Cut/Paste: AI Assesses 2 MRD Op Eds (CRC and H&N)

 This is a cut paste where I ask AI to assess two complementary Op Eds on ctDNA.

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Main article

https://www.discoveriesinhealthpolicy.com/2023/07/pair-of-papers-shines-lights-on.html

HPV OP ED LANGO

 

In this op-ed by Dr. Miriam N. Lango, the focus is on the potential use of circulating human papillomavirus (HPV) tumor DNA as a means of detecting and surveilling HPV-associated oropharyngeal squamous cell carcinoma (SCC), a type of head and neck cancer.

The article discusses the transformative impact of detecting cell-free tumor DNA fragments in the bloodstream, which provides valuable information about the mutational landscape of certain cancer types. While this approach has been successful for many cancers, it has not been extensively explored for head and neck cancer.

The specific focus of interest is on oropharyngeal SCC, which is uniquely associated with HPV and has a distinct molecular signature. Recent technological advancements have allowed for the sensitive and reliable identification and quantification of low copy number HPV gene expression in the blood. The commercially available NavDx test (Naveris) is one such blood test or liquid biopsy that can detect circulating HPV tumor DNA.

The op-ed discusses a study by Ferrandino et al., published in the same issue of JAMA Otolaryngology–Head & Neck Surgery. The study evaluated the accuracy of tumor tissue–modified HPV DNA (TTMV-HPV DNA) using the NavDx test for diagnosing and surveilling HPV-associated oropharyngeal SCC.

In the diagnostic component of the study, the NavDx test showed a high sensitivity (91.5%) and specificity (100%) in detecting positive circulating HPV tumor DNA in patients with biopsy-proven p16-positive SCC before treatment. 

The test's performance was comparable to polymerase chain reaction–based HPV testing of cytologic specimens and better than cytopathologic results using p16 staining. The study suggests that the blood test may potentially replace fine needle aspiration biopsies with p16 staining in diagnosing some patients with oropharyngeal SCC.

However, the op-ed highlights some limitations. Not all p16-positive SCCs are HPV-related, and the TTMV-HPV DNA test detected HPV only in the context of HPV-associated disease. Thus, the test's positive result is not sufficient to confirm a diagnosis of SCC, and tumor tissue confirmation is still required.

[BQ: I would read this as: a negative result (no TTM HPV ctDNA) is not able to "rule out" the presence of SCC.]

The study also explored the use of TTMV-HPV DNA testing in surveillance. Among the patients in the surveillance cohort, the test successfully predicted the recurrence of cancer in some cases, with a positive predictive value of 100%. However, the appropriate interval for surveillance testing and the overall surveillance guidelines need further validation through prospective clinical studies.

The op-ed concludes by emphasizing the promising potential of this technology in identifying and monitoring patients with HPV-related disease. As the test becomes more widely available commercially, there is a need to establish evidence-based surveillance guidelines for its effective implementation in routine clinical care and to share this knowledge with the broader cancer community. Further research and validation studies are necessary to fully realize the clinical benefits of this approach.

 

 

 

RUIZ BANOBRE CRC

 

In this op-ed article titled "Liquid Biopsy Assessment of Molecular Residual Disease in Localized Colorectal Cancer - Is It Ready for Prime Time?" by Juan Ruiz-Bañobre, MD, PhD, the author discusses the potential of liquid biopsy, specifically the detection of circulating tumor DNA (ctDNA), as a promising strategy in the clinical management of patients with colorectal cancer (CRC). The article is based on a study by Mo et al., which explores the clinical utility of a tumor-naive plasma ctDNA assay called ColonAiQ to identify and monitor molecular residual disease in patients with stage I to III CRC who underwent treatment [surgery] with curative intent.

The author starts by providing some context, stating that colorectal cancer is the third most common cancer in the US and that surgery remains the primary treatment for localized CRC. However, some patients also benefit from adjuvant chemotherapy to target micrometastatic lesions and reduce the risk of recurrence. The decision to use adjuvant chemotherapy in stage II CRC remains debatable, but evidence from stage III disease suggests its potential benefit.

The article then delves into the concept of molecular residual disease, which refers to the detection of ctDNA after curative-intent therapy. Previous studies have shown a high risk of recurrence when ctDNA is present in patients with localized tumors. The author highlights that different approaches exist to measure molecular residual disease, including tumor-informed data (based on the primary tumor's mutational profile) and tumor-naive data (examining fixed molecular alterations without prior knowledge of the primary tumor's profile). While the latter approach is easier to perform, it tends to be less sensitive than the tumor-informed approach.

The study by Mo and colleagues, discussed in the article, focuses on the tumor-naive approach using the ColonAiQ assay, which analyzes the methylation levels of six markers specifically associated with CRC. The study demonstrates that molecular residual disease can be effectively detected by ColonAiQ as early as four weeks after surgery with curative intent. Moreover, combining molecular residual disease detection with carcinoembryonic antigen levels improves recurrence prediction.

The author emphasizes that molecular residual disease identified by ColonAiQ is the most significant risk factor for recurrence in stage I to III CRC, surpassing traditional clinicopathological risk factors. The study also confirms the prognostic utility of molecular residual disease in terms of recurrence-free survival even after adjuvant chemotherapy and during follow-up.

The op-ed suggests that ColonAiQ could help guide the management of localized CRC patients, such as escalating or intensifying adjuvant treatment in molecular residual disease-positive patients and de-escalating treatment in those with undetectable molecular residual disease after curative-intent surgery.

While the field of liquid biopsy is rapidly evolving, the author highlights the importance of prospectively validating ColonAiQ's clinical significance through randomized clinical trials. [SEE NEXT QUESTION]

 If successful, this liquid biopsy assay could provide a simple and cost-effective means for widespread implementation in routine clinical practice.

In conclusion, the op-ed discusses the potential of liquid biopsy, particularly ColonAiQ, in assessing molecular residual disease in localized colorectal cancer. The article presents evidence from a study suggesting that this approach could significantly impact patient management and recurrence prediction, leading to potential changes in treatment strategies. However, further validation through clinical trials is needed to establish its clinical utility definitively.

 

QUESTION ON RUIZ CRC OP ED

 

If the data is so good, showing the strong performance of MRD testing with ctDNA and detecting recurrence earlier than imaging, why is it important to do prospective clinical trials? Why is that better than this observational data?

 

 

Conducting prospective clinical trials is essential for several reasons, even if observational data shows promising results for MRD (Molecular Residual Disease) testing with ctDNA and its ability to detect recurrence earlier than imaging.

1.     Establishing causality: Observational studies can show associations and correlations between variables but cannot establish causality definitively. Prospective clinical trials, on the other hand, are designed to determine cause and effect relationships. By randomizing patients into different groups and controlling for confounding variables, clinical trials can provide more robust evidence regarding the true impact of MRD testing on patient outcomes.

2.     Eliminating bias: Observational studies may suffer from selection bias, confounding, and other biases inherent in their design. In contrast, prospective clinical trials are designed to minimize bias, as patients are randomly assigned to different interventions, reducing the risk of systematic differences between groups.

3.     Sample size and statistical power: Clinical trials are designed with specific sample sizes and statistical power calculations to detect meaningful differences between groups. This ensures that the study has sufficient statistical strength to draw reliable conclusions. Observational studies may not always have adequate sample sizes or statistical power to make definitive conclusions.

4.     Reproducibility and generalizability: Prospective clinical trials that show consistent results across different populations and settings increase confidence in the findings' reproducibility and generalizability. Observational studies, especially single-center studies, may not capture the full spectrum of patient characteristics and treatment variations seen in diverse clinical settings.

5.     Regulatory approval and clinical guidelines: Prospective clinical trial data play a crucial role in obtaining regulatory approvals for new medical interventions, such as MRD testing assays. Additionally, clinical guidelines are often developed based on data from well-designed clinical trials, guiding healthcare practices for specific conditions.

6.     Ethical considerations: Prospective clinical trials are conducted under strict ethical guidelines to ensure patient safety and informed consent. These trials are monitored by ethical review boards to protect patients' rights and welfare during the study.

7.     Health economics and cost-effectiveness: Clinical trials can also provide data on the cost-effectiveness of MRD testing compared to existing standard procedures. This information is valuable for healthcare decision-makers and insurers when considering the implementation of new technologies or treatments.

8.     Long-term outcomes: Prospective clinical trials are better suited to evaluate long-term outcomes, including survival rates, recurrence rates, and quality of life measures. Observational data might not have sufficient follow-up periods to assess these important aspects.

In summary, while observational data can provide valuable insights and generate hypotheses, prospective clinical trials are the gold standard for establishing the clinical utility and efficacy of new interventions, such as MRD testing with ctDNA. These trials provide more reliable evidence, which is crucial for guiding clinical decision-making, obtaining regulatory approval, and informing healthcare policies.

 

 

QUESTION:  CONTRAST AND COMPARE THE TWO OP EDS

 

 

Comparison:

1.     Disease Focus: The first editorial by LANGO focuses on the potential use of circulating human papillomavirus (HPV) tumor DNA for detecting and surveilling HPV-associated oropharyngeal squamous cell carcinoma (SCC) in head and neck cancer patients.   The second editorial by RUIZ BANOBRE focuses on the use of circulating tumor DNA (ctDNA) as a strategy for assessing molecular residual disease in localized colorectal cancer (CRC) patients.

2.     Test Evaluation: Both editorials discuss the evaluation of liquid biopsy tests for cancer detection, but they use different approaches. The first editorial evaluates the performance of a blood test (NavDx) that detects circulating HPV tumor DNA in head and neck cancer patients. The second editorial evaluates the performance of a tumor-naive plasma ctDNA assay (ColonAiQ) that analyzes methylation levels of markers associated with CRC.

3.     Study Population: The first editorial focuses on patients with HPV-associated oropharyngeal SCC, a subset of head and neck cancer patients with a distinct molecular signature. The second editorial focuses on patients with stage I to III localized colorectal cancer who underwent treatment with curative intent.

4.     Clinical Impact: Both editorials discuss the potential clinical impact of the evaluated tests. The first editorial suggests that the NavDx blood test could potentially replace certain diagnostic methods and aid in surveillance for HPV-related disease. The second editorial highlights that ColonAiQ may significantly impact patient management by guiding treatment decisions based on the detection of molecular residual disease and predicting recurrence risk.

5.     Recommendation Strength: The first editorial (LANGO) appears to be more cautious in its recommendations. It acknowledges the promising potential of the NavDx test but emphasizes the need for further research, validation, and evidence-based guidelines before widespread implementation in routine clinical care. On the other hand, the second editorial (RUIZ BANOBRE) appears more optimistic about the clinical utility of ColonAiQ. It suggests potential changes in treatment strategies based on the assay's results and advocates for its widespread implementation if prospectively validated through clinical trials.

6.     Cancer Type and Detection Complexity: While both tests focus on detecting ctDNA, the complexities of detecting HPV-associated oropharyngeal SCC are discussed in the first editorial. The presence of HPV does not necessarily confirm an HPV-related SCC, and further confirmation from tumor tissue is required. In contrast, the second editorial suggests that molecular residual disease detected by ColonAiQ in localized CRC is a significant risk factor for recurrence and has prognostic utility even after adjuvant chemotherapy.

7.     Validation Needs: Both editorials stress the importance of validation studies. The first editorial calls for further research to establish evidence-based surveillance guidelines for the NavDx test. The second editorial emphasizes the need for prospective validation of ColonAiQ through randomized clinical trials to definitively establish its clinical significance.

Overall, both editorials recognize the potential of liquid biopsy tests, but the second editorial (RUIZ BANOBRE) seems more confident in recommending ColonAiQ as a promising tool for managing localized CRC. The first editorial (LANGO) is more cautious in its approach, acknowledging the potential of the NavDx test but highlighting the need for further research and validation before widespread adoption.