As the number of actionable mutations increases in non–small cell lung cancer (NSCLC), widespread comprehensive molecular testing starting with reflex testing is critical to ensuring patients receive optimal care, according to Mark A. Socinski, MD, and Martin F. Dietrich, MD, PhD.
“We think of cancer as a disease of the DNA, so you have to interrogate the DNA to see whether it [holds] any secrets,” Socinski explained. “We know there are a number of mutations, fusions, [and] protein expressions [which are] important in certain cases. I believe that comprehensive genomic testing is a part of the diagnosis.”
Socinski is a thoracic medical oncologist and the executive medical director of AdventHealth Cancer Institute in Orlando, Florida. Dietrich is a medical oncologist at Cancer Care Centers of Brevard, part of The US Oncology Network, in Rockledge, Florida.
During an OncLive® Insights program titled, “My Treatment Approach: NSCLC Testing and Management of Complex Cases,” Dietrich and Socinski unpacked their respective institutions’ molecular testing methodologies for NSCLC and discussed how they might approach 2 complex cases.
Best Molecular Testing Practices in NSCLC: Key Takeaways
- The best way to minimize delays and achieve the most comprehensive testing practice possible is to employ a reflex testing approach.
- Reflex testing involves the pathologist being responsible for initiating molecular testing within a context of parameters defined by the multidisciplinary care team but without the requirement for a formal request from the oncologist.
- Data from a single-institution retrospective cohort study published in the Journal of Thoracic Oncology showed that the rate of comprehensive molecular testing increased from 39.2% (n = 183 of 466) to 45.8% (n = 318 of 695) after the reflex approach was adopted.
What are the current standards for NSCLC biomarker testing in the real-world setting?
The investigators began their conversation by providing an overview of the role biomarker testing and how they integrate it into their clinical practice. “It’s not OK to [just] say a patient has adenocarcinoma of the lung. You’ve got to make sure they don’t have 1 of the mutations or fusions that would make a big difference in their initial treatment,” Socinski commented.
Socinski noted that at his institution testing is predominately handled internally at the time of biopsy. Fifty- and 500-gene panels are used to help determine frontline treatment approaches, with the 500-gene panel informing possible clinical trial enrollment for patients with mutations in genes such as STK11 and KEAP1, he added. He noted that results from the 50-gene panel are available in 7 to 8 business days, with results from the 500-gene panel taking 2 to 3 days longer. Immunohistochemistry testing is usually handled externally, he said.
“In the early-stage [setting] there are really only 2 molecular markers that we need to know about: EGFR and ALK,” Socinski explained. “The real conundrum comes up when, [for example], you find a RET fusion in a stage II or stage III surgical patient. We don’t have data in that space, but we certainly have data in the EGFR and ALK spaces, and these drivers tend to be fairly consistent in [determining] the value of targeted therapy.”
Dietrich noted that the best way to minimize delays and achieve the most comprehensive testing practice possible is to employ a reflex testing approach. Reflex testing refers to a testing strategy in which the pathologist is responsible for initiating molecular testing within a context of parameters defined by the multidisciplinary care team but without the requirement for a formal request from the oncologist.1 This methodology enables biomarker testing to begin as soon as the pathological diagnosis is confirmed and ensures that all patients are receiving optimal care in the community setting.
Findings from a retrospective cohort study published in the Journal of Thoracic Oncology revealed that reflex testing in newly diagnosed patients with stage IV nonsquamous NSCLC increased the proportion of patients who underwent comprehensive tissue-based molecular testing upon initial diagnosis.2 Specifically, after reflex testing was implemented the rate of comprehensive molecular testing increased from 39.2% (n = 183 of 466) to 45.8% (n = 318 of 695). Ninety-six percent of the total number of molecular tests (n = 549) were initiated through the reflex pathway following its introduction.
“The reflex pattern is the ideal way to minimize delays and have most comprehensive testing done,” Dietrich explained. “We typically order this manually in the clinic. When we see patients, they rarely come with a molecular profile, unless they come from our institution.”
How should molecular testing be approached in a complex case?
The experts transitioned their conversation to consider their molecular testing approaches in 2 complex example cases. The first case was a 58-year-old female patient who was a former smoker with 5 pack-years who quit 20 years ago. She presented with persistent cough, right-sided pleuritic chest pain, and unintentional weight loss. Findings from a CT scan showed a 4.2-cm spiculated mass in the right upper lobe with small ipsilateral mediastinal lymphadenopathy that was confirmed by a PET/CT scan. Findings from a brain MRI were negative for metastases.
In the event of an adenocarcinoma, Socinski indicated that he would want to ensure that the patient was tested for EGFR and ALK alterations. He noted that next-generation sequencing (NGS) would be the preferred testing method due to the risk of disease recurrence.
“We know that stage III, either surgical or nonsurgical, disease has an [approximately] 50% chance of becoming stage IV,” he explained. “If you have that [NGS] information, it’s helpful in making decisions if [their disease] became stage IV.”
The second case was that of a 59-year-old female, lifelong nonsmoker who presented with a 3-week history of dull left shoulder pain radiating to the upper chest. The woman subsequently developed exertional dyspnea and fatigue. Findings from a chest CT scan revealed a 2.8-cm spiculated mass in the left upper lobe apex, abutting the pleura with no obvious lymphadenopathy. PET/CT results showed no distant disease, and the brain MRI was negative for metastases. A CT-guided core biopsy showed a poorly differentiated carcinoma and findings from the initial biomarker panel showed that the patient’s disease was negative for PD-L1, EGFR, ALK, ROS1, and KRAS G12C, although a TP53 mutation was detected.
Dietrich noted that negative NGS findings in a patient who is a never smoker raises suspicion and would trigger him to opt for a repeat tissue NGS from a second sample based on the nodes. “I want to see those [negative findings] get confirmed, [because absence of an oncogenic driver in a never smoker] is highly suspicious. I would like to double check that there’s not a fusion event or any other rare genetic alteration that may be helpful.”
References
- Gosney JR, Paz-Ares L, Jänne P, et al. Pathologist-initiated reflex testing for biomarkers in non-small-cell lung cancer: expert consensus on the rationale and considerations for implementation. ESMO Open. 2023;8(4):101587. doi:10.1016/j.esmoop.2023.101587
- Marmarelis M, Berman A, Scholes D, et al. Impact of reflex testing on pathology based molecular testing in patients with advanced non-squamous non-small cell lung cancer (NSCLC). J Thorac Oncol. 2021;16(10):S1157. doi:10.1016/j.jtho.2021.08.610
