Patient characteristics are shown in Tables 1 and 2. During the study period, a total of 1394 patients with unresectable and recurrent PC underwent CGP tests. Of these, 803 were male (58%), with a median (range) age of 64 (20–86) years. Histological subtypes included adenocarcinoma in 1273 patients, adenosquamous carcinoma in 33 patients, acinar cell carcinoma in 25 patients, anaplastic carcinoma in 7 patients, and other subtypes in 56 patients, respectively. Patients with distant metastases were observed in 1257 patients (90%). The family history of cancer was present in 1070 patients (77%), and 118 patients (8%) had a history of multiple cancers. The CGP tests used were F1CDx in 1030 patients (74%) and NOP in 364 patients (26%). Tissue samples submitted consisted of surgical specimens in 481 patients, biopsy specimens in 907 patients, and 6 patients were of unknown origin. The primary treatment consisted of GnP in 957 patients (69%) and FFX in 437 patients (31%). Comparison between the HRD group and non-HRD group showed a higher prevalence of acinar cell carcinoma in the HRD group (P = 0.049). Although the HRD group tended to be younger and have more patients with a family history of cancer, the differences were not statistically significant. When comparing regimens, the FFX cohort was significantly younger and had a higher proportion of males. In the GnP cohort, there was a significant increase in the submission of surgical specimens, resulting in a significantly higher rate of GnP therapy for postoperative recurrence. In the GnP cohort, 2nd line chemotherapy introduction rate was similarly high in the HRD and non-HRD groups (93% and 90%, p = 0.54). Furthermore, the frequency of using platinum regimens in second-line and later treatment was comparable between the HRD group (59%) and the non-HRD group (52%) (Supplementary Table 1).

Details of major gene abnormalities in PC are shown in Table 3. Among the 1394 patients, mutations in KRAS, TP53, CDKN2A, SMAD4 were observed in 1266 (91%), 1026 (74%), 262 (19%), 245 (18%), respectively. When comparing the HRD group and the non-HRD group, mutations in KRAS, TP53, and CDKN2A were significantly more common in the non-HRD group. Six patients (0.4%) exhibited MSI-high, and 39 patients (2.8%) exhibited TMB-high. The median (range) TMB was 2.5 (0–231.8) mut/Mb. Patients with TMB-high were significantly more frequent in the HRD group (10.3% vs 2.2%, P < 0.01), and median TMB was also significantly higher in the HRD group (3.0 mut/Mb vs 2.5 mut/Mb, P < 0.01). In the HRD group, BRCA2 was the most common mutation observed in 51 patients (47.7%), followed by ATM in 34 patients (31.8%), and BRCA1/PALB2 in 9 patients each (8.4%).

Patients with a family history of HRD-related cancers are shown in Supplementary Table 2. A family history of HRD-related cancers, a family history of HRD-related cancers within third-degree relatives, and a family history of HRD-related cancers in individuals under 50 years old were significantly correlated with HRD.

The efficacy of the platinum-based regimen is shown in Table 4. In the FFX cohort, ORR and DCR were 33% and 66%, respectively. ORR in the HRD group was 56%, significantly higher than the 32% observed in the non-HRD group (P = 0.01). While DCR was favorable in the HRD group, there was no significant difference between the two groups (P = 0.26). The median TTF was significantly longer in the HRD group, with a median of 7.3 (95% CI: 4.2–9.4) months compared with 4.7 (95% CI: 4.0–5.3) months in the non-HRD group (P < 0.01, Fig. 1a). In the GnP cohort, ORR and DCR were 33% and 74%, respectively. ORR was 32% in the HRD group and 33% in the non-HRD group, showing similar rates between both groups (P = 0.90). Similarly, the DCR did not significantly differ between the two groups (P = 0.41). The median TTF was comparable between the HRD group (5.3 months, 95% CI: 4.5–6.1 months) and the non-HRD group (4.6 months, 95% CI: 4.4–5.1 months) in the GnP cohort (P = 0.44, Fig. 1b).

Comparison of TTF in FFX and GnP Cohort (HRD vs non-HRD). A In the FFX cohort, the median TTF was significantly better in the HRD group, with a median of 7.3 (95% CI: 4.2–9.4) months compared with 4.7 (95% CI: 4–5.3) months in the non-HRD group. B In the GnP cohort, the median TTF was comparable between the HRD group (5.3 months, 95% CI: 4.5–6.1 months) and the non-HRD group (4.6 months, 95% CI: 4.4–5.1 months). TTF time-to-treatment failure, FFX FOLFIRINOX, GnP;gemcitabine and nab-paclitaxel, HRD homologous recombination deficiency, CI confidence interval

In the FFX cohort, the median OS was significantly longer in the HRD group, with a median of 36.6 months (95% CI: 21.8—not available), compared with 19.9 months (95% CI: 17.1–22.8) in the non-HRD group (P < 0.01, Fig. 2a). In the GnP cohort, the median OS was comparable between the HRD group, with a median of 30.3 months (95% CI: 24.1–46.0), and the non-HRD group, with a median of 25.8 months (95% CI: 23.9–27.6), showing no significant difference between the two groups (P = 0.09, Fig. 2b).

Comparison of OS in FFX and GnP Cohort (HRD vs non-HRD). A In the FFX cohort, the median OS was significantly longer in the HRD group, with a median of 36.6 months (95% CI: 21.8-not available), compared with 19.9 months (95% CI: 17.1–22.8) in the non-HRD group (P < 0.01). B In the GnP cohort, the median OS was comparable between the HRD group, with a median of 30.3 months (95% CI: 24.1–46), and the non-HRD group, with a median of 25.8 months (95% CI: 23.9–27.6). Therefore, this showed no significant difference between the two groups. OS overall survival, FFX FOLFIRINOX, GnP gemcitabine and nab-paclitaxel, HRD homologous recombination deficiency, CI confidence interval

When comparing the median OS of FFX and GnP in the HRD group, no significant difference was observed between the two groups (36.6 months vs 30.3 months, P = 0.50).

In the FFX cohort, the median TTF was significantly longer in the BRCA/PALB group, with a median of 9.2 months (95% CI: 4.2–12.6), compared with 6.3 months (95% CI: 1.6–7.6) in the Other HRRm group, and 4.7 months (95% CI: 4–5.3) in the non-HRD group (P < 0.01, Fig. 3a). In the GnP cohort, the median TTF was comparable between the three groups (P = 0.13, Fig. 3b).

Comparison of TTF in FFX and GnP Cohort (BRCA/PALB group vs Other HRRm group vs non-HRD group). A In the FFX cohort, the median TTF was significantly longer in the BRCA/PALB group, with a median of 9.2 months (95% CI: 4.2–12.6), compared with 6.3 months (95% CI: 1.6–7.6) in the Other HRRm group, and 4.7 months (95% CI: 4.0–5.3) in the non-HRD group (P < 0.01). B In the GnP cohort, the median TTF was comparable between the three groups (P = 0.13). TTF time-to-treatment failure, FFX FOLFIRINOX, GnP gemcitabine and nab-paclitaxel, HRRm homologous recombination repair-related gene mutations, HRD homologous recombination deficiency, CI confidence interval