Clinical Significance of Multi-Cancer Genome Profiling: Data from A Japan Hospital

doi:10.21203/rs.3.rs-3144856/v1

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Clinical Significance of Multi-Cancer Genome Profiling: Data from A Japan Hospital

https://doi.org/10.21203/rs.3.rs-3144856/v1

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Aim

New hopes for “precision cancer care” hinge on the success of individualized cancer genome profiling at predicting the therapeutic efficacy of various anticancer drug treatments in eligible patients. We aimed to clarify the significance of cancer genome profiling in Japan by analyzing the clinical data from cancer genome testing of various solid cancers at our hospital.

Materials and Methods

A total of 230 patients examined by one of three tests for multi-cancer genome profiling including NCC Oncopanel, FoundationOne CDx, and FoundationOne Liquid were retrospectively enrolled. Adequate treatment for each patient was discussed at the expert panel meeting according to the results from the genome profiling tests.

Results

The most frequent cancer types enrolled in this study were pancreas cancer, bowel cancer, and biliary cancer. Druggable cases comprised 108 (47%) of 230 cases, and 21 (9.1%) of 230 cases actually received medication. Partial Response (PR) was found in 7 (33%) of the 21 cases Three cases of biliary cancer and three cases of BRCA2 mutation were included among the seven PR cases.

Conclusion

Twenty-one (9.1%) of 230 patients were medicated in accord with multi-cancer panel data. Japanese patients with biliary tumors might derive benefit from multi-cancer genome profiling.

cancer geneme profiling testing

precision cancer medicine

C-CAT date

actionable

druggable

genome

Precision medicine, which provides individually appropriate treatment according to personal variants, has been eagerly anticipated in oncology. Cancer gene profiling tests have been performed under the national health insurance system[1]as a precision cancer medicine since 2019. The purpose of cancer genome profiling is to build a useful genetic database for predicting the therapeutic efficacy of novel anticancer drug treatments for eligible patients not suited for standard therapy[2]. In Osaka Metropolitan University Hospital, NCC OncoPanel has been available since December 2019, and FoundationOne CDx[3] since April 2020. In addition, the FoundationOne Liquid CDx test[4] began in December 2021. The percentage of cases in which a new treatment is applied based on cancer genome profiling, which collectively analyzes many genetic abnormalities (mutations, base substitutions, insertions/deletions, copy number abnormalities, rearrangements, fusions, etc.), has been estimated between 10% and 20% of all patients[5–7]. There are higher frequencies of such cases outside of Japan; however, the present usefulness of cancer genome profiling has not been fully confirmed here[8, 9]. In this study, we analyzed clinical data from cancer genome profiling for various solid cancers at our hospital, with the aim of clarifying the significance of cancer genome profiling in Japan.

Patients

A total of 237 patients was enrolled between December 2019 and January 2023 at Osaka Metropolitan University Hospital. Because 7 patients died before expert panel, we analyzed 230 patients in this study.

Cancer genome profiling testing

These patients have examined NCC Oncopanel examination which tested for 114 gene variants[5], FoundationOne CDx examination for 324 gene variants[3], or FoundationOne Liquid CDx examination which extracts circulating tumor DNA from the blood for 324 gene variants[4]. The type of panel testing was selected according to tumor size and sample type. Subsequently, Expert panel was performed after C-CAT (Center for Cancer Genomics and Advanced Therapeutics in Japan) data repoted. We considered pathological significance about gene variant using Clinvar (https://www.ncbi.nlm.nih.gov) and Varsome (https://varsome.com).

Microsatellite status and tumor mutational burden

MSI status (stable vs. high) was determined using 114 intronic homopolymer repeat loci with adequate coverage on the panel testing. These sequences were analyzed for length variability and compiled into an overall score using principal components analysis[10]. Tumor mutation burden (TMB) is a major factor in the selection of immune checkpoint therapies[11]. The high tumor mutational burden (TMB-high) is defined by over 10 mutations / megabase (Mut/Mb)[12].

Expert panel

In the Expert Panel the attending physician or physicians meet with several experts representing various fields, including an oncologist, physicians in charge of clinical trials, genetic counselors, pathologists, and physicians specializing in clinical genetics, who convene after results for a patient are obtained from the NCC Oncopanel report, the FoundationOne CDx report, FoundationOne Liquid CDx report, or the C-CAT report. The possibility of a hereditary tumor and the best treatment based on the cancer gene profiles were discussed at the meeting of the expert panel, whose final report was then prepared and returned to the attending physician.

Clinicopathological features of patients with refractory tumor

Characteristics of the 230 patients are summarized in Table I. The 230 patients included 118 males and 112 females. The medium age was 62 (range 12–88) years. There were 205 patients with metastasis. NCC Oncopanel was used in 17 patients, FoundationOne CDs in 182 patients, and FoundationOne CDs Liquid in the remaining 31 patients. The average period from order panel testing to expert panel was 29.7 days.

The most frequent cancer types examined by panel test were pancreas cancer (N = 42, 18.3%), bowel cancer (N = 41 cases, 17.8%), biliary cancer (N = 27, 11.7%), in descending order. Test sites were the primary tumor in 141 patients (61.3%, blood in 31 patients (13.5%) of liquid tumors, and metastases in 58 patients. The metastasis sites with the highest frequency were liver (15 cases, 6.5%), peritoneum (N = 15, 6.5%), lung (N = 9, 3.9%), and lymph node (N = 7, 3.0%). Among the pathological classifications, 202 cases (87.8%) were epithelial cancer and 22 cases (10%) were non-epithelial. Of the genes tested, we analyzed in greater detail the 31 genes for which the frequency of occurrence of pathological variants was 3.0% or higher in our study population.

Treatment cases and dropped out cases

Of the 108 druggable cases, 21 cases actually received approved treatment (Table II). Of these, a partial response (PR) was found in 7 cases, stable disease (SD) in 4 cases, and progressive disease in 10 cases. Three cases of biliary tumor were found in the 7 PR cases. Pathological gene variants most common among the 21 cases were TMB-high in 5 cases and BRCA2 mutation in 4 cases. All 4 cases with BRCA2 mutation showed PR or SD. On the other hand, 87 of the 108 cases dropped out (Table III), mainly because of the use of alternative therapies or the ineligibility for clinical studies, such as non-fulfillment of eligibility criteria, being outside the registration period, or the poor condition of patients. Most patients with advanced-stage disease are not eligible for many clinical studies.

In this study, a total of 230 patients were analyzed using three multi-cancer genome profiling tests including NCC Oncopanel, FoundationOne CDx, and FoundationOne Liquid. Among the three panel tests, FoundationOne CDx examination was frequently (79.1%) performed, while NCC Oncopanel was less frequently performed (7.4%). One of the reasons for the more frequent use of FoundationOne CDx might be that FoundationOne CDx screens for more genes than NCC Oncopanel.

The average period from the panel test orders to the convening of the expert panel was 29.8 days in our study, similar to findings from previous reports from Japan[6, 11]. This period seems to be longer than those reported from overseas[4, 11]. One of the reasons for the delay might be due to the requirement for the expert panel in Japan, but such delays are typical for clinical settings in Japan[13, 14]. Assistance by artificial intelligence might contribute to shortening the period.

The tumor type with the highest frequency of pathogenic variants was the pancreas, followed by bowel, biliary tract, and breast. Genes with the high frequency of pathogenic variants were TP53, KRAS, CDKN2A, and APC. Few approved drugs against these pathogenic variants have been developed. It will be necessary to develop useful drugs against these major pathogenic variants in the near future.

In this study, druggable cases comprised 108 (47.0%) of the 230 cases. However, 87 (81%) of the 108 druggable cases dropped out, mainly because of the use of alternative therapies, the ineligibility for clinical studies, such as non-fulfillment of eligibility criteria, being outside the registration period, or the poor condition of patients. Most patients with advanced-stage disease are not eligible for many clinical studies. At this time in Japan, cancer genome profiling is only performed on patients with advanced solid tumors who have failed to respond to standard therapies[13]. Some reports suggest that cancer genome testing should be performed before first-line treatment[14–16]. Since the final reports from cancer gene profiling take time to prepare, our experience suggests that cancer genome profiling should be undertaken as early as possible to increase opportunities for “precision cancer care” based on genetic variants.

The cancer types with the highest frequency of panel testing were pancreas cancer, bowel cancer, and biliary cancer; the 108 druggable cases also had a predominance of pancreas tumor and bowel tumor cases (15 cases each), followed by biliary tumor (n = 14) and breast tumor (n = 11). Although bowel tumors led in the number of druggable cases, none of those cases received medication. In addition, the ratio of druggable cases was highest in breast tumors (84.6%), but only one breast tumor case was medicated. Of the 108 druggable cases, only 34 cases were approved for experimental drug treatment. These findings might suggest that the development of novel molecular-targeted drugs might be urgently necessary, especially in bowel cancer and breast cancer.

Only 21 of the 108 cases actually received medication, amounting to 9.1% of all 230 cases. Seven (33.3%) of the 21 medicated cases showed a maximum treatment benefit of PR. Three cases of biliary tumor were included among these 7 PR cases, suggesting that at this time in Japan, patients with biliary tumors might derive benefit from multi-cancer genome profiling. Among the druggable cases, the pathological gene variants that actually received medication were TMB-high and BRCA2 mutation, with all BRCA2 mutations showing PR or SD.

In conclusion, we reported 230 cases of multi-cancer genome profiling in our hospital. Although around half of the cases were deemed druggable cases, only 21 (9.1%) actually received medication due largely to delays and limited access to drugs/clinical trials. Biliary-tract tumors showed relatively good response to individualized medication, suggesting that patients with this cancer in Japan might derive benefit from multi-cancer genome profiling. It is necessary to accelerate the development of molecular-targeted drugs against major pathogenic variants.

Ethics approval and consent to participate:

This study was approved by Osaka Metropolitan University Hospital Certified Review Board (Permission number: 3925) and carried out according to the guidelines of the committee. Informed consent was obtained in writing from all patients included in the study. And this study has been conducted according to the principles of the declaration of Helsinki. All data in this study were handled in accordance with the Japanese personal information protection law.

Consent for publication

Written informed consent was obtained from the patient to publish genomic data.

Availability of data and materials

The data supporting the conclusions of this article are included within the article.

Competing interests

The authors declare no competing interests in association with the present study.

Funding

This study is partially founded by KAKENHI (Grant-in-Aid for Scientific Research) 21H03008.

Authors’ contributions

RA and MY designed and summarized data and co-wrote the manuscript. RA and MY contributed equally.HN, KK, SK, YY, and SN collected the data. All authors read and approved the final manuscript.

Acknowledgements

We thank Drs. (Osaka City Graduate School of Medicine, Osaka, Japan), and Chiaki Kawano (Genetic Counseling Unit, Osaka Metropolitan University, Graduate School of Medicine, Osaka, Japan) who contributed to this study.

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Table I. Clinicopathologic features of 230 patients.

Variables	Case number (n=230)	Frequency of 230 cases (%)	Druggable case (n=106)	Frequency of druggable case (%)
Sex Male Female	118 112	51% 49%	52 56	48.1 50.0
Age 0 - 9 10-19 20-29 30-39 40-49 50-59 60-69 70-79 80-89 90-	0 4 2 7 30 41 64 71 11 0	0 1.7 0.9 3.0 13.0 17.8 27.8 30.9 4.8 0	0 2 1 3 13 23 27 33 6 0	0 50.0 50.0 42.9 43.3 56.1 42.2 46.5 54.5 0
Type of Panel testing FoundationOne CDx FoundationOne Liquid CDx NCC Oncopanel	182 31 17	79.1 13.5 7.4	90 13 5	49.4 41.9 29.4
Tumor type Pancreas Bowel Biliary tract Soft tissue Lung Breast Stomach Esophagus Uterus Brain Ovary Liver Prostate Other	42 41 27 15 15 13 13 10 9 8 7 6 5 19	18.3 17.8 11.7 6.5 6.5 5.7 5.7 4.3 3.9 3.5 3.0 2.6 2.2 12.1	15 15 14 8 6 11 8 3 4 5 2 4 4 9	35.7 36.6 51.9 53.3 40.0 84.6 61.5 30.0 44.4 62.5 28.6 66.7 80.0 47.4
Specimen lesion Primary lesion Pancreas Bowel Biliary tract Soft tissue Lung Stomach Breast Esophagus Uterus Brain Ovary Liver Prostate Small intestine Eye Other Metastasis lesion Liver Pleuroperitoneal Lung Lymph node Soft tissue Other Liquid Pancreas Bowel Lung Biliary tract Other	141 24 21 17 11 9 8 7 7 7 6 6 4 4 3 2 5 58 15 15 9 7 3 9 31 13 5 5 3 5	60.9 17.0 14.9 12.1 7.8 6.4 5.7 5.0 5.0 5.0 4.3 4.3 2.8 2.8 2.1 1.4 3.5 25.2 25.9 25.9 15.5 12.1 5.2 15.5 13.5 41.9 16.1 16.1 9.7 16.1	67 9 8 9 6 3 5 7 2 3 4 1 3 0 2 2 3 26 6 5 5 4 1 5 13 4 3 3 0 3	47.9 46.7 38.1 52.9 54.5 33.3 62.5 100.0 28.6 42.9 66.7 16.7 75.0 0 66.7 100.0 60.0 44.8 40.0 33.3 55.6 57.1 33.3 55.6 41.9 30.8 60.0 60.0 0 60.0
Pathological tissue Epithelial carcinoma Non-epithelial carcinoma	208 22	90.4 9.7	97 11	42.2 50.0

Table II. Outcomes of 21 medicated cases.

Case number	Gene	Disease	Panel testing	Specimen	Drug	Maximum benefit
1	BRCA2 A938fs21*	Ovary	NCC Oncopanel	Metastastic tumor	Olaparib (Approved Drug)	PR
2	BRCA2 I1859fs3*	Prostate	FoundationOne CDx	Primary tumor	Olaparib (Approved Drug)	PR
3	BRAF G469A	Extrahepatic bile duct	FoundationOne CDx	Primary tumor	Binietinib / encorafenib (Patient-Proposed Healthcare Services)	PR
4	FGFR2-HNRNPA1 rearrangement	Intrahepatic bile duct	FoundationOne CDx	Primary tumor	Pemigatinib (Approved Drug)	PR
5	ERBB2 amplification	Gallbladder	FoundationOne CDx	Primary tumor	Trastuzumab (approved drug)	PR
6	BRCA2 S2219*	Pancreas	FoundationOne CDx	Primary tumor	Olaparib (approved drug)	PR
7	TMB-high	Duodenum	FoundationOne CDx	Primary tumor	Pembrolizumab (approved drug)	PR
8	BRCA2 Q486fs28*	Breast	FoundationOne CDx	Metastastic tumor	Olaparib (approved drug)	SD
9	TMB-high	Stomach	FoundationOne CDx	Primary tumor	Pembrolizumab (approved drug)	SD
10	RET-KIF5B fusion	Lung	FoundationOne Liquid	Liquid	Selpercatinib (approved drug)	SD
11	KRAS G12C	Lung	FoundationOne CDx	Primary tumor	Sotorasib (approved drug)	SD
12	CHEK2 c.441+1G>A	Intrahepatic bile duct	FoundationOne CDx	Metastastic tumor	Olaparib (Off-label Use)	PD
13	TSC 2 loss	Bone	FoundationOne CDx	Metastastic tumor	Everolimus (patient-proposed healthcare services)	PD
14	TMB-high	Liver	FoundationOne CDx	Primary tumor	Atezolizumab+bevacizumab →pembrolizumab (approved drug)	PD
15	ATM E376,* P2982fs3*	Pancreas	FoundationOne CDx	Primary tumor	Olaparib (approved drug)	PD
16	PIK3CA H1047R	Pancreas	FoundationOne CDx	Metastastic tumor	Everolimus (patient-proposed healthcare services)	PD
17	ERBB2 amplification	Stomach	FoundationOne CDx	Primary tumor	Trastuzumab (approved drug)	PD
18	TMB-high	Brain	FoundationOne CDx	Primary tumor	Pembrolizumab (approved drug)	PD
19	TMB-high	Uterus	FoundationOne CDx	Primary tumor	Pembrolizumab (approved drug)	PD
20	MSI-high	Extrahepatic bile duct	FoundationOne CDx	Primary tumor	Pembrolizumab (approved drug)	Dead prior to evaluation
21	PDGFRA amplification	Bone	FoundationOne CDx	Primary tumor	Imatinib (off-label use)	Dead prior to evaluation

Table III. Reasons for rejection of the genotype-matched therapy in 87 patients of 108 druggable cases.

Main reasons	n (%)
The patient or doctor wished anything other than the proposed treatment	37 (42%)
No clear reason	18 (14%)
Out of eligibility criteria or registration period	12 (20%)
Poor performance status	11 (13%)
Patient refused any treatment	5 (6%)
Financial situation of the patient	4 (5%)

No competing interests reported.

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Clinical Significance of Multi-Cancer Genome Profiling: Data from A Japan Hospital

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Version 1

Abstract

Aim

Materials and Methods

Results

Conclusion

Figures

Introduction

Material and Methods

Cancer genome profiling testing

Microsatellite status and tumor mutational burden

Expert panel

Results

Treatment cases and dropped out cases

Discussion

Declarations

References

Tables

Additional Declarations

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