CORM

The major projects of CORM include the following:

Website and telemedicine platform: A website and a telemedicine platform that facilitates connections between our hospital and 13 different oncology hospitals in the Marche region (www.corm-marche.it).

MTB: A multidisciplinary group dedicated to identifying personalized care pathways through advanced molecular analyses and translating complex molecular data into clinically useful information for prognostic purposes and predicting cancer treatment efficacy.

Clinical and translational research development: Initiatives include phase I trials with innovative drugs to provide new therapeutic options for patients with cancer in the Marche area.

Oncological genetics research promotion: This involves close collaboration with the Highly Specialized Regional Center in Oncological Genetics active at the same institution since 2004. The center is equipped with NGS technology to offer genetic counseling in oncology to individuals (and their families) at increased risk of cancer due to hereditary genetic predispositions.

Outreach projects: These are conducted with the full cooperation of voluntary associations [5].

MTB

The MTB consists of a core team and additional specialists. The core team includes a coordinator, secretary, oncologists (including preliminary assessment), pathologists, molecular biologists, geneticists, pharmacists, pharmacologists, data managers, research nurses, case managers, bioethicists, and clinical epidemiologists. Additional specialists such as radiologists, interventional radiologists, radiotherapists, surgeons, gastroenterologists, pulmonologists, or hematologists may be involved in specific consultations. Participation of the core team members is always guaranteed during MTB meetings, characterized by multidisciplinary and multi-professional collaboration, mutual trust, decision-making convergence, regular meetings, and effective coordination [5, 6].

A registered healthcare physician activates the MTB by submitting a request via the CORM's web-based teleconsultation platform and uploading the patient's health documentation. The case is discussed during semimonthly MTB meetings, where the requesting physician can participate via teleconference. The MTB addresses cases involving the following:

Patients with advanced/metastatic disease who have undergone genomic profiling and exhibit mutational alterations without unequivocal clinical classification or lack clinically approved molecularly targeted drugs.

Patients with advanced/metastatic disease and good Eastern Cooperative Oncology Group (ECOG) performance status (ECOG 0/1) who have exhausted standard therapeutic lines and may benefit from NGS genetic profiling.

Patients with rare diseases lacking recognized therapeutic approaches or with limited therapeutic alternatives, rapidly progressing after standard therapies, with good performance status for whom NGS profiling is indicated.

Patients with “oncogene-addicted” malignancies unresponsive to current molecular therapies.

Patients with a life expectancy of less than 6 months are excluded.

The MTB's responsibilities include the following:

Selecting patients eligible for molecular testing.

Choosing the most suitable and cost-effective molecular test to identify all potential tumor targets.

Selecting the appropriate sample (liquid biopsy or histological/cytological sample) based on the patient's clinical state, molecular method, and gene panel.

Verifying the technical and methodological feasibility of molecular investigations based on the quality and quantity of available biological material.

Interpreting molecular test reports, especially ambiguous cases, to define the biological significance of genetic abnormalities and determine therapeutic actionability. Results are compared with online databases to provide precise treatment recommendations, often off-label.

Integrating clinical and genomic data to define optimal treatments for individual patients, including evaluation for clinical trial access.

Issuing detailed reports summarizing relevant results and MTB decisions.

Collecting data on the clinical outcomes of patients receiving MTB-recommended therapies.

Molecular Tests Proposed by the MTB

During multidisciplinary discussions, the MTB determines which molecular tests are appropriate for each patient according to European (European Society for Medical Oncology [ESMO]) and national (Italian Association of Medical Oncology [AIOM]) guidelines. Italy's compliance with international guidelines was formalized with Law No. 233 of 29 December 2021, establishing the MTB and identifying specialist centers for NGS genomic profiling tests.

Patients must provide written informed consent for personal and genetic data processing. Molecular analyses are typically performed on tumor nucleic acids (DNA or RNA) extracted from formalin-fixed/paraffin-embedded (FFPE) histological samples, or circulating tumor DNA (ctDNA) from liquid biopsies if tumor tissue is unavailable. The MTB chooses between “singleplex” tests able to analyze specific known molecular targets (e.g., real-time polymerase chain reaction [RT-PCR]) and “multiplex” technologies, able to analyze different biomarkers for different patients simultaneously thanks to NGS.

Available tests at thed Department of Pathological Anatomy, of Ancona include the following:

RT-PCR kits:

Immunohistochemistry (ICH) analyses:

NGS technique kits via Illumina® MiSeq:

DNA gene panel with 17 genes. Myriapod® NGS Cancer Panel DNA cat. no. NG033, Illumina® (CE IVD). The test allows one to identify single-nucleotide variants (SNV) and insertions and deletions (indels) in 17 genes of clinical-diagnostic importance in the main neoplasms (ALK, BRAF, EGFR, ERBB2, FGFR3, HRAS, IDH1, IDH2, KIT, KRAS, MET, NRAS, PDGFRA, PIK3CA, RET, ROS1, POLE).

Starting material: DNA extracted from FFPE histological samples or ctDNA.

RNA gene panel with 10 genes. Myriapod® NGS Cancer Panel RNA, Illumina® (CE IVD). This is the panel dedicated to the study of gene fusions on 10 targets of interest (ALK, ROS1, RET, MET, PPARG, FGFR2, FGFR3, NTRK1, NTRK2, NTRK3) for the prediction of response to oncological drugs, from RNA extracted from tissue FFPE.

Starting material: RNA extracted from FFPE histological samples.

FoundationOne®CDx, a DNA single-tissue-based test with 324 genes. Test results include microsatellite instability (MSI) and tumor mutational burden (TMB).

FoundationOne®Liquid CDx, which analyzes 324 genes from circulating cell-free DNA.

FoundationOne®Heme combines > 400 DNA-sequenced and > 250 RNA-sequenced genes to detect all four main classes of genomic alterations, including sensitive identification of translocations and fusions.

Mutations that play a fundamental role in cancer development are called “drivers,” because they confer a growth advantage on the affected cells. In human tumors, about 350 driver genes implicated in the development of the disease have been identified to date. Tumors strictly dependent on driver mutations are defined as “mutation-addicted.”

Genetic alterations are classified as “actionable” when they are potentially responsive to a targeted therapy.

In order to offer some guidance, ESMO has published the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT), a system that essentially classifies variants according to their clinical impact.

Tier I: Alteration–drug match associated with improved outcomes in clinical trials.

Tier II: Alteration–drug match with known antitumor activity but unknown benefit magnitude.

Tier III: Alteration–drug match suspected to improve outcomes based on clinical trial data from other tumor types or similar alterations.

Tier IV: Preclinical evidence of actionability.

Tier V: Alteration–drug match with objective response but without clinically meaningful benefit.

Tier X: Lack of evidence for actionability.

Based on ESCAT, the ESMO Precision Medicine Working Group recommends using tumor multi-gene NGS in patients presenting with advanced non-squamous non-small cell lung cancer (NSCLC), advanced colorectal cancer, prostate cancer, ovarian cancer, and cholangiocarcinoma, characterized by ESCAT level I mutations.

AIOM then implemented the same recommendations.

On May, 2024, the ESMO Precision Medicine Working Group extended these recommendations to other tumor types (advanced breast cancer, gastrointestinal stromal tumors, sarcoma, thyroid cancer, cancer of unknown primary) [5,6,7,8,9,10,11].

MTB Outcome

MTB meeting results are summarized and communicated via a specific written report on the CORM platform, indicating the proposed therapeutic options:

Standard therapy: Common treatments include surgery, chemotherapy, and radiation, along with hormonal therapy, locoregional treatments, and targeted therapies such as immunotherapy.

Enrollment in clinical trials.

Access to drugs through other modes: Expanded access, off-label treatments, special funds for innovative drugs, etc.

Published real-world experiences indicate that patients treated according to MTB-recommended regimens, based on tumor molecular alterations, exhibit better outcomes in terms of progression-free and overall survival than those treated according to physician choice [2, 6, 7, 12].

The early access to drugs in Italy includes different possibilities:

Off-label drugs are used in clinical practice for conditions not included in the summary of product characteristics, and they are prescribed for different therapeutic indications based on documented scientific evidence and only if better therapeutic alternatives are unavailable.

Compassionate use means the provision, free of charge, by the pharmaceutical company of medicinal products that have not yet been authorized but have undergone clinical trials (successfully completed phase III or, in particular cases, phase II trials). It includes nominal use (individual patient use based on scientific evidence) and expanded access program (use in multiple patients under a defined clinical protocol).

Italian Medicines Agency (AIFA) National Fund Law 326/2003—“Fondo 5%” for orphan drugs treating rare diseases and drugs offering therapeutic hope for serious conditions, pending marketing.

At our Department of Oncology, a dedicated team of professionals coordinates and manages clinical trials of innovative therapies for the treatment of patients with solid tumors, access to which can be allowed through molecular analysis. Most studies involve the use of immunotherapies and biological therapies, either alone or in combination with traditional therapies.

These trials are conducted following Good Clinical Practice guidelines, an international standard of ethics and scientific quality for the design, conduct, and recording of clinical trials involving human subjects.

Within the department, a Phase I Clinical Unit has been activated. It has obtained accreditation from the AIFA for phase I clinical trials. There is a particular interest in early phase I/IIa clinical trials involving a dose-finding and pharmacokinetic analysis design.

The Department of Oncology of the AOU Marche is the only active phase I center in central Italy at the current time.

Data Organization

MTB activity and performance data, demographic data for patients discussed in MTB meetings, and data regarding their therapeutic paths were collected from June 2021 to May 2024 and recorded in a specifically designed database in order to analyze all aspects that will be described in detail in the next paragraph.

The study was conducted in accordance with the precepts of Good Clinical Practice and the ethical principles of the Declaration of Helsinki. Results presented in this article contain no personally identifiable information from the study. Ethical review and approval were waived for this study as per current regulations. Approval by the Chief Medical Officer and by the Quality Manager were required and were obtained (procedure reference: P001.DS).

Informed consent was obtained from all subjects involved in the study through the CORM (Cancer Center) platform.