Implementation of Liquid Biopsy in Non-Small-Cell Lung Cancer: An Ontario Perspective

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

Thank you for your interesting manuscript detailing implementation of liquid biopsy which I read with interest. 

Following minor suggestions:

Whilst I  appreciate that this is a local Ontario perspective I think the manuscript could be improved by drawing out potential lessons that can be taken by other comparable public healthcare systems. For example what would the funding model be for provision of the technology- patient self-funding or insurance, central funding or mixed? Would commercial platforms be used or would local academic centres have capacity to develop their own lower cost testing platforms? How will these expensive technologies be incorporated and reimbursed? In the NHS the main stumbling block is around cost and reimbursement so elaborating on this in the summary would add to the interest for general readership.

 

I am unclear after reading the manuscript as to whether the recommendations have been implemented or it is still in the discussion and planning stage- could you include in the summary whether liquid biopsy has been introduced into the public healthcare system as yet and if so in what indication? If not, what are the indications where you see this being applied first and in what timeframe? Again if it is possible to give some indication of practical application of the points covered it will increase interest. 

Regarding the eligibility criteria 2 around patients with expected lung cancer for which tissue biopsy is not feasible, this would appear to be a more experimental approach. At present the data would support the use of of liquid biopsy as a complementary test rather than a replacement for tissue biopsy, given the risk of false negatives etc, and this is what the referenced studies would suggest also. Can the authors elaborate more on this point, and the data to support matching patients to biomarker selected treatments on the bases if a liquid biopsy result only and no histopathological confirmation of NSCLC?

Author Response

Comment 1: Whilst I  appreciate that this is a local Ontario perspective I think the manuscript could be improved by drawing out potential lessons that can be taken by other comparable public healthcare systems. For example what would the funding model be for provision of the technology- patient self-funding or insurance, central funding or mixed? Would commercial platforms be used or would local academic centres have capacity to develop their own lower cost testing platforms? How will these expensive technologies be incorporated and reimbursed? In the NHS the main stumbling block is around cost and reimbursement so elaborating on this in the summary would add to the interest for general readership.

Response to comment 1: Although the purpose of this manuscript is to provide a local Ontario perspective on the implementation of liquid biopsy testing for NSCLC, we acknowledge that this is currently a relevant topic for many public healthcare systems. In our initial draft we provided some general considerations for test selection, implementation, and cost analysis that we feel could also apply to other jurisdictions (e.g. sections 4-6 and figures 1 and 2).

To address some of your specific questions, as we are stressing the need for equitable access to testing through universal public reimbursement, we feel that it would be difficult to discuss other funding models including patient self-funding or private insurance which are not relevant in the Canadian Healthcare system. We have revised some of the language throughout the manuscript to clarify this point further (see lines 95-96, 106-108, 121, 419-425).

In terms of using commercial vs. local lab developed tests, we have added a few sentences describing the advantages and disadvantages of these two testing options to consider further (see lines 290-297):

“Rather than adopting a commercial panel test, some laboratories may opt for a custom panel. This allows for more flexibility in selection of gene targets as new evidence emerges and allows for flexibility in reagent selection, which can decrease the cost per test. However, custom panels typically require a larger up front investment in terms of validation cost, as well as requiring a bioinformatician to build a custom analysis pipeline. In contrast, commercial panels may be more costly per test but have a shorter validation process and more streamlined analytical pipelines to offer. Thus, validation process and costs, as well as data analysis requirements and bioinformatics resources available at each testing site, will impact test selection.”

In terms of how these technologies will be incorporated and reimbursed, based on reimbursement of tissue molecular profiling, we believe Ontario Health will base their funding decisions for liquid biopsy on estimates of cost-effectiveness and total budget impact and provide clear eligibility criteria and a reimbursement cost per test. We have added the following to reflect this:

Lines 304-308: As current public funding for tissue-based molecular profiling in Ontario is delivered as a flat reimbursement price per test, selection of a liquid biopsy test will also depend on the funding price per test set by Ontario Health. Decisions on funding criteria and cost allocation are discussed in section 6 below.

Lines 381-384: Implementation of universal access to liquid biopsy in Ontario through public reimbursement requires Ontario Health to review estimates of cost-effectiveness and total budget impact for liquid biopsy across various scenarios and cost models to determine appropriate eligibility criteria and cost per test.

Comment 2: I am unclear after reading the manuscript as to whether the recommendations have been implemented or it is still in the discussion and planning stage- could you include in the summary whether liquid biopsy has been introduced into the public healthcare system as yet and if so in what indication? If not, what are the indications where you see this being applied first and in what timeframe? Again if it is possible to give some indication of practical application of the points covered it will increase interest. 

Response to comment 2: To clarify that liquid biopsy has not yet been introduced and that we have proposed criteria which should be prioritized for eligibility, we have revised the following sentences in the introduction and summary:

Lines 90-97: “However, routine liquid biopsy testing in Ontario is still in the early steps of implementation as a standard-of-care test with it being only available through private-funding, research protocols or institutional funding at select centres, leaving many patients without access. Given the challenges of tissue molecular profiling and the importance of genotyping results for appropriate front-line treatment decisions, there is a significant need for public funding of liquid biopsy for Ontario patients with NSCLC to ensure equitable and timely access to molecular profiling.”

Lines 416-419: “Universal access to liquid biopsy testing for patients with advanced NSCLC remains a significant unmet need in Ontario. Our working group proposed key eligibility criteria that should be prioritized for public funding of liquid biopsy testing in Ontario based on the highest clinical need and the robustness of the supporting evidence (Table 1).”

Comment 3: Regarding the eligibility criteria 2 around patients with expected lung cancer for which tissue biopsy is not feasible, this would appear to be a more experimental approach. At present the data would support the use of of liquid biopsy as a complementary test rather than a replacement for tissue biopsy, given the risk of false negatives etc, and this is what the referenced studies would suggest also. Can the authors elaborate more on this point, and the data to support matching patients to biomarker selected treatments on the bases if a liquid biopsy result only and no histopathological confirmation of NSCLC?

Response to comment 3: We have adjusted the wording in section 3.2 to expand on the rationale and data to support liquid biopsy in patients without a histopathological confirmation of NSCLC:

Line 176-225: “Patients with suspected advanced NSCLC who are unable to get a tissue biopsy due to technical limitations or co-morbidities cannot get a histological diagnosis, which presents a significant clinical challenge. Although rates vary by study population, approximately 3% of patients with suspected advanced NSCLC are unable to receive a histological diagnosis due to inability to perform a tissue biopsy or a tissue biopsy failure [17,50]. Liquid biopsy provides an opportunity to match these patients to targeted therapy, where management options would otherwise be limited.

Evidence for the utility of liquid biopsy in patients with suspected advanced lung cancer where a tissue biopsy is not be feasible is somewhat limited. A single clinical trial and several case series, including an example from an Ontario-based community hospital, have demonstrated success in using liquid biopsy in this setting, particularly to match patients to EGFR tyrosine kinase inhibitors [51-54]. In addition, results from studies evaluating a liquid biopsy-first strategy in patients with suspected advanced NSCLC in order to accelerate time to treatment may be extrapolated to support the feasibility and clinical utility of liquid biopsy in suspected advanced NSCLC [17, 55, 56]. For example, in the ACCELARATE study conducted at the Princess Margaret Hospital in Toronto, Ontario, 70% of patients with suspected advanced NSCLC had biopsy-proven advanced NSCLC [17]. Among those with confirmed non-squamous NSCLC (60%), 23% started targeted therapy before tissue NGS results were available and 12% had actionable alterations only detected through liquid biopsy testing, supporting the benefit of a liquid biopsy-first strategy. Interestingly, among the patients without a histological diagnosis of NSCLC, 3 of 5 patients who did not undergo biopsy and all 3 patients with insufficient tissue from biopsy for diagnosis had tumor-associated variants detected in plasma. Additionally, 3 of 18 patients diagnosed with other malignancies had an informative liquid biopsy result. Given the substantial percentage of patients diagnosed with small cell lung cancer or other malignancies, the authors concluded that liquid biopsy remains a complementary, rather than alternative approach to tissue biopsy, with histological confirmation still needed to guide treatment. While the working group agrees that tissue confirmation should be prioritized, in cases where it is not feasible, this data suggests that liquid biopsy has the potential to inform diagnosis and/or treatment decisions. This sentiment is reflected in guidelines from the European Society for Medical Oncology [13]. Additionally, other Canadian provinces, including Quebec, New Brunswick, and Nova Scotia, are planning to implement liquid biopsy testing for patients who are unable to get a tissue biopsy [16, 57, 58].”

The working group acknowledges the limitations of liquid biopsy when NSCLC is not histologically confirmed, including the possibility of false negative or false positive results. However, given that these patients have no alternative for diagnosis and molecular profiling, it was felt that the potential benefits for liquid biopsy in the case where an actionable genomic alteration is identified and targeted therapy could be administered, would outweigh these risks.

A footnote has also been added to criterion 2 in Table 1 to emphasize that a tissue diagnosis is still strongly recommended where feasible:

Lines 126-129: Guidelines support use of liquid biopsy when tissue biopsy is not feasible and/or use of liquid biopsy prior to diagnosis or at time of diagnostic biopsy; however, use in suspected advanced NSCLC is not consistently stated. A tissue diagnosis is still strongly recommended where feasible.

Reviewer 2 Report

Comments and Suggestions for Authors

This paper presents the outcomes of a multidisciplinary working group in Ontario, which proposed eligibility criteria for liquid biopsy testing in patients with advanced NSCLC. The group also considered reimbursement factors, assay selection (hybrid-capture vs. amplicon-based methods), implementation strategies within the healthcare system, and the economic impact of these tests. Their discussions and conclusions provide valuable insights for both cancer researchers and clinicians, emphasizing the importance on liquid biopsy.

One minor suggestion: it would be beneficial for the authors to expand further on emerging technologies or strategies related to cfRNA, metabolomics, or microbiome analysis by analyzing liquid biopsy, if applicable. This would provide a more comprehensive view of the current landscape.

Author Response

Comment 1: One minor suggestion: it would be beneficial for the authors to expand further on emerging technologies or strategies related to cfRNA, metabolomics, or microbiome analysis by analyzing liquid biopsy, if applicable. This would provide a more comprehensive view of the current landscape.

Response to comment 1: We agree that there are many emerging technologies in the current landscape of liquid biopsy that show promise for being clinically useful in the future. Although a detailed discussion of these technologies would be out of scope for this paper, we have included a sentence in the conclusion (lines 465-468) which outline some of these emerging technologies, along with a citation that allows readers to explore these applications further if desired:

“Liquid biopsies that utilize other fluids, such as urine, saliva, or cerebrospinal fluid, as well as other analytes, such as circulating tumour cells, various cfRNA species (e.g. miRNA), exosomes, metabolites, and microbial cell-free DNA are also emerging as tools to inform the management of patients with cancer [78].”