The initial assessment of expert panel performance in core hospitals for cancer genomic medicine in Japan

The investigators, who were representatives of each EP at all of the core hospitals, are nominated. On February 27, 2020, an investigator meeting was held and the operation and performance of EPs was discussed. As a pre-meeting survey, we collected data on consecutive cases in which CGP tests were performed at all core hospitals between June 2019 and January 2020 and evaluated the number of cases that received genomically matched treatments and in which patients were referred for genetic counseling according to the recommendation by the EP. After consultation with the NCC Institutional Review Board (IRB), the IRB officially confirmed that the current study does not require IRB approval.

Two simulated cases were developed by medical oncologists (KS, YN and TY) at the National Cancer Center Hospital (NCCH) and National Cancer Center Hospital East (NCCHE), which are the most experienced core hospitals and which have performed the largest number of CGP tests thus far.

Case 1 was a male with advanced colorectal cancer who had failed to respond to standard chemotherapies. The patient harbored the following somatic genetic alterations as follows: BRAF V600E, ATM R35*, NF1 Y1521*, TP53 R273H, APC c.1312+1G>A, ARAF R326* and NTRK2 L138P, and BRCA2 V208G germline variant. Case 2 was a female with advanced breast cancer whose disease progressed on standard therapies, who showed PIK3CA H1047R, ERBB2 S310Y and CCND1 amplification. Cases 1 and 2 were tested by the OncoGuide NCC Oncopanel System and FoundationOne CDx Cancer Genomic Profile, respectively (Table 1). Simulated CGP result reports of these two cases were prepared by the medical oncologists (KS, YN, and TY), and simulated C-CAT Findings were prepared by C-CAT. Then, these reports (clinical history, results of the simulated CGP test and simulated C-CAT findings) were delivered to all EPs at core hospitals on December 24, 2019.

Each EP discussed the simulated CGP test results and simulated C-CAT findings and made recommended genomically matched treatment according to the evidence level and necessity of genetic counseling during their routine EP meetings, between December 25, 2019 and January 31, 2020. Note that the developers of simulated cases (KS, YN, and TY) never joined in the discussion at the EP meetings for these cases. The evidence level was defined in “Consensus clinical practice guidance for the CGP tests,” which was issued by three cancer-related major Japanese societies in October 2017 [12]. The annotated reports from each EP were centrally assessed by the developers (KS, YN, and TY) before the investigator meeting held on February 27, 2020.

At the investigator meeting, investigators from each EP demonstrated their daily work at the EP and we recognized that all of the EPs mainly discussed the applicability to genomically matched treatment, including IND trials, and the necessity of genetic counseling. In addition, for all investigators, it was suggested that all pre-reviewing would be carefully carried out by the key members of each EP to make the conference more interactive and to also save time.

A total of 1522 cases (core hospitals, n = 747; cooperative hospitals, n = 775) underwent CGP tests from June 2019 to January 2020. Among the 747 cases in core hospitals, 28 cases (3.7%, range 0–7.6%) received genomically matched treatments (Table 2); 16 of the 28 cases (2.1%) participated in the IND trials and three cases (0.4%) received genomically-matched treatment as an off-label treatment. The remaining eight cases (1.0%) received approved molecular-targeted drugs. The most common treatments were HER2 inhibitors for ERBB2 alterations (n = 6), followed by FGFR inhibitors for FGFR/FGF alterations (n = 4), EGFR inhibitors for EGFR mutations (n = 2), NTRK inhibitors for NTRK fusions and mTOR inhibitors for PIK3CA mutations (n = 2) (Supplementary Table 1). Regarding the germline findings, 17 of 747 cases (2.3%, range 0–15%) were referred for genetic counselling (Supplementary Table 2).

Nine of 11 EPs recommended dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) combination therapy for a BRAF V600E mutation. Triplet therapy with encorafenib (BRAF inhibitor), binimetinib (MEK inhibitor), and cetuximab was recommended by four sites (Sites C, E, I and K) because the triplet/doublet (encorafenib plus cetuximab) regimens showed a survival benefit in pre-treated metastatic colorectal cancer patients with BRAF V600E mutation in the BEACON global phase 3 trial [13, 14]. Although the ANCHOR global phase 2 trial with the triplet regimen was ongoing in Japan at that time, the eligibility was restricted to chemotherapy-naïve patients; thus, the other seven sites did not recommend it [15]. TP0903, an AXL kinase inhibitor, was recommended by Sites F and I [16]. For ATM truncating mutation, two sites (Sites E and F) recommended BAY-1895344, ATR inhibitor [17], and Site E recommended talazoparib plus avelumab [18]. Regarding other candidate therapies, LXH254 (a pan-RAF inhibitor) [19], TP0903, TAK931 (a CDC7 inhibitor) [20], and olaparib (based on a phase 2 trial for advanced solid tumors) [21], and talazoparib + avelumab were considered by Site A, while trametinib was considered by Site F. Site G concluded that there was no recommendation and dabrafenib and trametinib therapy was considered as a treatment option. All 11 sites annotated BRCA2 V208G as a germline variant of uncertain significance (VUS). Considering the familial history of breast cancers, two EPs (Sites D and H) recommended genetic counseling (Supplementary Table 3).

One site (Site D) recommended everolimus plus exemestane for PIK3CA mutation. That regimen was also considered as a treatment option by Sites A, F and J. Alpelisib or PI3K inhibitor, which are approved by the FDA for hormone receptor-positive breast cancer with PIK3CA mutation [22], were recommended by three sites (Sites H, I, and K), but not recommended by the other 8 sites due to closure of the clinical trial in Japan. Trastuzumab deruxtecan was recommended by two sites (Sites C and D) for HER2 IHC1+ [23]. No sites evaluated ERBB2 S310Y and CCND1 amplification as druggable. Two sites (Sites B and G) concluded that no genomically matched treatment was available for this patient (Supplementary Table 4).