Precision Oncology
Research Description
The Precision Oncology Program headed by Silvia Marsoni is the bridge that translates preclinical discoveries into clinical benefit for cancer patients - often referred to the concept From Bench to Bedside. The group has been crucial to sustain the development of two large consortia and clinical networks within the field of colorectal and breast cancer.
Discussion of pre-clinical and clinical evidences with collaborators is essential for the Precision Oncology Unit (POU) to generate hypothesis-driven and "transformative" clinical trials. Thus, POU is focused in trial designing (including protocol and informed consent writing), in supervising study specific-documents, in developing electronic Case Report Forms (eCRFs) and in managing samples shipments and road traffic data produced by our translational partners, acting ultimately as a bridge between clinical centers and laboratories.
Figure 1: CRC and BC networks related to ALFAΩMEGA and METAMECH Master Observational Trials (MOT)
Background
Colorectal cancer (CRC) and Breast cancer (BC) are ranked within the top five lethal cancers. In Italy, the 5-years survival rate for breast cancer is now reported at 87% and falls to the 65% in colorectal cancer. At the beginning of the century these percentages showed a worse scenario, counting 84% and 59% respectively. Although mortality by CRC and BC has progressively declined due to more effective therapies, clinical research has still to satisfy several unmet medical needs such as the post-surgical management of molecular minimal residual disease, how to shift from a "one-type-fits-all" therapy to an individually tailored approach and, last but not least, how to turn hot immunologically cold tumors.
Ongoing Projects
ALFAΩMEGA and METAMECH are two clinical translational platform that will follow a cohort of patients from diagnosis to cure/death to navigate the evolutionary pathways of CRC and BC respectively, during their natural history and under the Darwinian pressure of therapies. These clinical resources for integrative clinical data, imaging and samples collection will allow the molecular story-telling of CRC and BC spread in genetic, functional and immunological terms along time and space, and the selection of appropriate patients for experimentally-driven trials (e.g. PEGASUS in CRC) focused on tumor evolution.
Focusing on CRC, we chose to further investigate within PEGASUS and ARETHUSA trials, two major issues strictly connected with the patients' quality of life.
On one hand, PEGASUS trial aims to establish the feasibility of using longitudinal liquid biopsies (LBs) to guide the post-surgical and post-adjuvant treatments of operable stage III or T4N0 stage II CRC patients. The PEGASUS study couples circulating tumor DNA detection in plasma (LBs) and guided chemotherapy in order to improve patients' clinical outcome and to reduce their toxicity exposure. Importantly, we are addressing the tumor from different research perspectives, thanks to the involvement of PEGASUS patients in the ALFAΩMEGA protocol. This approach allows a comprehensive collection of information that starts from the definition of the single cell molecular pattern and the identification of the tumor immunological landscape, through genome characterization and microbiome analysis. Exploiting artificial intelligence, we are trying to recognize new integrative markers to predict the response to therapies, with the radiologists and pathologists' precious support.
On the other hand, ARETHUSA is an interventional phase II trial in metastatic CRC patients, which attempts to turn mismatch repair proficient (MMRp), "immune-cold" tumors, into hypermutated "immune-hot" tumors by ectopically increasing the mutational burden in cancer cells with a DNA-alkylating agent that can drive inactivation of the MMR machinery. Patients with immunologically hot-induced MMRp tumors or with MMRd/MSI tumors, which are more likely to achieve a clinical response from immunotherapy, are then treated with a PD-1 inhibitor.
In BC, up-and-coming experimental results are currently being considered to finalize the design of a study for a treatment that could restore the immunocompetent system of so-called triple negative tumors - with a particularly bad prognosis.
Active clinical trials
ALFΩMEGA e ALFAΩMEGA RETRÒ
General Information
Title: A Master Protocol Empowering Precision Research in Colorectal Cancer
Study Type: Prospective Observational (Master Observational Trial – MOT)
Actual Study Start Date: October 15, 2019
Estimated Study Completion Date: December 2025
Estimated Enrollment: 500 patients
Treatment: Standard Clinical Practice
ClinicalTrials.gov Identifier: NCT04120935
Project
AlfaΩmega is a prospective master observational study that will enroll a stage-mixed cohort of approximately 500 patients with colorectal cancer. Patients are treated by their own referring physician, following standard clinical practice and undergo standard-of-care or clinical trial-directed treatments or both in succession, which means that treatments and procedures are not influenced by the study protocol. Participants will be followed for a minimum of 5 years. AlfaΩmega will enable the identification and validation of new predictive and prognostic biomarkers connected to tumor evolution, the characterization of new therapeutic approaches in pertinent patient-derived models, and ultimately the selection of patients into innovative clinical trials.
Objectives
AlfaΩmega has been designed with the intention of studying the mechanisms that drive and regulate the evolution of colorectal cancer, and exploiting discoveries to identify new vulnerabilities and therapeutic strategies. AlfaΩmega is the main engine of a Precision Oncology ecosystem in colorectal cancer, sustaining translational pre- and co-clinical research by feeding the group labs with annotated clinical data and biological samples on one side (from bed to bench-side), and speeding up the translation of the hypotheses born in the labs into new promising clinical applications on the other one (from bench to bedside). Through AlfaΩmega, patients can donate their data and samples, which will be processed and analyzed by the research groups involved in the project in order to try to significantly improve clinical outcomes, such as reducing the risk of tumor recurrence and increasing patient survival.
ALFAΩMEGA - RETRÒ
AlfaΩmega-Retrò study is the retrospective companion of AlfaΩmega and brings to the platform a whole new level of information by providing ‘on command' large numbers of patients' samples for markers validation studies. AlfaΩmega-Retrò is mostly targeted to patients who cannot be reached for informed consent, and allows the collection of clinical and imaging data and biological samples retrievable in hospital archives.
ALFAΩMEGA – Virtual Knowledge Space (the VIKS)
Data empowers patients, clinicians and scientists. A vast effort in AlfaΩmega is thus dedicated to the data integration platform that will collect the numerous rivers of host-and-tumor led information flowing from the labs and the clinic for each participating patient. Delivering higher-informative science and better patient outcomes requires the power of integrated learning, and tools like artificial intelligence. The VIKS will bring about this integration allowing for previously uncharted integrative analysis of molecular and clinical landscape.
Network
AlfaΩmega is mainly supported by an AIRC 5X1000 funding program (AIRC Foundation - "Insights into the evolving heterogeneity of colorectal cancer: from mechanisms to therapies" coordinated by Prof. Alberto Bardelli - 21091) and encompasses a multidisciplinary network of basic, translational and clinical scientists that synergize by contributing with different expertise in a unique relevant scientific and clinical effort. In this scenario, AlfaΩmega represents an integrated reservoir of pre-clinical, co-clinical and clinical information, fostering the development of a biological rounded vision of colon cancer, which thus acquires unexpected nuances and renewed prospective for discovering new therapeutic vulnerabilities.
Sites
Italy
- Niguarda Cancer Center (Milano)
- Istituto Nazionale Tumori (Milano)
- Istituto Oncologico Veneto (Padova)
- Istituto Europeo di Oncologia (Milano)
- Policlinico San Martino (Genova)
- Ospedale Ordine Mauriziano (Torino)
- Ospedale San Luigi Gonzaga (Orbassano, TO)
Spain
- Vall d'Hebron Institute of Oncology (Barcellona)
- Hospital del Mar (Barcellona)
- INCLIVA Instituto de Investigación Sanitaria (Valencia)
References
METAMECH
General Information
Title: A Master Protocol Empowering Mechanobiology Translational Research in Breast Cancer
Study Type: Observational (Master Observational Trial – MOT)
Actual Study Start Date: July 16, 2020
Estimated Study Completion Date: December 2026
Estimated Enrollment: 500 patients
Treatment: Standard Clinical Practice
ClinicalTrials.gov Identifier: NCT04625023
Project
Different tumors show a variety of specific behavior and characteristics. However, distinctions can still be observed within a cohort of patients affected by a particular type of cancer. Specific molecular "signatures" seem to determine these fluctuations. In this scenario, METAMECH trial will investigate the peculiarities connected with the molecular "signatures", exploring recently discovered aspects. In fact, physical effects may influence cancer evolution. How can mechanical stimuli be translated inside the cell? Which is the contribution of surrounding tissues? Do physical changes influence tumor survival? These are just some of the questions the study aims to examine.
Objectives
METAMECH underpins research in order to identify new therapeutic windows, hidden under tumor's characteristics. Patients' data and biological samples represent the most powerful resource that can be exploited in the investigation of future biomarkers. Specifically, the trial will look for new molecular "signatures" related to mechanotransduction following METAMECH breast cancer patients under anticancer standard treatments. Gathering evidences of mechano biology dysregulation directly from patients samples will allow researchers and clinicians to face the disease and to monitor cancer progression as a whole. The study structure includes different tiers to provide maximum flexibility in samples and data gathering. In a near future, METAMECH will also offer to patients the opportunity to be selected and triaged into molecular-based clinical studies on the basis of their specific tumoral characteristics - fulfilling the aspiration of truly tailoring treatment to patients rather than ‘dressing' patients into a one-fit treatment.
Network
Patients, oncologists, molecular biologists, chemical engineers, surgeons, pathologists, radiologists and many others: cancer treatment and management need strong collaboration within the network not only between researchers and experts, but also with patients. This large team is supported by AIRC Foundation as part of the project AIRC 5X1000 Breast Cancer "Metastasis as Mechanodisease" coordinated by Prof. Stefano Piccolo - 22759. As in a living organism, each partner performs an indispensable but at the same time useless function if actions are not related to the heterogeneous and complex system that constitutes the entire living being. Taking part in METAMECH trial, as a patient or as a researcher, will leave a mark, big or small, on the way of future therapies. A completely new combination of biology and engineering, which allows a glimpse of colorful horizons.
Sites
- Istituto Oncologico Veneto (Padova)
- Istituto dei Tumori Regina Elena (Roma)
- ASST Papa Giovanni XXIII (Bergamo)
- Azienda Ospedaliera Universitaria Maggiore della Carità (Novara)
- Istituto Neurologico Carlo Besta (Milano)
- Policlinico San Matteo (Pavia)
- Istituto Nazionale dei Tumori (Milano)
References
PEGASUS
General Information
Title: Post-surgical liquid biopsy-guided treatment of stage III and high-risk stage II colon cancer patients – The PEGASUS Trial
Study Type: Interventional – Phase II
Actual Study Start Date: June 16, 2020
Estimated Study Completion Date: December 15, 2023
Estimated Enrollment: 140 patients
Treatment: CAPOX; Capecitabine (CAPE); FOLFIRI
ClinicalTrials.gov Identifier: NCT04259944
Project
The current post-surgical management of stage III and high-risk stage II colon cancer consist of adjuvant chemotherapy regimens based on oxaliplatin and fluorouracil or capecitabine. On the contrary patients with a stage I and low-risk stage II tumor do not receive any adjuvant treatment. These evidence-based chemotherapy regimens were established almost two decades ago with recent trials mostly addressing the optimal length of treatment. However, from the same clinical trials it was also proven that:
- Between 40% and 50% of stage III and high-risk stage II colon cancer patients are exposed to excessive and toxic treatments, since surgery alone ensures a complete cancer eradication;
- Between 10% and 15% of colon cancer population with stage I and low-risk stage II experiences metastatic relapse while not receiving any chemotherapy regimen, thus being undertreated.
This happens because assigning the right treatment for each patient is a challenge not yet satisfactorily addressed with current risk classifiers. In contrast, recent studies have shown that the presence of circulating tumor DNA (ctDNA) in the blood heralds the presence of residual microscopic tumor's deposits after removal of the primary tumor. Patients with ctDNA positive liquid biopsies after surgery have a manyfold higher risk of developing distant metastases than negative patients.
The PEGASUS trial has been designed to investigate the feasibility of using ctDNA detection in liquid biopsies to help inform adjuvant treatment decisions. ctDNA is on its way to become a promising prognostic biomarker related to the post-surgical discovery of colon cancer micrometastasis that escape the detection by standard imaging techniques because of sensitivity limitations.
To better explore liquid biopsy potential, PEGASUS aims at proposing an unprecedented way of guiding therapeutic decision-making in colon cancer treatment.
Figure 1: Pegasus trial design
Objectives
Three main questions underpin PEGASUS trial in order to support liquid biopsy possible future applications:
1) Can post-surgery ctDNA detection be used to personalize adjuvant treatment in stage III and high-risk stage II colon cancer?
2) Can post-adjuvant treatment ctDNA detection be used as a proxy of adjuvant treatment efficacy and to further guide treatment choices?
3) How can we protect our patients from false negative liquid biopsies results and consequent risk of undertreatment?
PEGASUS declines its possible goals in a map, taking charge of patient needs for the purpose of offering them better outcomes, such as improved quality of life and advanced personalized treatments.
Network
PEGASUS is the first trial fully embedded within the ALFAOMEGA platform. Intertwined since birth, PEGASUS and ALFAOMEGA together acquire further value, allowing the collection of clinical data and samples coming from PEGASUS patients and offering to ALFAOMEGA participants the possibility to be selected and involved in this interventional phase II trial. The translational potential of the platform reaches a new level (TIER 3) showing the empowerment presented with the union of pre-clinical and clinical strengths. All this would not have been possible without the support of AIRC Foundation (AIRC 5X1000 - "Insights into the evolving heterogeneity of colorectal cancer: from mechanisms to therapies" coordinated by Prof. Alberto Bardelli – 21091), which sustained the ideas and activities of the colon cancer dedicated team.
Sites
Italy
- Istituto Oncologico Veneto (Padova)
- Istituto Nazionale Tumori (Milano)
- Niguarda Cancer Center (Milano)
- Policlinico San Martino (Genova)
- Istituto Europeo di Oncologia
Spain
- Vall d'Hebron Institute of Oncology (Barcellona)
- Hospital del Mar (Barcellona)
- INCLIVA Instituto de Investigación Sanitaria (Valencia)
References
ClinicalTrials.gov
Journal of Clinical Oncology
Cancer Research
Photogallery
Clinical Trial