Treatment Guided by Both Tissue + Liquid Biopsies Led to Better Outcomes Compared to Standard of Care

While decision-making for genomics-driven therapy in patients with advanced, recurrent and/or metastatic, solid tumors is generally guided by results from a tissue biopsy, a question remained if a liquid biopsy, testing for circulating tumor DNA (ctDNA) for the genomic profiling of solid cancers could be beneficial. Which method would yield more accurate results and benefit treatment decision-making?

To answer the question, scientists in Italy developed a study to evaluate the efficacy (i.e overall response rate Objective Response Rate/ORR) of targeted therapy vs Standard of Care in patients with progressive disease of breast cancer, metastatic gastro-intestinal tumors, non small cell lung cancer (NSCLC) or others.

The results from this phase 2, multicenter ROME trial (NCT04591431) were presented at the annual meeting of American Association for Cancer Research (AACR), held April 25-30, 2025 in Chicago, Illinois, shows that patients with advanced solid tumors experienced significantly improved survival outcomes when receiving a tailored therapy based on the detection of the same genomic alteration in both tissue and liquid biopsies compared with both standard-of-care (SoC) treatment and tailored therapy that was based on either biopsy on its own.[1][2]

Precision oncology
Genomic profiling is used as part of precision oncology to help identify specific actionable alterations in a tumor that can be targeted with a therapeutic.

While tests can be performed using either a liquid biopsy (blood) or tissue sample, it remains unclear which method should be preferred in clinical practice and under which specific circumstances, according to Paolo Marchetti, MD, scientific director at the Istituto Dermopatico dell’Immacolata (IDI-IRCCS) in Rome, Italy.

Invasive procedure
Tissue biopsies get a sample directly from the tumor but require an invasive surgical procedure. Since the sample is taken from a specific area of the tumor, the test may miss mutations in other parts of the tumor. Liquid biopsies only require a sample of blood but may not detect mutations from tumors that do not shed enough cells into the bloodstream. These differences in how samples are collected can lead to discordant results.

“Investigating discordance in molecular alterations between tissue and liquid biopsies is critical for precision oncology,” explained Paolo-Marchetti, MD, Scientific director at the Istituto Dermopatico dell’Immacolata (IDI-IRCCS) in Rome, Italy, who presented the trial results.

“Tumor characteristics in different sites can lead to the identification of different clinical actionable targets, yet current biopsy strategies often fail to capture this heterogeneity,” he added.

Between November 2020 and August 2023, 1,794 adult patients with advanced or metastatic solid tumors who were on their second or third line of treatment were enrolled in the ROME trial.

In this study, each patient was required to provide samples for both a liquid biopsy (FoundationOne Liquid CDx)* and a tissue biopsy (FoundationOne CDx).**

Next-generation Sequencing (NGS), also known as massively parallel sequencing or deep sequencing, a technology that allows scientists to rapidly and efficiently determine the sequence of DNA or RNA, was performed on the samples. The results were analyzed by a molecular tumor board to assess both concordance and discordance based on alterations considered actionable. Concordance was defined as the detection of the same significant alterations in both biopsy types; discordance indicated detection in only one. The board identified 400 patients with alterations that could be targeted with tailored therapy.

Actionable alterations
Of these 400 patients, tissue and liquid biopsies identified the same actionable alterations in 49.2% of cases (197 patients, T+L group), while actionable alterations were exclusively detected via tissue biopsy in 34.7% of cases (139 patients) and exclusively in liquid biopsies in 16% (64 patients). In each arm, patients were randomly assigned to receive either tailored therapy or standard of care as chosen by the clinician presenting the case.

Median overall survival (OS) was 11.05 months in the T+L group that received tailored therapy vs. 7.7 months in the standard-of-care group, with a 26% reduction in the risk of death for those in the T+L group. The median progression-free survival (PFS) in these groups was 4.93 months vs. 2.8 months, respectively, with a 45% reduction in the risk of progression in the T+L group. In contrast, the survival benefit of tailored therapy was less pronounced or absent in patients with discordant results.

Overall, OS was higher in the T+L group (11.05 months), followed by the tissue-only group (9.93 months), and the liquid-only group (4.05 months). PFS followed a similar pattern, with the longest PFS in the T+L group (4.93 months) vs. 3.06 months in the tissue-only group and 2.07 months in the liquid-only group.

Additionally, the 12-month OS rate was 47.8% in the T+L group that received tailored therapy and 38.8% in the standard-of-care group, while the 12-month PFS rates were 27.2% and 9.1%, respectively. Among T+L patients, the objective response rate was 20% in the tailored therapy arm vs. 11.8% in standard-of-care arm.

Superior findings: concordant biopsy
“The superior outcomes observed in patients with concordant biopsy findings highlight the potential of combined molecular profiling approaches to optimize patient selection for tailored therapies,” Marchetti said. “The concordance may be related to the tumor expressing the same genomic alteration in different metastatic sites. Expanding the analyses to account for more factors, such as disease subtype, metastatic sites, and biopsy location could help define a new, more effective diagnostic pathway.”

Discordant cases were attributed to discrepancies found in the detection of molecular alterations (43.3%), high tumor mutational burden (35%), and microsatellite instability (1%), as well as test failures (21%). The two pathways with the highest discordance rates were PI3K/PTEN/AKT/mTOR and ERBB2.

Address discordance
Based on the outcome, Marchetti explained that strategies need to be developed to address discordance, such as by incorporating additional molecular profiling methods or enhancing the sensitivity and specificity of existing technologies. His group will also work to validate these findings in a multicenter cohort using integrated liquid and tissue profiling at serial timepoints.

“By addressing the challenges of discordance and leveraging the strengths of both biopsy modalities, future strategies can refine precision oncology algorithms and enhance clinical outcomes for patients with advanced cancers,” Marchetti noted

Study limitations
Limitations of this study include the exploratory nature of the analysis and the absence of predefined statistical power for subgroup comparisons, which limit the generalizability of the findings. Samples for the tissue and liquid biopsies were taken at different times, which may have affected the results. Finally, the relatively small size of certain subgroups, particularly the liquid-only group, may limit the robustness of conclusions for these populations.

The trial was funded by Roche, Bristol Myers Squibb, Incyte, Novartis, Pfizer, Takeda, Merck, and Eli Lilly and Company. Marchetti has had a consultant/advisory role for Bristol Myers Squibb, Roche/Genentech, MSD, Novartis, Amgen, Merck Serono, Pierre Fabre, and Incyte. He is also a member of the advisory board of Drug-PIN Ag.

__

Note:* FoundationOne Liquid CDx is a genomic profiling test that analyzes circulating tumor DNA (ctDNA) in the blood of advanced cancer patients. It identifies genomic alterations and biomarkers that may indicate a patient’s eligibility for specific targeted therapies or precision medicine approaches.

** FoundationOne CDx is the first US Food and Drug Administration (FDA) companion diagnostic designed to analyzes tumor tissue samples to identify genetic variations and other biomarkers in solid tumors. The diagnostic test is approved for various cancer types, including non-small cell lung cancer, melanoma, breast cancer, and more and analyzes a wide range of genes, including those related to gene fusions (including ROS1 and NTRK1, 2, 3), and biomarkers like microsatellite instability (MSI) and tumor mutational burden (TMB).

Clinical trials
The Rome Trial From Histology to Target: the Road to Personalize Target Therapy and Immunotherapy (ROME) – ClinicalTrials.gov ID NCT04591431

Reference
[1] Marchetti P, Scagnoli S, Crimini E, Pisegna S, Verkhovskaia S, Curigliano G, Lonardi S, Guarneri V, Cremolini C, Malapelle U, Capoluongo ED, Ascierto PA, Puglisi F, Pruneri G, D’Amati G, Cerbelli B, Biffoni M, Tonini G, Del Mastro L, Botticelli A. Combined tissue and liquid biopsy improves outcomes in advanced solid tumors: an exploratory analysis of the ROME trial. In: Proceedings of the 116th Annual Meeting of the American Association for Cancer Research; 2025 April 25-30; Chicago, IL.: AACR; 2025. Abstract nr 6372.
[2] Botticelli1 A, Scagnoli S, Conte P, Cremolini C, Ascierto PA, Cappuzzo F, Aglietta M, Mazzuca F, Capoluongo E, Blandino G, Malapelle U, Nuti M, D’Amati G, Cerbelli B, Pruneri G, Biffoni M, Giannini G, Cognetti F, Curigliano G, Marchett P. The Rome trial from histology to target: The road to personalize targeted therapy and immunotherapy. Annals of Oncology (2024) 35 (suppl_2): 1-72. 10.1016/annonc/annonc1623 [Abstract LBA7]

Featured image: the AACR 2019 Annual Meeting Photo courtesy: 2019 – 2025 © AACR/Phil McCarten. Used with permission.

DOI