Patient characteristics

Patient characteristics are summarized in Table 1. In 4682 cases, 3554 underwent F1 CDx (76%) and 1128 underwent NOP (24%). Adenocarcinoma was the predominant histological subtype accounting for 95%. There were no significant differences in patient characteristics between the two CGP test groups, except for sex distribution (56% male in F1 CDx vs. 60% in NOP, P < 0.001). In addition, the proportions of surgical specimens (55% in F1 CDx vs. 36% in NOP, P < 0.001) and previously treated specimens (43% in F1 CDx vs. 36% in NOP, P < 0.001) were different between the two groups.

Table 1 Clinical characteristicsDetails of actionable gene aberrations

The breakdown of actionable gene aberrations and the 10 most common actionable abnormalities are shown in Table 2. The 10 most common genetic abnormalities are shown in Supplementary Table 1. In total, actionable gene aberrations were observed in 1,264 cases (27%). The most common actionable gene abnormalities were BRCA2 (3.4%), followed by ATM (2.9%), ERBB2 (2.8%), PIK3 CA (2.5%), and BRAF (1.9%), in addition to MSI-H (0.5%) and TMB-H (2.4%). The median (range) TMB was 2.3 (0–281.4) mut/Mb. Actionable gene aberrations were more likely to be observed in F1 CDx than in NOP (30% vs. 18%, P < 0.001). The frequency of MSI-H was not different between the two tests (0.5% vs. 0.4%, P = 0.80), but the TMB-H detection rate was higher in NOP (1.7% vs. 4.3%, P < 0.001). The most common gene abnormality, regardless of evidence level, was KRAS (88.4%) (Supplementary Table 1).

Table 2 The breakdown of actionable gene aberrations and the 10 most common actionable abnormalitiesFactors associated with the actionable gene aberrations

The results of univariate and multivariable logistic regression for factors associated with actionable gene aberrations detected by CGP tests are shown in Table 3. In the univariate analyses, age (< 40 years), double cancer (presence of another tumor), the histology of ACC, sampling from metastasis, sampling by biopsy, KRASWT status, and use of F1 CDx were associated with the detection of actionable gene aberrations. Multivariable analysis revealed the histology of ACC (Odds ratio [OR] 1.87, 95% confidence interval [CI] 1.00–2.67, P = 0.043), KRASWT status (OR 3.09, 95% CI 2.49–3.85, P < 0.001), and use of F1 CDx (OR 2.38, 95% CI 1.98–2.85, P < 0.001) as significant factors associated with the detection of actionable gene aberrations.

Table 3 Univariate and multivariable logistic regression of factors associated with actionable gene aberrations

The results of the additional analysis for surgical and biopsy samples, considering mutations with a VAF ≥ 5% as relevant, are shown in Supplementary Tables 2 and 3, respectively. Consistent with the findings for the entire cohort, these additional analyses revealed that the histology of ACC, KRASWT status, and the use of F1 CDx were independent factors associated with actionable gene aberrations in the multivariate analyses.

Actionable gene aberrations according to the histological type, KRAS status, and CGP tests

Details of actionable gene aberrations according to the histological type, KRAS status, and CGP test are shown in Fig. 2. Actionable gene aberrations were more common in ACC cases than in other histological types (55% vs 27%, P < 0.001). Furthermore, actionable BRCA2 (16% vs 3%, P < 0.001), ATM (9% vs 3%, P < 0.001), BRAF (6% vs 2%, P < 0.001), and PALB2 (5% vs 1%, P < 0.001) mutations were more frequent than in PDAC (Fig. 2b). A higher proportion of TMB-H (6% vs 2%, P < 0.001) and MSI-H (1.3% vs 0.3%, P = 0.010) mutations were observed in cases with KRASWT compared to KRAS mutant (KRASmt). In addition, KRASWT cases were more likely to harbor mutations in BRCA2 (7% vs 4%, P < 0.001), PIK3 CA (5% vs 3%, P < 0.001), PALB2 (3% vs 1%, P = 0.032), PTEN (2% vs 1%, P = 0.042), and BRIP1 (1.3% vs 0.3%, P = 0.002) compared to KRASmt cases (Fig. 2e, f). A higher incidence of fusion genes was noted in KRASWT cases, including BRAF (4% vs 0%, P < 0.001), FGFR2 (1% vs 0%, P < 0.001), and RAF1 (1% vs 0%, P < 0.001). The KRAS G12 C mutation was detected in 16 cases (0.4%).

Fig. 2

Summary of CGP tests submitted and actionable gene aberrations. a Pancreatic ductal adenocarcinoma. b Acinar cell carcinoma. c Adenosquamous carcinoma. d Anaplastic carcinoma. e KRAS mutant. f KRAS wild type. g FoundationOne CDx®. h OncoGuide™ NCC Oncopanel FoundationOne CDx

There was no difference in the detection of actionable gene abnormalities between F1 CDx and NOP in a gene-by-gene comparison for all genetic abnormalities detected (Fig. 2g, h).

Subgroup analysis between the two CGP tests

A forest plot illustrating the favorability of the two CGP tests in detecting actionable gene aberrations across subgroups is shown in Fig. 3. Despite differences in the recommended quantity and quality of submitted specimens for the two CGP tests, F1 CDx contributed to the detection of actionable gene aberrations in most groups, particularly in those with ACC (OR 6.01, 95% CI 2.34–10.4) and KRASWT (OR 3.55, 95% CI 2.38–5.29). No subgroups were identified in which NOP contributed to the detection of actionable gene aberrations.

Fig. 3

Forest plot for the detection rate of actionable gene aberration. Odds ratio in background factors for each test is shown