In patients with non-small-cell lung cancer (NSCLC: comprising 80% of all lung cancers), long-term survival outcomes can be poor even for those who have had surgery at an apparently early stage of disease (stages I and II)***. This is mainly because in some of these patients, the disease has spread (metastasised), but the metastases are undetectable. Research on a new lung cancer assay, published Online First by The Lancet, shows it is possible to more accurately predict which patients will be cured by surgery and those who may die within five years of the operation. The study is by Dr Michael J Mann and Professor David M Jablons, University of California, San Francisco (UCSF) Thoracic Surgery Division, San Francisco, CA, USA, and colleagues.
The assay measures the activity of fourteen genes in tumor tissue from individual patients. Unlike most previous research published in this field, the genetic activity can be measured in tissue that undergoes routine handling after removal by surgery, making the test available to all patients. The pattern of gene activity levels is then analyzed, yielding a risk score that places the patient in one of three risk categories: high, intermediate or low. This assay has undergone two rigorous, independent and large blinded validation trials that are the subject of The Lancet report.
The concept of the assay was initially developed at UCSF and then licensed and developed into the current assay technology by Pinpoint Genomics, Inc—a molecular diagnostics company in Mountain View, CA, USA. It was then validated in Kaiser Permanente Hospitals in Northern California and subsequently in a group of patients from the China Clinical Trials Consortium (CCTC). In the Northern California patients, 5 year overall survival was predicted to be 71% in low-risk, 58% in intermediate-risk, and 49% in high-risk patients. Similar analysis of the CCTC cohort indicated 5 year overall survivals of 74% in low-risk, 57%, in intermediate-risk, and 45% in high-risk patients.
The authors say: "The molecular assay was the strongest predictor of 5-year mortality compared with standard criteria such as sex, age, smoking status, tumour size, and even disease stage, and outperformed National Comprehensive Cancer Network guidelines used to identify high-risk patients with stage I disease."
They add: "This assay provides prognostic differentiation of patients with early stage disease and might be helpful in the identification of the most appropriate application of treatment guidelines to improve clinical outcomes."
The authors now plan a prospective study in which patients with stage I disease identified as high risk by the molecular assay will be randomly allocated to observation versus chemotherapy, and which will directly test the effectiveness of the application of guidelines for adjuvant treatment on the basis of this molecular enhancement of risk stratification. However, they warn that during the many years required to complete such a study, thousands of patients with apparent stage I NSCLC, but with 'hidden' metastases, will undergo surgery but succumb to recurrent disease. The authors add*: "Current guidelines already recommend consideration of chemotherapy in stage I patients whose tumors show various characteristics that are felt to place them at high risk of mortality. The data reported in The Lancet indicate that this molecular assay outperforms all of those criteria in terms of accurately identifying the patients at highest risk."
In a linked Comment**, Dr Yang Xie and Professor John Minna, University of Texas, Southwestern Medical Center, Dallas, TX, USA, say*: "In addition to identifying patients with bad prognosis that need additional treatment it will be important to have biomarker signatures that that will be predictive of better survival when coupled with a specific type of adjuvant chemotherapy—a different type of information than biomarkers for prognosis. Together, prognostic and predictive markers will allow 'personalised medicine' for each lung cancer patient— determining who needs additional therapy and what specific type of therapy to use. Of course it is possible a signature could contain both prognostic and predictive information. Further studies will tell whether the genes in this new assay are of functional relevance and whether they also will provide information on how a lung cancer patient will respond to adjuvant therapy."
For Dr Michael J Mann and Professor David M Jablons, University of California, San Francisco (UCSF) Thoracic Surgery Division, San Francisco, CA, USA, please contact Jason Bardi in the Media Relations Office. T) +1 415 502-4608 / +1 415 317-3760 E) Jason.Bardi@ucsf.edu
Professor John Minna, University of Texas, Southwestern Medical Center, Dallas, TX, USA. Please contact Alex Lyda, Media Relations. T) +1 214 648-3404 E) Alex.Lyda@UTSouthwestern.edu
Note to editors: *Quotes direct from authors, not exactly as they appear in the Article
**Linked Comment not available until the paper appears in a future print issue; however Prof Minna is happy to speak to the press about the study at this time under the above embargo
***the China validation study confirmed the accurate identification of high risk patients in stage II as well as stage I. Compliance with existing therapeutic guidelines is currently suboptimal in stage II patients, and this new assay should definitely aid patients and their doctors in improving compliance at least in the highest risk stage II patients who need adjuvant therapy the most.
Journal
The Lancet