Case Studies

To address the need for more efficient cancer genomic testing, Italy’s national oncology network, Alleanza Contro il Cancro (ACC – Alliance against Cancer), launched the GerSom initiative. This three-year study tested the feasibility of combining somatic and germline genetic profiling at cancer diagnosis, enabling doctors to identify both treatment-relevant mutations and map genetic risk (inherited variants of Cancer Predisposing Genes, CPGs) through a single test. To this aim, ACC developed and validated a cost-effective, high-throughput gene panel that analyzes 467 tumour-related genes including 172 CPGs, in addition to 196 pharmacogenomic variants, in under one week.

The project had a double ambition: to better treat patients by identifying the potentially most effective drugs and to prevent cancers in their high-risk family members by directing them towards dedicated prevention pathways.

Traditionally, the diagnostic pathways for identifying “actionable” tumour mutations (informative for prognosis and treatment) and for mapping genetic risk through inherited variants in cancer predisposing genes (CPGs) have been separate. However, substantial overlap between these areas suggests benefits to an integrated approach. For example, 10% of somatically mutated genes are also associated with cancer susceptibility, and 40% of CPGs are also found mutated in tumours. Moreover, many CPGs are themselves actionable, and maintaining separate diagnostic workflows for somatic and germline testing increases overall costs.

In response, and following legislation (Law 232/2016) allocating national research and infrastructure funding, Alleanza Contro il Cancro (ACC) – Italy’s national oncology network – launched the GerSom project. This multi-centre, three-year initiative (2019–2022) aimed to test the feasibility of a joint diagnostic pathway at the time of cancer diagnosis, enabling the simultaneous identification of:

1. actionable somatic gene mutations to inform treatment decisions, and
2. hereditary CPG mutations to assess cancer genetic risk.

The project was funded by the Ministry of Health with €6.4 million and involved 26 hospitals. Its goals included:

• Recruiting 4,000 patients with a high genetic risk (those with ovarian cancer or triple-negative breast cancer, and young patients with breast cancer (younger than 40) or colorectal cancer (younger than 50).
• Validating a custom sequencing panel encompassing 467 tumour-related genes including 172 CPGs, in addition to 196 pharmacogenomic variants.
• Equipping 17 research hospitals with cutting-edge next-generation sequencing (NGS) infrastructure.
• Hiring 20 fellows, including clinical researchers and data managers.
• Developing shared standard operating procedures (SOPs) and clinical guidelines for interpreting both somatic and germline findings.
• Establishing a national database and a supra-institutional Molecular Tumor Board to support interpretation of complex cases.

Despite delays caused by public procurement processes and the COVID-19 pandemic, the project achieved several of its goals, including the genomic profiling of all recruited patients (2,569 out of the planned 4,000), the equipment of 17 research hospitals with NGS infrastructure and 20 personnel units to support local expertise in bioinformatics and clinical data analysis. To discuss the most difficult to interpret cases deriving from genomic profiling with the GerSom panel, a supra-institutional Molecular Tumor Board was established consisting of clinical geneticists, pathologists, clinicians, biostatisticians, bioinformaticians and molecular analysis experts. The GerSom Molecular Tumor Board has worked on the creation of guidelines for internal use for the interpretation of germline and somatic variants.

Enablers: Key enablers included strong political and financial backing from the Ministry of Health (Governance, financing), multidisciplinary collaboration, coordinated infrastructure and protocol development across centres (Resources). Shared SOPs and centralized decision-making through the Molecular Tumor Board also supported implementation.

Barriers: Challenges included delayed recruitment due to bureaucratic hurdles and the COVID-19 pandemic, as well as variability in engagement across participating centres. Additionally, patient enrolment monitoring could have been improved with more frequent operational meetings.

Lessons learned: While high-level issues were addressed through steering committee meetings, the introduction of regular operational plenary meetings with researchers and pathologists could have strengthened day-to-day coordination, improved monitoring of progress and fostered more consistent engagement across all participating centres. The GerSom initiative also created opportunities for synergies with other European projects. The validated GerSom panel was leveraged in the EU-funded CAN.HEAL project for the analysis of liquid biopsy samples within its clinical arm.

For more information

GerSom – Alleanza contro il cancro: https://alleanzacontroilcancro.it/en/progetti/italia/gersom