We report here for the first time the initial assessment of the utility of CGP testing for patients with metastatic breast cancer under Japanese universal health insurance system. In the first 18 months after implementation of reimbursement for CGP tests, 310 CGP tests were conducted in our institute during the study period and thirty-five patients with metastatic breast cancer were evaluated. Actionable gene mutations were detected in 30 patients (85.7%), and participation in a clinical trial was recommended to 7 patients (20.0%). The drug was administered to only 2 patients (5.7%), as 3 patients (8.6%) had newly suspected germline pathological variants, and the results were subject to disclosure.
There have been many reports on treatment strategies for metastatic breast cancer using CGP testing. Huang et al. reported that genomic landscape of 312 patients with breast cancer using the FDA-approved Foundation One CDx assay, and the top 5 detected genes in descending order were PIK3CA, TP53, RAD21, NBN, and CCND1 in HR+/HER2− disease subset, TP53, CDK12, PIK3CA, MYC, and RAD21 in HER2+ disease subset, TP53, RAD21, MYC, PIK3CA, and NBN in TNBC disease subset15. Wheler et al. reported that of the 339 patients who successfully performed analysis of CGP testing, 122 patients (36.0%) received treatment according to the gene mutations16. Although the results of the genomic landscape of breast cancer using Foundation One CDx assay was almost the same as those of our study, there was a large difference in the drug accessibility rate.
In Japan, several studies using CGP test have been reported. Firstly, as an analysis for research purpose, Kawaji et al. reported the results of Foundation One CDx assay from 109 Japanese breast cancer patients and also reported 54% of patients had clinical evidence level A mutations according to the consensus of three major Japanese cancer related societies and the Center for Cancer Genomics and Advanced Therapeutics17. However, the report by Kawaji et al. was for research purposes and did not evaluate the achievement rate of treatment according to gene mutations or the usefulness of CGP testing in actual clinical practice. Secondly, as for the current status of CGP testing under universal health insurance in Japan, 805 patients underwent CGP testing between June and October 2019, and it was reported that 10.9% of these patients were then treated based on their gene mutations18. Furthermore, according to a report from 11 core hospitals for cancer genomic medicine, among the 747 cases in which CGP tests were conducted (from June 2019 to January 2020), 28 patients (3.7%) received genome-matched treatment19. Of these 28 patients treated according to their gene mutations, only 2 patients had breast cancer, and both were treated with an mTOR inhibitor for a PIK3CA mutation in that study19. However, since mTOR inhibitor are not approved for PIK3CA mutations, it is not appropriate to evaluate these cases as having been treated strictly according to the gene mutations.
Although there are few previous reports on turn-around time, we reported the median turn-around time from obtaining consent to the molecular tumor board was 44 days, and from obtaining consent to explaining the CGP test results was 56 days. The Foundation Medicine estimates that it takes about 12 days from receipt of specimens to return of analysis results to medical institutions. The reasons for the longer TAT might be as follows. The first reason is that it took several days to a week to transport specimens from Japan to Foundation Medicine. The second reason is that the results of CGP testing are required to be reviewed by molecular tumor board before being returned to the patient under national health insurance in Japan. The third reason is that medical fees (480,00 yen) can only be charged when the results of CGP testing are explained in an outpatient visit. In our study, there was a patient who required 92 days to explain the results in the outpatient clinic after discharge due to prolonged inpatient treatment due to disease progression.
The novelty and importance of our report in comparison with these previous foreign and Japanese reports are as follows. Firstly, our report not only showed low drug accessibility rate for metastatic breast cancer with CGP testing under Japanese universal health insurance system, but also discusses in detail the reasons for the cases in which treatments according to the gene mutations were recommended by molecular tumor board but could not be administered. Secondly, we examined in detail the turn-around time of CGP testing performed under Japanese universal health insurance system. Thirdly, we revealed that approximately 8% of patients died due to disease progression before the test results were disclosed; thus, the results of the CGP tests could not be explained.
Possible causes of these issues include the indication and official pricing system of reimbursement of CGP testing covered by Japanese universal health insurance system. The indication for CGP testing covered by insurance in Japan is restricted to patients with advanced solid tumors exhibiting disease progression during standard therapy (including those expected to be completed) or patients for whom there are no appropriate standard treatments, including those with rare cancers and carcinoma of unknown primary origin8,9,10. Furthermore, reimbursement for the cost of a CGP test is 560,000 yen, paid in two steps. The first reimbursement is 80,000 yen after applying for the informed consent for CGP testing and preparation of tumor samples. The second reimbursement of 480,000 yen is paid when the patient receives an explanation of the CGP test results in an only outpatient visit after assessment by the molecular tumor board.
As mentioned above, the results of our analysis were almost identical to the genomic landscape of breast cancer reported by Huang RSP et al. Even though CGP testing is now limited to after the completion of standard treatment due to insurance requirements in Japan, experts in each field examined the results of CGP testing in detail in molecular tumor board and could provide new treatment options, such as those available in clinical trials to 7 patients (20.0%). However, 5 (14.3%) of these patients were unable to undergo genome-matched treatment due to disease progression after the CGP test. Therefore, our study revealed that the benefits of CGP testing might not be fully extended to patients with metastatic breast cancer due to the indication for CGP testing covered by insurance in Japan.
Although the definition of the standard treatment for metastatic breast cancer prior to CGP testing remains controversial, the treatments strongly recommended in the guidelines of the Japanese Breast Cancer Society are considered candidates in Japan20. However, the patient may be eligible for CGP testing without all standard therapies, depending on the efficacy and safety of previous therapies, the patient’s general condition, and patient preference in consideration of the 6- to 8-week turnaround time from submission of tumor tissue to return of analysis results. Furthermore, the Consensus clinical practice guidance for CGP testing in Japan was updated and now recommends CGP test would be recommended, regardless of the line of treatment21. Therefore, our results suggest that CGP testing conducted at the appropriate time and based on the efficacy of previous therapy, the patient’s general condition, and patient preference might improve the drug accessibility rate.
It is also very important to conduct multiple CGP testing as needed to evaluate the acquired mutations and resistance-acquired mutations due to therapeutic modification and utilize them in treatment strategies22. Although CGP testing are only allowed to be used once per patient under Japanese universal health insurance system, multiple CGP testing, including the CGP test using blood samples, might provide greater benefits to patients.
As mentioned above, CGP testing is currently restricted to patients who finished standard therapies in order to avoid unnecessary investigations and reduce the burden for the molecular tumor board. However, patients who finished standard therapies for metastatic or recurrent cancer tend to have poor prognosis due to disease progression. Therefore, it is important to perform the CGP test at the diagnosis of metastatic breast cancer. Also, changes to the insurance system should be considered, in addition to increasing the number of clinical trials and promoting efforts to standardize quality while reducing the burden on the molecular tumor board.
In summary, it has been almost 2 years since CGP testing covered by the universal health insurance system was first introduced in Japan, and implementation of cancer genomic medicine is progressing. We reported here the initial assessment of CGP testing for patients with metastatic breast cancer and revealed that the percentage of patients who could reach clinical trials is low. In our sample group, a number of patients died before the test results were disclosed, although more than 80% of the patients had actionable mutations. In order to make CGP testing clinically valuable for patients with metastatic breast cancer, it will be necessary to solve problems associated with the current program of insurance coverage for CGP testing in Japan.