Thoracic oncology has witnessed a rapid development of targeted therapies during the past several decades. As a result of this progress, patients are remaining on treatment longer and living long enough to develop complex resistance.
Under therapeutic pressure, tumor evolution—or “switching”—can manifest in various ways, branching into different phenotypes and clones with distinct behaviors and treatment sensitivities. This process involves a constellation of mechanisms and is a key driver of drug resistance, creating significant challenges for treatment decision-making.
During the 2026 European Lung Cancer Congress (ELCC) in Copenhagen, Denmark. Experts explored these challenges and reviewed strategies for managing resistance during a session titled Dynamic Tumor Switching in Lung Cancer: From Detection to Clinical Decision-Making.
Intratumor Heterogeneity: A Mosaic of Mutations
Targeted therapies do not simply select resistant clones but can completely reshape the tumor biology. From a biological perspective, when therapeutic pressure is applied to tumor clones, they do not evolve linearly but rather heterogeneously.
Roberto Ferrara, MD, discussed the impact of intratumor heterogeneity on targeted therapy, noting that greater intratumor heterogeneity is associated with poorer prognostic factors in non-small cell lung cancer (NSCLC), where 75% of mutations are subclonal. He said our understanding of oncogene addiction has become more complex, comparing it to a Gaudí mosaic.
“The Gaudí mosaic resembles the heatmaps of certain EGFR‑mutant NSCLCs, where we see not only the EGFR mutation but also many concurrent alterations, which increase intratumor heterogeneity,” Dr. Ferrara said.
Additionally, the more effectively the tumors are treated, the more complex the resistance mechanisms become.
“We must remember a very important law of physics: Newton’s third law of motion. When we apply a force to a system, it generates a contracting force of equal intensity but in the opposite direction,” he said. “So, when we hit the cancer harder, the cancer responds with increased heterogeneity.”
Histological Transformations: The “Zebra” in the Room
Using the zebra metaphor from the rare disease world, Antonio Calles Blanco, MD, presented data on mechanisms of resistance in lung cancer, focusing on histological transformations and the challenges of detecting these changes.
“The fact is that histological transformation is a zebra. It’s really infrequent, not easy to detect, and requires serial biopsies post-treatment,” he said.
Dr. Calles Blanco identified phenotypic drift—or gradual changes in tumor phenotype over time—and epithelial-mesenchymal plasticity (EMP) as key drivers of tumor evolution.
“We know there is genomic instability of tumors driving more mutations in these patients,” he said. “But phenotypical changes are also a property of cancer cells and are linked to combating cells for the tumor microenvironment (TME) as well as systemic interactions with the host.”
Dr. Calles Blanco then examined lineage plasticity as a hallmark of lung cancer and shared evidence indicating that sequencing targeted therapies affects the profile of resistance mutations. Additionally, tumor plasticity is a key driver of histological changes in lung cancer.
“You have probably heard about histological transformation, mostly in patients with driver mutations, but these changes have also been described in patients undergoing treatment with immunotherapy, chemotherapy, or chemoimmunotherapy,” Dr. Calles Blanco said.
He also outlined the clinical characteristics of histological transformations, noting that patients typically receive prolonged treatment and frequently develop central nervous system (CNS) metastases.
Dr. Calles Blanco noted that radiological imaging and clinical assessment alone cannot detect histologic transformation; however, there are red flags that may suggest its presence:
- Rapid disease progression
- Loss of response to targeted therapy
- Neuroendocrine features in post-treatment biopsies
- Recurrent CNS disease
- New metastatic growth or growth patterns
When histologic transformation is suspected, he said repeat biopsy is important to confirm any new histology, perform molecular testing, and guide treatment decisions.
Decisions, Decisions: Using Biology to Guide Therapy
Raffaele Califano, MD, discussed the role and timing of tissue re-biopsy, liquid biopsy, and integrated molecular monitoring. He identified tumor biopsy and liquid biopsy as clinical tools for detecting tumor switching in patients, highlighting the strengths and limitations of each.
“These are not competing tools. These are two different tools that will answer different questions,” Dr. Califano said.
While tissue biopsy offers advantages such as histological confirmation, neuroendocrine markers, phenotypic assessments, and genomic profiling, it also has limitations that include:
- Invasiveness
- Safety or feasibility concerns
- Sampling bias
- Spatial heterogeneity
Similarly, liquid biopsies offer advantages such as detecting resistance mutations, emerging clones, and clearance kinetics; however, they also have limitations, including a lack of histological transformation data and complex interpretation.
“ctDNA is helpful if we witness systemic progression, multiple new lesions, if the biopsy site is quite difficult, and if there is a high suspicion of resistance mutations,” Dr. Califano said. “Conversely, we should proceed directly to tissue if there is oligo-progression, atypical radiology, suspected small cell lung cancer (SCLC) or squamous cell transformation, or if there is a discordant behavior.”
Dr. Califano introduced an integrated model—the Califano Model—which begins by defining a biological question at disease progression, rather than immediately proceeding to the next line of treatment.
He said if phenotypic resistance is suspected, tissue biopsy is preferred; if genomic resistance is suspected, ctDNA testing should be done first. Though Dr. Califano noted that sometimes both are necessary. Once you have this information, you can hold a multidisciplinary team (MDT) discussion to determine the most appropriate therapeutic strategy.
“Realistically, tumor switching is not optional. It’s an expected consequence of the therapeutic pressure that we apply to tumor clones,” Dr. Califano said. “When you witness clinical progression, the first question to ask should not be what drugs to administer next, but what kind of biology are we looking at, because treatment decisions must follow biology, not assumptions.”
Reshaping Clinical Strategy
How can all of this be translated into concrete treatment options? Chiara Bennati, MD, aimed to address how clinicians can reshape what is clinically available to define optimal sequencing to counteract switching.
Dr. Bennati said resistance mechanisms have spatial and temporal interconnections, which pose challenges to linear sequencing, including:
- Target disappearance
- Target displacement
- Target decentralization
- Phenotypic disguise
- Interactions between tumor cells and non-malignant cells within the TME
Given the changes in the immune microenvironment across time points, Dr. Bennati proposed shifting from a “hit-the-target” approach to one that embraces the microenvironment’s complexities.
“The hit-the-target approach ultimately proves unsuccessful because interrupting only one resistance mechanism leads to an alternative in its place,” she said. “Perhaps we should consider drug-tolerant persister cells.”
Dr. Bennati also said it is important to embrace a multidisciplinary approach to ensure collaboration among specialists, improve adherence to guideline management, and enhance healthcare utilization. This includes ongoing interplay among dedicated tumor boards—or thoracic tumor boards—dedicated to specific patient needs (e.g., fertility tumor boards, organ-specific tumor boards, etc.).
“Understanding tumor evolution requires a multi- and interdisciplinary approach, and also a tailored communication strategy, because we have to clearly convey these decisions to our patients,” she concluded.
