSTOS 1 study is a multicenter, randomized phase 2 trial with a ‘Pick the Winner’ design to assess the efficacy of nab-paclitaxel-based doublet as first line therapy in treatment-naïve CUP patients. In particular we will explore the activity of nab-paclitaxel in combination with the two most active drugs (carboplatin or gemcitabine). The trial is ethically approved and currently ongoing in 10 Italian Institutions under the coordination of the Candiolo Cancer Institute. We plan to enroll 60 patients in each arm of the trial.
• The AGNOSTOS Companion Translational study is aimed at the collection of vital tissues from CUP patients to establish patient-derived-xenografts (PDX) and cancer stem cells (in vitro). Furthermore we aim to collect blood/plasma from CUP patients to obtain free tumor DNA from plasma to follow tumor burden and clonal evolution in CUPs patients (liquid biopsy), and circulating cancer stem cells.
Conclusions and perspectives:
• AGNOSTOS trial will establish whether nab-paclitaxel, a more effective taxane analogue, can be safely and effectively combined to gemcitabine or carboplatin, the two most used CUP drugs, to improve disease control and outcome of these patients.
• AGNOSTOS translational study will deploy the extensive genomic work-up of enrolled patients to pinpoint common denominators of the hypermetastatic phenotype and it will exploit patient-derived-xenograft for an in-depth molecular characterization of these tumors, with the potential to unravel the molecular link between cancer stemness and the hypermetastatic phenotype.