Advanced molecular diagnostics are fundamentally transforming patient outcomes. Historically, diagnosis and treatment relied on the location and stage of the tumour. Now, increasingly sophisticated approaches allow healthcare professionals to understand cancer in much greater depth, enabling the selection of personalized treatments that target specific biological pathways. This detailed understanding can improve effectiveness and reduce the chance of severe side effects.

• BRCA Mutation Testing: The medical benefit of knowing BRCA status has increased steadily since its discovery 30 years ago. Professor Pujol discusses how BRCA mutations, which affect about one in 200 individuals, are vital not only for prevention but also for personalized treatments using PARP inhibitors across breast, ovarian, prostate, and pancreas cancers. ASCO guidelines now propose testing any woman with breast cancer under 65, any man with breast cancer, and every woman with ovarian cancer.

• Tissue-Agnostic Therapies and Trial Design: Progress in defining molecular alterations shows that frequent or rare alterations (like gene fusions or MSI) can be present across cancers regardless of their site of origin. This requires researchers to think beyond the primary tumour site. The podcast delves into novel clinical trial designs, such as basket trials and synthetic control arms, developed to rapidly test genetic mutation-drug matches across multiple cancer types.

• Biomarkers in Immunotherapy: We explore the role of Micro Satellite Instability (MSI) as a predictive biomarker for sensitivity to immunotherapies. While the FDA granted immune checkpoint inhibitor the first tissue agnostic approval for MSI-high/dMMR solid tumours, the pan-European (EMA) and national regulatory landscapes show variation in approval and access.

• The Power of NGS and Liquid Biopsies: Next-Generation Sequencing (NGS) is considered the standard of care for lung cancer, where over 10 alterations are targetable. NGS is widely seen as more cost-effective than sequential testing methods. Furthermore, liquid biopsies are becoming a highly promising tool for monitoring resistance, identifying minimal residual disease, and even moving towards early detection and screening.

Despite these incredible medical advances, complex regulatory and reimbursement pathways in European countries are slowing the availability of new technologies and contributing to inequalities in cancer outcomes. The discussion highlights the urgent need for policymakers to act in five key priority areas to ensure health systems are ready to adopt advanced diagnostics and achieve better testing and better treatment for all people with cancer.

Ready to learn how we can move from under-considering diagnostics to making them a priority? Download the full episode, "

Targeted therapies in cancer: From clinic to labs

" to hear the full discussion on these vital issues.

Isabelle Bedrosian et al. Germline Testing in Patients With Breast Cancer: ASCO–Society of Surgical Oncology Guideline. J Clin Oncol 42, 584-604(2024). 

Casak SJ, Marcus L, Fashoyin-Aje L, Mushti SL, Cheng J, Shen YL, Pierce WF, Her L, Goldberg KB, Theoret MR, Kluetz PG, Pazdur R, Lemery SJ. FDA Approval Summary: Pembrolizumab for the First-line Treatment of Patients with MSI-H/dMMR Advanced Unresectable or Metastatic Colorectal Carcinoma. Clin Cancer Res. 2021 Sep 1;27(17):4680-4684.

We're bringing back a must-listen episode of the Diaceutics podcast series

. Diaceutics is committed to enabling better testing and better treatment, placing labs at the centre of this mission.

In this lively discussion, we feature two leading experts: 

 (CEO of the Comprehensive Regional Cancer Institute Centre Jean PERRIN, France, and Deputy President, UNICANCER) and 

 (Head of Cancer Genetics department at the University Hospital of Montpellier, France, and President of the French Society of Predictive and Personalized Medicine). They explore the challenges and opportunities in implementing targeted therapies in cancer, specifically from a European point of view.

An oncogenic fusion is a hybrid gene formed when a portion of one gene fuses with a portion of another, often resulting from structural variants such as translocations or inversions at the DNA level. This leads to a chimeric, aberrant protein.

In lung cancer, these fusions are often the "driver mutation" of the tumour. Identifying these drivers is crucial because effective, targeted treatments exist for fusions such as ALK, ROS1, and RET. Dr. Saxena emphasises that if testing isn't performed, patients miss out on these treatments. For example, studies on ALK-targeted therapy in metastatic lung cancer showed that after five years, the median progression-free survival had not yet been reached, highlighting the amazing, life-changing responses possible if the fusion is detected.

It is standard practice to test for these fusions in virtually all patients with non-small cell lung cancer (NSCLC), particularly those with stage four or metastatic disease, or those with lung adenocarcinomas, as effective therapies are available.

The discussion highlights the diverse methodologies available for detection. While low-throughput methods like Immunohistochemistry (IHC) and Fluorescent In Situ Hybridization (FISH) are used, more comprehensive approaches are becoming standard.

• IHC is widely available and provides fast results, which can be useful for quickly informing decisions (such as what not to give, like immunotherapy in ALK-positive patients). However, IHC is generally better used as a screening tool for many fusions (except ALK) and requires confirmatory testing.

• Sequencing methods offer higher throughput. DNA-based sequencing can be challenging because fusion breakpoints often occur in large intronic regions that are difficult to cover.

• RNA sequencing is highly recommended and often utilized, as it sequences the expressed RNA transcripts after the intronic regions have been spliced out. This method demonstrates a clear benefit: a highly cited study by Reema K. Benayed et al.

, found that performing RNA sequencing detected a previously undetected driver alteration in up to approximately 14% of cases that were DNA sequencing negative.

Comprehensive panels often include both DNA and RNA sequencing simultaneously to maximize detection capability. Dr. Solomon notes that comprehensive sequencing helps detect rare and novel fusions.

The clinical relevance of testing necessitates clear and rapid communication between the lab and the treating physician. Turnaround time (TAT) is constantly being optimized as it is crucial for patient management.

To facilitate treatment decisions, reports must be clear and concise. Oncologists, like Dr. Saxena, appreciate reports that prioritize FDA-approved or known relevant mutations upfront. Both experts agreed that having descriptive blurbs that provide context and knowledge about the specific mutation (e.g., efficacy data or clinical trial status) is very useful, rather than just positive/negative listings. Pathologists often rely on vast knowledge bases (like 

) to ensure accuracy and relevance when drafting these interpretations.

Molecular pathology is rapidly changing. Although common fusions (ALK, ROS1) are well-established, newer fusions like NTRK and NRG1 are seen in very small percentages of cases (less than 1% to 2%).

 Dr. Solomon believes that increased, comprehensive RNA sequencing on more tumours will lead to the recognition of additional targetable fusions.

Ultimately, better testing enables better treatment.

Listen to the full episode of the Diaceutics 

Solomon BJ, Liu G, Felip E, Mok TSK, Soo RA, Mazieres J, Shaw AT, de Marinis F, Goto Y, Wu YL, Kim DW, Martini JF, Messina R, Paolini J, Polli A, Thomaidou D, Toffalorio F, Bauer TM. Lorlatinib Versus Crizotinib in Patients With Advanced 

-Positive Non-Small Cell Lung Cancer: 5-Year Outcomes From the Phase III CROWN Study. J Clin Oncol. 2024 Oct 10;42(29):3400-3409.

Benayed R, Offin M, Mullaney K, Sukhadia P, Rios K, Desmeules P, Ptashkin R, Won H, Chang J, Halpenny D, Schram AM, Rudin CM, Hyman DM, Arcila ME, Berger MF, Zehir A, Kris MG, Drilon A, Ladanyi M. High Yield of RNA Sequencing for Targetable Kinase Fusions in Lung Adenocarcinomas with No Mitogenic Driver Alteration Detected by DNA Sequencing and Low Tumor Mutation Burden. Clin Cancer Res. 2019 Aug 1;25(15):4712-4722.

O’Haire, S., Franchini, F., Kang, YJ. et al. Systematic review of NTRK 1/2/3 fusion prevalence pan-cancer and across solid tumours. Sci Rep 13, 4116 (2023).

Sushma Jonna; Rebecca A. Feldman; Jeffrey Swensen; Zoran Gatalica; Wolfgang M. Korn; Hossein Borghaei; Patrick C. Ma; Jorge J. Nieva; Alexander I. Spira; Ari M. Vanderwalde; Antoinette J. Wozniak; Edward S. Kim; Stephen V. Liu. Detection of NRG1 Gene Fusions in Solid Tumors. Clin Cancer Res (2019) 25 (16): 4966–4972.

We are re-promoting the insightful fifth episode of the Diaceutics "Better Testing, Better Treatment" podcast series: "

Oncogenic Fusion Detection and Reporting in NSCLC and solid tumors: from clinic to lab

In this highly important episode, we hear from 

, Assistant Professor of Pathology and Laboratory Medicine at Weill Cornell Medicine, and 

, Assistant Professor of Medicine at Weill Cornell Medical College, as they discuss the practical considerations for oncogenic fusion detection and reporting.

The episode explores the vital connection between pathologists and oncologists, a partnership central to Diaceutics' mission of enabling better testing and better treatment. Dr. Park and Dr. Talwalkar emphasize that this collaboration is critical in the field of precision medicine. Pathologists are described as the "detectives of the medical world," unravelling disease mysteries through microscopic examination, while oncologists are the "warriors on the front lines," using those discoveries to design lifesaving treatments.

A powerful case study highlighted how their close working relationship—facilitated by quick communication via text or secure chat—changed a patient’s treatment course. When Dr. Park needed HER2 IHC 3+ testing for a patient with stage 4 bladder cancer to qualify them for an FDA-approved pan-tumour treatment, Dr. Talwalkar was able to prioritize the IHC assay, providing results in 24 to 48 hours, unlike mutation analysis which can take days or weeks.

Optimising Testing and Navigating Barriers

The experts discuss key strategies for optimising diagnostics and tissue procurement. For instance, in bladder cancer, they implemented an FGFR reflex testing protocol for newly diagnosed, eligible patients, ensuring results are automatically ordered by the pathologist signing out the case. This expedites patient care by having results available when the oncologist sees the patient.

The panel also addressed the challenges in the field, noting that insufficient tissue remains a significant barrier to optimum patient care. Historic tissue, often used for diagnosis, may have DNA that is damaged or denatured by the time new testing is required.

Looking ahead, Dr. Park and Dr. Talwalkar discuss how innovation will strengthen their relationship. They agree that the biggest change for pathologists will be the digitalization of glass slides, coupled with the deployment of AI to improve diagnosis and turnaround time. AI can already be used for tasks such as Gleason scoring and complex data analysis for immunotherapy purposes.

However, the rise of molecular diagnostics will lead to reports containing more information, such as NGS reports with 30 or 40 actionable mutations. This flood of data will necessitate even stronger communication between pathologists and oncologists to determine the true driver mutation and predict clinical benefit.

At the heart of the conversation is the understanding that communication is the key to improving patient survival and care.

The Pathology-Oncology Connection: Labs in Action

Did you miss Episode 8 of the Better Testing, Better Treatment podcast series, titled "The Pathology-Oncology Connection: Labs in Action"?

 leads a lively discussion with two critical voices in the fight against cancer: 

, a Genito urinary medical oncologist and Co-director of GU cancer clinical trials at the Norton Cancer Institute, and 

, a hematopathologist and molecular pathologist at CPA Lab, Norton Healthcare.


The Hematopathology Team: from Slide to Strategy 

In episode 9, we are joined by Dr. Philip Kuriakose and Dr. Juan Gomez-Gelvez, who analyse how collaboration within hematopathology drives optimal patient care.

Dr. Philip Kuriakose, MD is a Hematology Medical Oncologist and the Medical Director of the Hemophilia and Thrombosis Treatment Center at Henry Ford Health.

Dr. Juan Gomez-Gelvez, MD is a Hematopathologist, Molecular Pathologist and the Section Head of Molecular Hematopathology also at Henry Ford Health.

The Better Testing, Better Treatment Podcast series

We are excited to announce that our ninth episode is now available!

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Insights

Unlock the Future of Cancer Treatment: Targeted Therapies from a European Perspective

Oncogenic Fusion Detection - Bridging the Gap from Clinic to Lab

The Pathology-Oncology Connection: Labs in Action – Why This Dynamic Partnership Drives Precision Medicine

The Hematopathology Team: from Slide to Strategy

Building Expertise in the Lab: DXRX and the Evolving Role of Technicians in Haemato-Oncology