The Race Against Time: Evaluating the Speed of Gene Panel Result Delivery in NSCLC Patient Management

doi:10.21203/rs.3.rs-3560728/v1

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The Race Against Time: Evaluating the Speed of Gene Panel Result Delivery in NSCLC Patient Management

https://doi.org/10.21203/rs.3.rs-3560728/v1

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Background

In this study, we aimed to compare the clinical utility of the Oncomine Dx® Target Test (Oncomine) with that of the AMOY Dx® Pan Lung Cancer PCR panel (AMOY), focusing on their turn-around times (TATs).

Methods

Data on the specimens, fresh-frozen (FF) or formalin-fixed paraffin-embedded (FFPE) tissue samples, the success rate and detected driver alterations, submitted for these gene panel analyses were also collected from medical records. Further, for the comparison of the two methods, TATs defined as: T1, the period from first visit to specimen submission at an external laboratory; T2, the period from first visit to when the attending physician ordered the gene panel test; and T3, the period from first visit until the availability of the analysis results, were measured.

Results

In total, 213 patients, with 157 and 56 who submitted specimens for Oncomine and AMOY, respectively, were enrolled. The success rate of the analyses were 98.0% for Oncomine and 100.0% for AMOY. Further, the detection rates of driver alterations were 57.9% and 50.9% for Oncomine and AMOY, respectively, and 95.9% specimens submitted for Oncomine were FFPE, while 78.2% of those submitted for AMOY were FF. Further, the TATs, T1, T2, and T3, tended to be significantly shorter in AMOY cases. Specifically, the median TAT for AMOY cases, particularly T3, was 12 days (range, 4–26 days).

Conclusions

AMOY showed shorter TATs and a higher success rate than Oncomine. Therefore, its application using FF specimens may be effectively utilized in oncologic emergencies.

non-small cell lung cancer

driver alteration

gene panel

turn-around time

The rapid and accurate identification of targetable driver alterations is essential for treatment planning for local or advanced-stage lung cancer(1–4). Next-generation sequencing (NGS) and multiplex real-time or reverse transcription (RT)-polymerase chain reaction (PCR) tests are required to simultaneously detect multiple driver alterations(5, 6). Currently, the use of the Oncomine Dx® Target Test (Oncomine) (Thermo Fisher Scientific Inc., Waltham, MA, USA)(7), which is based on NGS, is recognized by medical insurance in Europe, the United States, and other parts of the world, while the AMOY Dx® Pan Lung Cancer PCR panel (AMOY) (Amoy Diagnostics Co., Ltd., Xiamen, China)(8), which is based on multiplex PCR testing, in addition to Oncomine, is recognized mainly in Asia. Each region has its own locally available gene panel. In Japan, for example, the use of any one of the three gene panels, Oncomine Dx, AMOY panel, and Lung Cancer Compact PanelTM (DNA Chip Research Inc., Tokyo, Japan)(9), mainly in advanced disease stages, is currently recognized by medical insurance for lung cancer. However, due to cost, insurance companies only cover the use of one of these gene panels, and deciding which of these gene panels to use in clinical practice is still challenging as there are no clear guidelines in this regard.

Further, several major differences exist between Oncomine and AMOY, e.g., for targeted sequencing, Oncomine is based on multiplex PCR with NGS, whereas AMOY is based on RT-PCR. This results in significant differences in terms of the variants that can be detected by each method. Further, Oncomine allows for a total of 927 variant searches on 56 genes(7), whereas AMOY allows for a total of 167 variant searches on nine genes(8). However, NGS makes the Oncomine testing process more complex, time-consuming, and costly. Conversely, AMOY is less complicated and requires less machinery; therefore, it is easier to perform at each facility, leading to a significant decrease in turnaround time (TAT) for the disclosure of the test results(8). Given the testing process, the amounts of DNA and RNA required for successful analysis as well as the risk of test failure are likely to be lower for AMOY than Oncomine.

As described above, there are significant differences between Oncomine and AMOY. However, it is still unclear how the corresponding gene panels should be used in clinical practice. Therefore, in this study, we retrospectively analyzed data from the corresponding gene panels at our institution and evaluated the specimens used in the analyses as well as the success rates and TATs of the analyses. We hope that our results will provide guidance for the use of these gene panels in clinical practice.

Patients and clinical characteristics

Data on patients for whom Oncomine or AMOY testing was ordered at our institution between April 2022 and May 2023 were retrospectively collected from the electronic medical record database. Oncomine and AMOY in this study were performed by subcontracted testing. The reason for setting the start period for case accumulation to April 2022 was that AMOY only received marketing authorization as a companion diagnostic strategy in Japan on March 22, 2022. For each case, we collected information regarding age, sex, smoking history (current, ever, or never smoking), lung cancer histopathology, clinical stage of disease based on the AJCC 8th edition TNM staging manual, success or failure of gene panel testing, gene alterations detected by the panel, type of specimen submitted to gene panel testing (formalin-fixed paraffin-embedded tissue (FFPE) or fresh frozen tissue (FF)), method of specimen collection (surgical biopsy, transbronchial biopsy (TBB), endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA), computed tomography (CT), echo guided biopsy, etc.). The methods for submitting FF specimens for each specimen collection method were as previously described(10).

Pathological assessment of FFPE specimens for gene panels

FFPE specimens were assessed for their suitability for the gene panel testing using hematoxylin and eosin (HE)-stained slides. The assessment criteria followed the standards of our laboratory; however, adjustments were made, e.g., increasing the number of paraffin-embedded sections submitted, at the discretion of the pathologist. Ten paraffin sections were submitted if the FFPE block met the criteria of a tumor area of at least 4 mm² and a tumor cell content of at least 30%. For AMOY, fewer tumor cells than Oncomine were expected. Specifically, specimens with tumor content less than 30% but more than 20%, or with tumor area less than 4 mm² were submitted for AMOY, i.e., if a specimen did not meet the submission criteria for Oncomine and was submitted for AMOY based on the AMOY criteria. It was deemed irrelevant to submit a specimen for any of the tests if its tumor content was less than 20% or if its tumor area was less than 2 mm². The tumor cell content and area were assessed visually by a single pathologist and not digitally.

Rapid on-site evaluation (ROSE) of FF specimens

For all the FF specimens, the presence of tumor cells was confirmed via ROSE(11) before submission. For TBB and EBUS-TBNA specimens, three and two biopsies were submitted, respectively. Further, for CT- or echo-guided specimens, two biopsies were submitted, and for surgical specimens, a block specimen of at least 3 mm³ of grossly visible tumor tissue was submitted. Finally, for fluid specimens, such as pleural fluid, a 100 mL pleural fluid specimens were spun down(10).

Definition of turn-around time (TAT)

TATs in days were defined as follows: T1, starting from the day when paraffin sectioning from FFPE specimens was completed and the FFPE and FF specimens were shipped from the hospital to an external laboratory; T2, starting from the day the attending physician confirmed the pathology results and ordered Oncomine or AMOY gene panel testing; and T3, starting from the date of the patient's first visit to the hospital to when the test results were made available (Fig. 1). We excluded cases for whom specimens were previously archived prior to the diagnosis of advanced-stage lung cancer.

Statistical analysis

Continuous variables were analyzed using Student’s t-test. All p-values were two-sided, and p < 0.05 was considered statistically significant. The statistical analyses were performed using EZR software version 1.29 (Saitama Medical Center, Jichi Medical University, Saitama, Japan)(12).

Patient characteristics and sampling methods for genome analysis

A total of 213 samples were submitted for gene panel testing at our institution between April 2022 and May 2023 (Fig. 2). Of these, 157 and 56 samples were submitted for Oncomine and AMOY, respectively. Further, 5 samples were switched from Oncomine to AMOY due to insufficient tumor tissue volume, as diagnosed by the pathologist. The analysis of five specimens (four Oncomine and one AMOY) was discontinued due to the inability to extract sufficient amounts of nucleic acids for DNA and RNA extraction. Thus, final analyses were performed on 148 and 55 cases for Oncomine and AMOY, respectively. The success rates of the analyses was 98.0% and 100.0% for Oncomine and AMOY, respectively. The patient characteristics for each gene panel are shown in Supplementary Table 1. The histological types of the lung cancer cases analyzed were as follows: 74.3% adenocarcinoma, 18.2% squamous carcinoma, and 7.5% non-small cell lung carcinoma (NSCLC) for Oncomine, and 74.5% adenocarcinoma, 9.1% squamous carcinoma, and 16.5% NSCLC for AMOY.

The collection methods for the specimens submitted to each gene panel test are shown in Fig. 3. In the Oncomine analysis, 95.9% of the samples were FFPE specimens and 4.1% were FF specimens. Further, 54.8% of the FFPE cases were surgical biopsies, 25.6% were TBB, 12.7% were EBUS-TBNA, 2.7% were CT- or echo-guided biopsies, and 0.1% were others. All the FF specimens were surgical biopsy specimens. For the AMOY analysis, 78.2% of the samples were FF specimens and 21.8% were FFPE specimens. For the FF cases in particular, 30.8% were EBUS-TBNA, 29.1% were TBB, 12.7% were CT- or echo-guided biopsy, 3.6% were fluid samples, and 1.8% were surgical biopsies. For the FFPE cases, 18.2% were TBB and 3.6% were surgical biopsies.

Detected driver alterations

The driver alterations detected via each gene panel testing are shown in Fig. 4. Via Oncomine, various alterations were detected in 57.9% of the analyzed cases. These included EGFR mutations in 25.6% of cases (L858R, 10.8%; Ex.19 deletion, 10.1%; and others, 4.7%), KRAS mutations in 12.1% of cases (G12C, 1.3%; others, 10.8%), MET ex.14 skipping mutation in 6.6% of cases, HER2 mutation and ALK fusion, each in 2.7% of cases, RET fusion in 2.0% of cases, ROS1 fusion in 1.4% of cases, and NRAS and BRAF V600E mutations in 0.7% and 3.4% of cases, respectively. Via AMOY, several alterations were also detected in 50.9% of patients. These included EGFR mutations in 32.8% of the cases (L858R, 9.1%; Ex. 19 deletions, 18.2%; and others,5.5%), KRAS mutations in 9.1% of cases (G 12C, 7.3% and others,1.8%), MET ex.14 skipping mutation and ALK fusion each in 3.6% of cases, and BRAF V600E mutation in 1.8% of cases.

Turn around time

The median value of T1 was 8 days [range, 6–22 days] for Oncomine and 6 days [3–10 days] for AMOY (p < 0.001) (Fig. 5A). Further, the median T2 value was 13 days [8–27 days] for Oncomine and 6 days [3–18 days] for AMOY (p < 0.001) (Fig. 5B), and for T3, it was 30 days [8–66 days] for Oncomine and 12 days [4–26] for AMOY (p < 0.001) (Fig. 5C).

A case in which AMOY using an FF specimen enabled rapid induction of treatment during national holidays

A 79-year-old non-smoking woman was referred to our hospital because of difficulty in walking owing to left lower back pain and suspected osteosarcoma. Chest CT showed a nodule and numerous micronodules in the right lung field (Fig. 6A). Blood samples showed elevated serum carcinoembryonic antigen levels. Thus, clinical adenocarcinoma of the lungs was suspected. On the day of the visit, an echo-guided needle biopsy of the left iliac mass was performed (Fig. 6B and C). ROSE of the biopsy specimen showed atypical cells with irregular nuclear shapes and numerous nuclei, suggestive of osteoclasts (Fig. 6D). The patient was unable to walk and was admitted to the hospital on the day of the visit. The FF of the needle biopsy specimen was submitted for AMOY, and a report of EGFR ex.19 deletion detection was received 4 days after submission (Day 5). The patient was then prescribed osimertinib for EGFR ex.19 deletion. This treatment was started on Day 5, and by Day 12, the patient was able to walk with no pain. Thus, the patient was then discharged (Fig. 6E).

In this study, we examined the usefulness of Oncomine and AMOY, two gene panels used in clinical practice for lung cancer(7, 8). The present study specifically focused on TAT to compare the usefulness of the two panels, which involve several processes. Specifically, the TATs included the periods from the patient's arrival at the hospital to the collection of the tumor tissue specimens (T1), the period from the pathological evaluation of the specimen to the ordering of the gene panel test based on the pathological evaluation (T2), and the period from the patient’s first visit to the arrival of the analysis report (T3). In advanced-stage lung cancer, it is necessary to identify driver alterations as soon as possible, and for oncologic emergency cases most especially, the administration of molecularly targeted agents, which can be expected to reduce tumor size even in patients with poor performance status, can have a significant impact on patient prognosis(13–15). Using the same tumor tissue specimen, AMOY showed a higher success rate than Oncomine(8), and a high driver alteration detection rate could be expected even for specimens with unknown tumor content, such as FF. Further, the TAT for AMOY using an FF specimen for a particular case was as fast as 12 days from the time the patient arrived the hospital until the availability of the analysis report. In this present case, an EGFR ex.19 deletion was identified, and an EGFR tyrosine kinase inhibitor was successfully administered as early as at 5 days after the first visit (specimens were collected on the same day of the first visit). Therefore, AMOY using FF specimens was identified as the fastest screening method for genetic mutations in clinical practice.

The use of AMOY is clearly less common than the use of Oncomine for the identification of retrieved driver alteration variants. In the present study, various genetic alterations were detected in 57.9% (85/148) of the Oncomine cases and 50.9% (28/55) of the AMOY cases, with Oncomine showing a trend toward a higher genetic alteration detection rate. Of the nine genes in AMOY, Oncomine covers more variants for seven genes, except for two mutations, BRAF V600E and MET ex.14 skipping. Further, NGS has a higher detection rate, particularly for insertion mutations(16, 17), and it covers 98 variants of EGFR ex.20 insertion, whereas AMOY only covers 32. Therefore, EGFR ex.20 insertion mutations have been identified more frequently ever since the introduction of genetic mutation analysis via NGS. For HER2, 54 and five variants are covered by Oncomine and AMOY, respectively. It is also important not to consider difference in the searchable variants of the HER2 mutation when trastuzumab deruxtecan for HER2 is introduced in clinical trials in the near future(18, 19). AMOY also covers fewer fusion gene variants than Oncomine, and the identification of fusion genes for the use of promising molecularly targeted agents that are expected to control disease for more than 2 years is critical in the selection of therapeutic regimens(20), and in this respect, screening via AMOY is insufficient relative to screening via Oncomine. Notably, Oncomine and AMOY are not simultaneously covered by Japan’s medical insurance system; therefore, only one of them can be used. If screening is performed using AMOY, it is advisable to re-examine the results using a comprehensive genome profiling panel, such as the Foundation One panel(21, 22).

The significantly shorter TAT of AMOY than that of Oncomine in this study was partly because many cases were tested using FF specimens. Another factor is that AMOY, based on RT-PCR, requires fewer steps, and is associated with a simpler analytical process(23, 24), whereas Oncomine uses NGS, which is more complex(25). It is recommended that gene panel analysis be performed only after evaluating the tumor cell content of tumor tissues(26). In the case of FF specimens, the exact number of tumor cells present in the submitted specimen is unknown. However, pathological evaluation must be performed to assess tumor content, and a period of 5–7 days is required for the preparation of the specimens and pathology evaluation(27), after which the attending physician requires additional days to order the tests and cut out the sample to be submitted from the FFPE specimens. In this study, the difference in the number of days between T2 and T1 corresponded to the time required for specimen submission, which was approximately 5 days at our institution. Additionally, it takes approximately 17 days from the time a patient first visits the clinic and undergoes testing to obtain tumor tissue samples until the results of the pathological analysis are available. This duration corresponds to the difference in the number of days between T3 and T2. These days are expected to be drastically shortened if a pathologist, rather than an attending physician, orders the gene panel tests. Further, utilizing FF specimens can significantly shorten the TAT. We performed ROSE on all FF specimens submitted for the gene panel analysis as an indirect assessment of the tumor cell content of the specimens, and only specimens with malignant cells confirmed via ROSE were submitted for testing, thereby reducing the risk of false negatives(28, 29). One of the major issues associated with the use of FF specimens is that the specimens are submitted without a definitive histological diagnosis of lung cancer. It is also a major issue, e.g., the cost burden to the patient, when the cancer is small cell carcinoma or a metastasis of another organ cancer. Thus, the attending physician should consider the use of AMOY with FF specimens only in cases where NSCLC is strongly suspected clinically and when it is a matter of urgency.

Presently, the co-mutation profile of driver alterations does not determine the appropriateness of the use of molecularly targeted agents as a therapeutic strategy for NSCLC(1–3). Therefore, it is important to determine the presence or absence of driver alterations. In this regard, AMOY using RT-PCR is useful for the rapid and easy identification of driver alterations. However, it has been reported that co-mutation profiles can affect the therapeutic efficacy of molecularly targeted drugs(30–33). Therefore in future, the use of NGS-based gene panels will be essential if the indication of molecularly targeted drugs is to be considered based on co-mutation profiles. Improvements in technology to speed up the NGS testing process are currently underway(34, 35), and it is expected that NGS tests with sufficiently short TATs will be introduced in clinical practice in the near future.

This study had some limitations. First, this was a single-center retrospective study, and individual differences among attending physicians may have affected the method of specimen collection for submission and the timing of test orders. Second, regarding the evaluation of TAT, there are likely to be differences among institutions in terms of the time required for pathologists to perform tissue evaluation and the time required for sample preparation, including the cutting out of the specimens to be submitted. Therefore, caution must be exercised in generalizing the results of this study. Third, we did not examine the effects of the molecularly targeted drugs administered against detected driver alterations or to improve patient prognosis. Therefore, it is not possible to conclude whether shortening the TAT leads to real benefits, such as improved patient prognosis.

In cases of oncological emergencies, the application of AMOY using FF specimens may offer the possibility to detect treatable driver alterations within 7 days of presentation. Although the limited number of variants covered by AMOY and the use of FF specimens without pathological evaluation are not without risks, their application could be useful in oncologic emergencies. Regardless, it is necessary to use different gene panels for different conditions.

NGS: next-generation sequencing

RT-PCR: reverse transcription-polymerase chain reaction

TATs: turn around times

FF: fresh frozen

FFPE: formalin-fixed paraffin-embedded

AJCC: The American Joint Committee on Cancer

TBB: transbronchial biopsy

EBUS-TBNA: endobronchial ultrasound-guided transbronchial needle aspiration

CT: computed tomography

HE: hematoxylin and eosin

ROSE: rapid on-site evaluation

NSCLC: non-small cell lung carcinoma

EGFR: epidermal growth factor receptor

KRAS: Kirsten rat sarcoma

MET: MET proto-oncogene

ALK: anaplastic lymphoma kinase

RET: rearranged during transfection

ROS: ROS proto-oncogene

NRAS: neuroblastoma rat sarcoma

BRAF: B-Raf proto-oncogene

Ethic approval and consent to participate

Written informed consent was obtained from all the patients. The study protocol was approved by the Ethics Committee of Osaka International Cancer Institute (approval number 20172). This study was conducted in accordance with the principles of the Declaration of Helsinki.

Consent for publication

Not applicable

Availability of data and materials

The data that support the findings of this study are not publicly available due to their containing information that could compromise the privacy of research participants but are available from the corresponding author (Kei Kunimasa, [email protected]) upon reasonable request. Further enquiries can be directed to the corresponding author.

Competing interests

The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Kunimasa reports honoraria for lecture from AstraZeneca, Chugai Pharma and Novartis; Dr. Tamiya reports receiving grants from Boehringer Ingelheim, Ono, MSD, Eisai, Daiichi Sankyo, Chugai and Janssen and personal fees from Boehringer Ingelheim, Ono, MSD, Chugai, AstraZeneca, Taiho, Eli Lilly, Novartis, Asahi Kasei, Bristol-Myers Squibb, Bayer, Amgen, Kyowa-Kirin and Nippon Kayaku. Dr. Nishino reports receiving grants from Ono, TAIHO, MSD, AbbVie, DAIICHI SANKYO, Amgen, Eisai, Sanofi, Janssen, Novartis, Pfizer, Eli Lilly, Merck, Takeda, Chugai, Merus and personal fees from AstraZeneca, Chugai, Nippon Boehringer Ingerheim, Eli Lilly, Roche, Novartis, Pfizer, Merck, Janssen, Bristol Myers Squibb and Nippon Kayaku. The remaining authors declare no conflict of interest.

Funding Sources

There is no funding source for this study.

Author contributions

Conception and design: Kei Kunimasa

Administrative support: Kazumi Nishino

Provision of study materials or patients: All authors

Collection and assembly of data: Kei Kunimasa and Kazumi Nishino

Data analysis and interpretation: Kei Kunimasa and Kazumi Nishino

Manuscript writing: All authors

Final approval of manuscript: All authors

Accountable for all aspects of the work: All authors

Acknowledgement

We thank all patients who underwent gene panel testing at our hospital. We also thank Kanako Fujii and Hirotake Hayashibara of the Osaka International Cancer Institute for their assistance with specimen processing and data management in our daily practice.

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Competing interest reported. The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dr. Kunimasa reports honoraria for lecture from AstraZeneca, Chugai Pharma and Novartis; Dr. Tamiya reports receiving grants from Boehringer Ingelheim, Ono, MSD, Eisai, Daiichi Sankyo, Chugai and Janssen and personal fees from Boehringer Ingelheim, Ono, MSD, Chugai, AstraZeneca, Taiho, Eli Lilly, Novartis, Asahi Kasei, Bristol-Myers Squibb, Bayer, Amgen, Kyowa-Kirin and Nippon Kayaku. Dr. Nishino reports receiving grants from Ono, TAIHO, MSD, AbbVie, DAIICHI SANKYO, Amgen, Eisai, Sanofi, Janssen, Novartis, Pfizer, Eli Lilly, Merck, Takeda, Chugai, Merus and personal fees from AstraZeneca, Chugai, Nippon Boehringer Ingerheim, Eli Lilly, Roche, Novartis, Pfizer, Merck, Janssen, Bristol Myers Squibb and Nippon Kayaku. The remaining authors declare no conflict of interest.

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The Race Against Time: Evaluating the Speed of Gene Panel Result Delivery in NSCLC Patient Management

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Abstract

Background

Methods

Results

Conclusions

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Background

Materials and methods

Patients and clinical characteristics

Pathological assessment of FFPE specimens for gene panels

Rapid on-site evaluation (ROSE) of FF specimens

Definition of turn-around time (TAT)

Statistical analysis

Results

Patient characteristics and sampling methods for genome analysis

Detected driver alterations

Turn around time

Discussion

Conclusion

Abbreviations

Declarations

References

Additional Declarations

Supplementary Files

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