Fred R. Hirsch¹, Jin Ye Yeo²

¹Center for Thoracic Oncology, Tisch Cancer Institute at Mount Sinai, New York, NY, USA; ²TLCR Editorial Office, AME Publishing Company

Correspondence to: Jin Ye Yeo. TLCR Editorial Office, AME Publishing Company. Email: editors@TLCR.org

Expert Introduction

Dr. Fred R. Hirsch (Figure 1) is currently the Executive Director at the Center for Thoracic Oncology at Mount Sinai Health Systems (MSHS). He also serves as a Professor of Medicine and Pathology at the Icahn School of Medicine, as well as an Associate Director of the Tisch Cancer Institute. Prior to this arrival at MSHS, Dr. Hirsch was a Professor of Pathology at the University of Colorado for 18 years and CEO of the International Association for the Study of Lung Cancer (IASLC) for 5 years. He has been the recipient of awards and honors, including the IASLC Mary Matthews Award for Translational Research in Lung Cancer in 2007, the Japanese Lung Cancer Society Merit Award in 2010, the Addario Foundation Lecture Award in 2015, the Joe Lowe, and Louis Price Endowed Chair in Cancer Research at the Icahn School of Medicine in 2018. He was awarded the Wuan Ki Hong Lectureship Award in 2019 and the Heine H. Hansen Life-time Achievement Award by ESMO/IASLC in 2021. Dr. Hirsch has contributed to over 500 publications in peer-reviewed journals. He continues to lead research efforts as well as new research in various laboratories in the study of lung cancer.

Figure 1 Dr. Fred R. Hirsch

Interview

TLCR: What drove you into the field of lung cancer?

Dr. Hirsch: As a medical student, I had a close family member suffering from lung cancer. His doctor was Professor Heine Hansen in Copenhagen, who is a pioneer in lung cancer research, and he made me interested in the field and in research.

TLCR: Early in your career, you studied the heterogeneity of lung cancer and developed your mantra: 'The tissue is the issue'. How has (your understanding of) this mantra changed over the years?

Dr. Hirsch: Yes, my PhD thesis was about heterogeneity in small cell lung cancer and the clinical implications. In 2004, I made a presentation/discussion at the American Society of Clinical Oncology (ASCO) with the title “The Issue is the Tissue”. That was in the early stage of personalized therapy in lung cancer based on molecular profiling. The importance of molecular profiling has been over time more and more important! Today, it is crucial for optimal treatment of the individual patient.

TLCR: Could you provide an overview of the current landscape of publications in the translational research of lung cancer?

Dr. Hirsch: The current landscape of translational lung cancer publications is overwhelming. Every day, numerous publications about “new and potentially useful” biomarkers for the selection of patients and the characterization of resistance patterns for targeted therapies and immunotherapies in lung cancer emerge. While all these studies are important, we need to be critical in identifying the clinical validity of these studies before applying them to clinical practice. Having said that, the importance of translational research cannot be underestimated. We need this research for further clinical progress, and I would like to see more focused studies on biomarkers and their validation. Often, we are missing the answers to the most basic questions in biomarker validation studies. One example is: what is the “prognostic” association of a given biomarker in order to know the true “predictive” association. Also, we are very focused on cut-off values for a biomarker, which has a dynamic expression pattern. Finally, we need to focus more on composite biomarker studies rather than focus on one single biomarker.

TLCR: Earlier this year, you and Prof. Kim held a podcast about biomarker testing in the treatment of advanced non-small cell lung cancer (NSCLC), where you shared that the concept of tumor mutation burden (TMB) needs to be refined (1). What aspects of the concept do you think should be refined?

Dr. Hirsch: TMB is a very “generic” concept. Not all mutations are equally immunogenic! The concept needs to be refined; retrospective studies in NSCLC have already indicated that by adding HLA- expression to the TMB concept makes a better prediction for immunotherapy. Definitions of high versus low TMB vary much from one study to another, and the concept needs further harmonization, which may include platform comparisons.

TLCR: You also mentioned that education on biomarker testing remains lacking. In your opinion, what are some specific strategies or initiatives that could enhance the education of biomarker testing among relevant stakeholders?

Dr. Hirsch: Yes, unfortunately, even in countries with a high education level (e.g the US), the percentage of NSCLC undergoing biomarker testing is suboptimal, which has been demonstrated in several studies including real-world data. Academic organizations and industry organizations need to intensify the importance of biomarker testing in lung cancer, both in early and advanced stages. This is particularly relevant in communities and outside academic centers. Patients’ advocacy groups have a significant role to fill in this gap. Multidisciplinary tumor boards are also important parts of this education.

TLCR: In addition to research, you are also actively involved in international communication and global efforts to conquer lung cancer, one of which is through the International Association for the Study of Lung Cancer (IASLC). How has your involvement and leadership in the IASLC impacted the field of lung cancer and vice versa?

Dr. Hirsch: International communication and global effort to conquer lung cancer have always been a focus of mine, since I started lung cancer research in medical school in Copenhagen, Denmark. I have been instrumental in developing IASLC from the early beginning. This communication has also significantly impacted my research career. I have always favored and sought international scientific collaborations, which is reflected in my publication record, and also always sought international education in many ways. I also arranged numerous educational meetings in all regions of the world, long before I became the CEO of IASLC.

TLCR: During your tenure as the Chief Executive Director of IASLC, many activities were initiated with the goal of doubling the survival rate for lung cancer by 2025. As 2025 approaches, how is the progress towards achieving this goal? What are some notable initiatives that have contributed significantly to reaching this goal?

Dr. Hirsch: During my tenure as CEO of IASLC, I increased the IASLC membership from about 3000 members to around 10,000 members. With the increase in membership in an international organization, the most updated research and treatment results have been widely disseminated. Over the last 10-15 years, we have seen the overall “cure” rate for patients with lung cancer increase from 15% to more than 25% in the US and many other countries. The significant progress can be attributed to many things such as progress in lung cancer screening with low-dose computed tomography (CT) in high-risk populations and subsequent stage migration, development of personalized therapies including more subtypes of NSCLC, and significant improvements in educational activities globally. Developments in diagnostic technologies and therapeutic technologies have also significantly contributed to the progress seen.

TLCR: Moving forward, what are the critical next steps for achieving more success in improving lung cancer survival rate?

Dr. Hirsch: On a global basis, we need to be sure that the most optimal therapies will also be available in many “underserved” countries and for many “underserved” minorities, even in well-developed countries like the US and Europe. We still need to improve the diagnostic scenario and also improve therapies. Combination therapies are important, but they need to be based on a scientific rationale. We need to learn how to better combine therapies. We need to of course also gain a much better understanding of “resistance”, both acquired and early persistent resistance mechanisms. This is the only way we can design treatment sequences rationally. Much has yet to be learned both on targeted therapies and immunotherapies for early-stage NSCLC, and therapies for SCLC are still in general left behind. From a population-based perspective, improved implementation of lung cancer screening is needed globally and we also need to have a stronger focus on lung cancer in never-smokers. We are starting to learn more about the role of pollution and environmental causes and that type of research is much needed in the future. My personal hope and ambition is that we will soon have a better understanding of the immune landscape in early lung cancer development, and immunoprevention in pre-clinical stages might be relevant not too far in the future. Much has also yet to be learned about the interaction between mutations and the immunologic landscape and microenvironment.

TLCR: How has your experience been serving as the Honorary Editor-in-Chief of TLCR?

Dr. Hirsch: It has been a great pleasure following the great development of the TLCR journal, which signifies the importance of lung cancer translational research as discussed above. On a personal level, my role as Honorary Editor-in-Chief for TLCR has made it possible to reach out to broader international communities and the educational perspectives thereof have been very encouraging and personally inspiring.

TLCR: As the Honorary Editor-in-Chief, what are your expectations for TLCR? Would you like to provide any suggestions for the development of TLCR?

Dr. Hirsch: The role of translational lung cancer research cannot be underestimated and TLCR has an important mission to disseminate this knowledge through original publications, discussions, and commentaries. TLCR should focus on the dissemination of original translational research, but reviews and perspective articles should continue to have their space. Hopefully, TLCR will in the future have a more global dissemination.

Reference

1. Hirsch FR, Kim C. The Importance of Biomarker Testing in the Treatment of Advanced Non-Small Cell Lung Cancer: A Podcast. Oncol Ther. 2024. doi: 10.1007/s40487-024-00271-w.