Illustration of lungs: © yodiyim – stock.adobe.com
The landscape of lung cancer diagnosis has evolved, with bronchoscopic approaches emerging as the preferred first-line method for tissue acquisition. At the same time, comprehensive biomarker testing has become indispensable for guiding personalized treatment strategies in non–small cell lung cancer (NSCLC). These trends are linked by the need for reliable, adequate tissue samples to make a treatment plan.
Although advancements in technology and workflows, including liquid biopsies and reflex testing, are accelerating treatment initiation, continuous research and interdisciplinary collaboration are vital to addressing remaining questions regarding diagnostic yield optimization, cost-effectiveness, and the rapidly expanding field of molecular biomarkers.
“The role of tissue biopsy is critical for us,” said Martin F. Dietrich, MD, PhD, in an interview with Targeted Oncology. “We need to make sure that we understand the exact staging up front, and…the understanding of biomarkers and the molecular setup that tumor types have up front in a diagnosis. We need biomarker testing comprehensively in virtually every stage of disease.”
Dietrich is a medical oncologist with the US Oncology Network Cancer Care Centers of Brevard and an assistant professor of internal medicine at the University of Central Florida College of Medicine in Orlando, Florida. He said biomarker testing’s role is so vital to determining treatment that it is changing the traditional approach of histological diagnosis followed by evaluation for targeted therapy into one where targeted therapy is incorporated into the earliest evaluation of the patient. This makes inadequate tissue sampling a potential roadblock to patient care.
Expert Panel Addresses Preferred Biopsy Approach
In May of 2025, a multidisciplinary expert panel from the American Association of Bronchology and Interventional Pulmonology (AABIP) and the Early Detection and Screening Committee of the International Association for the Study of Lung Cancer (IASLC) published a clinical practice guideline comparing endobronchial ultrasound (EBUS)–guided biopsy with CT-guided percutaneous biopsy.1
“Our data reaffirmed that [EBUS] is a safer procedure because it is less invasive. But in terms of molecular and diagnostic yield, despite being less invasive, as we have advanced our tools…the biomarker testing is comparable,” said Abhinav Agrawal, MD, one of the lead authors of the report, in an interview with Targeted Oncology.
Agrawal, director of interventional pulmonology and bronchoscopy at Northwell Health in New Hyde Park, New York, said it was vital to address this question because biomarker testing is critical to designing a personalized treatment regimen. The review focused on interpreting data from the past 10 years when comprehensive biomarker testing was starting to see use, to confirm that sufficient tissue for all purposes was being obtained.
Dietrich agreed that the conclusions drawn by the panel were valuable for oncologists. “The summary for our clinical practice was that endobronchial approaches are safer and may have a bit of a tendency to be more proficient in procuring enough tissue for our analysis as well. I think this is a practice-changing summary…that helps us to prioritize endobronchial approaches and think of the percutaneous approaches only in a backup setting for most cases.”
Shortcomings of Tissue Biopsy
Lack of adequate tissue can have serious impacts on patients with lung cancer. Agrawal noted that a recent comparative study found a 70% to 80% yield in both navigational bronchoscopy and transthoracic needle biopsy,2 although he estimated that newer robotic bronchoscopy techniques may have a diagnostic yield above 90%.
Dietrich likewise estimated that between 20% and 30% of patients do not have adequate tissue for next-generation sequencing (NGS), which can vary depending on the patient and institution. He described this as a major challenge and a roadblock in making decisions, as lung cancer is a systemic disease that requires tailored systemic therapy in most cases.
“The role of tissue biopsy is such a hard stop in the decision-making process of delineating optimal therapy for patients,” Dietrich said. In the past, he had been involved in cases where tissue biopsy had already been done, but now he prefers to get involved as early as possible to guide site selection and tissue requirements.
“When I see a radiographic diagnosis of cancer, I think about the best biomarker evaluation strategy up front, delineating the best approach for endobronchial biopsies, giving me stage and tissue sufficiency for analysis,” he explained.
With targeted therapy being used not only in the metastatic NSCLC setting but also in earlier stages, the time it takes to get biomarker testing can make a difference. Dietrich said it can sometimes take 6 to 8 weeks to get through the steps of biopsy and processing if a rebiopsy is needed. Particularly in the neoadjuvant perioperative setting, there is a need for a fast approach when coordinating with the surgeon to ensure that delays for biomarker workup and targeted treatment do not interfere with resection.
Reflex Testing and Liquid Biopsy
The NCCN guidelines for NSCLC recommend broad-based genomic testing, including EGFR, ALK, ROS1, BRAF, KRAS, MET, RET, HER2 (ERBB2), NTRK1/2/3, and PD-L1 in advanced disease, with PD-L1, EGFR, and ALK testing done even in earlier-stage disease.3
Agrawal said that before performing biopsies, he may bring up cases to a tumor board and ask whether biomarker testing would be indicated. If the findings show locally advanced disease, he can request NGS immediately rather than waiting for the oncologist to order it. Reflex testing has been helpful, but he acknowledged that he works in a tertiary care center where it is easier to do. The traditional workflow would be to find a lesion, wait for a positive biopsy to return, then have the patient see the oncologist, who would order biomarker testing. “If you can move up the biomarker testing in that algorithm, the time from diagnosis to treatment goes down,” he noted.
In Dietrich’s experience, reflex testing can be institution-dependent, but ideally any patient with lymph node–positive disease or larger tumors would qualify for testing, and a stage-independent automated reflex protocol should allow NGS to be done as soon as possible. Logistical issues can lead to friction; he gave the example of a patient coming to clinic 7 days after disease histology was determined and only then having NGS testing ordered.
Dietrich is a proponent of greater use of liquid biopsy to test circulating tumor DNA (ctDNA) to get faster results in virtually all patients, although those with small cell lung cancer may benefit less. Because liquid biopsy lacks invasiveness, there is little risk of harm, and it can complement tissue biopsy, considering the possibility of insufficient tissue. “Especially the patients [whose disease is] more advanced, where speed is of the essence, the utility of liquid biopsy is enhanced,” he said.
The NCCN recommends that ctDNA testing should not be used in lieu of a histologic tissue diagnosis for NSCLC, and for stages I to III, tissue-based testing is preferred.3 It also states that metastatic disease confined to the thorax may have a higher yield with tissue-based testing.
Biomarkers Drive Treatment vs Histology
The introduction of targeted therapy and immunotherapy to the early-stage setting has changed treatment “tremendously,” according to Dietrich. These patients must be evaluated for potential EGFR- or ALK-targeted adjuvant therapy or neoadjuvant immunotherapy plus chemotherapy.
The phase 3 CheckMate 816 trial (NCT02998528) reported overall survival benefit for nivolumab (Opdivo) plus chemotherapy at 5 years regardless of PD-L1 status, making most patients with locally advanced disease eligible.4 However, Dietrich says PD-L1 status is still informative in earlier-stage cancer; he may prefer up-front surgery for a patient with PD-L1–negative stage II disease, whereas he would use neoadjuvant immunotherapy in one with PD-L1 of 80% and stage III disease.
In patients with unresectable locally advanced disease, immunotherapy and targeted therapy can be used in the consolidation setting after chemotherapy and radiation. “The opportunities are there across stages to translate our learning lessons from biomarker analysis from stage IV into stage III, into stage II, and—to a certain extent—even into stage I high risk,” Dietrich said.
Molecular characteristics now play a greater role in guiding treatment selection than histology. he traditional approach of first making a histologic diagnosis and then ordering tissue and liquid biopsy may be replaced by a more aggressive approach guided by rapid biomarker testing.
Communicating the Need for Biomarker Testing
To Agrawal, it is important to have a discussion between the pulmonologist or thoracic surgeon and the oncologist to evaluate the need for biomarker testing. “We don’t want the patients with stage I lung cancer to be sent for biomarker testing, but if there is locally advanced disease, then we want the tissue to be sent.”
Even in patients with smaller lung nodules that are pending diagnosis, a biopsy will be done to identify whether the patient has lung cancer. Then, with biomarker testing, the treatment team can develop a comprehensive treatment plan to guide treatment and assess whether the patient will benefit from targeted therapies for locally advanced disease.
Many academic institutions have perfected a multidisciplinary approach to tissue analysis, “from the interventionalist getting the tissue all the way to the tissue processing and interpretation,” Dietrich said. “They have made this a very streamlined process.” In the community setting, the process is less seamless, but the availability of liquid biopsy has contributed to making the right treatment decisions.
Dietrich has also talked to pathologists he works with to make clear his needs for histological staining and to promote awareness of tissue stewardship and conservancy. The recommendation to utilize EBUS-guided approaches is another helpful step for minimizing risk and delays while maximizing tissue proficiency.
“For our colleagues in the interventional procedures, we have an open channel of communication,” Dietrich said. “I explain to them, we are seeking this level of information, and the truth is, we’re not getting less in need of tissue, but it’s ever-growing. The number of biomarkers we’re seeking is getting bigger.”
The expert panel’s report pointed to newer techniques such as forceps and cryoprobe biopsy used in bronchoscopy that can acquire larger tissue samples. Agrawal said new studies should investigate whether these tools make a difference and translate to clinical benefit for patients. However, Dietrich pointed out that these technologies depend on institutional resources and the expertise of the interventionist, and oncologists must rely on their best efforts.
“What we are trying to do as a field of interventional pulmonology through the AABIP, in association with the IASLC, is to make sure that our diagnostics and our diagnostic approach match the advancement that we are seeing in targeted therapy,” Agrawal concluded.