Genomic landscape and clinical features of rare subtypes of pancreatic cancer: analysis with the national database of Japan

Frequency of rare-subtype pancreatic cancers and clinical features

The group of 2,691 patients in this study was composed of 44 patients (1.6%) with ACC, 54 (2.0%) with ASC, 25 (0.9%) with ACP, and 2,568 (95.4%) with PDAC (Fig. 1). Table 1 summarizes the clinical characteristics of all patients according to their cancer types. On grouping together patients with all four tumor types, the mean age was in the early 60 s, with most having ECOG-PS = 0 or 1. No significant differences were noted among the four groups in terms of age, sex, smoking habit, heavy alcohol consumption, ECOG-PS, sampling method, or site of tumor sampling. Among the genomic profiling tests, F1CDx was the most frequently performed in all groups, followed by NCC, with F1L being the least frequent, with significant differences among the four groups. No notable differences were noted in the proportion of lung and peritoneum metastasis, while the difference in lymph node metastasis was close to significance among the four groups. Moreover, liver metastasis was found in 72.2% of ASC patients, being significantly higher compared with that in PDAC patients (49.5%, p < 0.01).

Fig. 1figure 1

Flow diagram of the study. The diagram displays the tumor types which were excluded and the number of cases of acinar cell carcinoma (ACC), adenosquamous carcinoma (ASC), anaplastic carcinoma of the pancreas (ACP), and pancreatic ductal adenocarcinoma (PDAC), respectively

Table 1 Clinical characteristics by the subtypes of pancreatic cancerGenomic characteristics

Overall genomic alterations (small-scale variant, deletion, amplification, and rearrangement) with the MSI and TMB status of the four tumor types are shown in Fig. 2a–d, and the top 10 genes in PDAC are compared among the four groups by charts shown in Fig. 3a, b. The list of genes following these frequent gene mutations are presented in Supplemental Table 1. In PDAC patients, the most frequently observed variants were KRAS (85.1%), TP53 (69.1%), CDKN2A (35.4%), and SMAD4 (19.4%). ASC and ACP patients showed similar results, with 90.7 and 76.0% for KRAS, 85.2 and 68.0% for TP53, 51.9 and 40.0% for CDKN2A, and 25.9 and 8.0% for SMAD4, respectively. In contrast, in patients with ACC, KRAS and TP53 were significantly less frequently detected in comparison with the other three tumor types, at 13.6 and 15.9%, respectively (p < 0.01 for TP53 between ACC and ACP, p < 0.001 for the rest). In addition, CDKN2A alteration was found in 25.0% of ACC patients, which was also significantly lower than in ASC (p < 0.001). For more detail regarding KRAS, G12D and G12V were found to be the most common in either group, followed by G12R. G12C, which is well-known for its high detection rate in lung cancer and the recent development of its inhibitor sotorasib [23], was observed only in 2.2% of KRAS mutant PDAC patients, and none in ACC, ASC, and ACP patients (Fig. 3c). The genomic variants which followed the above top 4 variants in PDAC patients were CDKN2B (17.6%), ARID1A (7.1%), STK11 (7.0%), MYC (3.2%), KDM6A (3.0%), and DNMT3A (3.0%). The proportions of these genomic mutations in ACC, ASC, and ACP patients were as follows: CDKN2B (20.5, 29.6, and 36.0%, respectively), ARID1A (9.1, 14.8, and 8.0%, respectively), STK11 (4.6, 14,8, and 4.0%, respectively), MYC (0, 7.4, and 4.0%, respectively), KDM6A (2.3, 5.6, and 4.0%, respectively), and DNMT3A (4.6, 1.9, and 0%, respectively). No differences were observed for these genomic variants.

Fig. 2figure 2

Overview of the most common genomic alterations. Data are shown for a acinar cell carcinoma (ACC), b adenosquamous carcinoma (ASC), c anaplastic carcinoma of the pancreas (ACP), and d pancreatic ductal adenocarcinoma (PDAC). The genes most frequently found in PDAC are listed from the top to bottom

Fig. 3figure 3

The frequency of major genomic alterations among rare subtypes of pancreatic cancer and pancreatic ductal adenocarcinoma (PDAC). Data are shown for a top 4 and b 5th-10th gene mutations found in PDAC. c shows the distribution of KRAS subtypes, d and e show the frequencies of the representative homologous recombination repair (HRR) and mismatch repair (MMR) genes among the four tumor types, respectively

Representative HRR gene mutations are shown in Fig. 3d. These genes were chosen based on previous reports [24, 25]. In PDAC patients, the frequencies of ATM, ATR, BRCA1, BRCA2, and PALB2 were 2.5, 0.2, 0.9, 2.9, and 0.9%, respectively. HRR genes were generally less common in ASC and ACP patients, with only 3.7% for BRCA2 in ASC and 4% for PALB2 in ACP. On the other hand, in ACC patients, the rates for ATR and BRCA1 were not high (0 and 2.3%, respectively), while ATM and BRCA2 were 11.4 and 13.6%, respectively, which were both significantly higher compared with PDAC patients (p < 0.05 and p < 0.01, respectively). Thus, 15.9% of ACC patients had BRCA1 or BRCA2, and 25.0% had at least one of these five genes, both of which were markedly more frequent in comparison with PDAC patients. Detailed data on the other 13 HRR genes including BAP1, BARD1, BRIP1, CHEK1/2, RAD51B/C/D, FANCA/C/L, MRE, and NBN, are shown in Supplemental Table 1 (with yellow markers). Considering all these 18 HRR genes, 9.4% of PDAC patients, 25% of ACC patients, 9.3% of ASC patients, and 4.0% of ACP patients had at least one of the HRR genes, showing markedly higher rates in ACC compared with PDAC (p = 0.01).

Data regarding mismatch repair (MMR) gene alterations are presented in Fig. 3e. In PDAC patients, the frequencies of MLH1, MSH2, MSH6, and PMS2 were 0.3, 0.2, 1.6, and 0.04%, respectively. MSH6 was found in 4.6% of ACC patients, 1.9% of ASC patients, and 4.0% of ACP patients. MLH1 was detected in 3.7% of patients with ASC. There were no cases of patients with ACC, ASC, or ACP with MSH2 or PMS2.

Other notable gene mutations besides those mentioned above included BRAF and CTNNB1. BRAF alterations was detected in 15.9% of ACC patients, being significantly higher than that of PDAC (1.7%, p < 0.001). In particular, BRAF fusions were detected in 13.6% of ACC, 0.2% of PDAC, and none of ASC or ACP, indicating that this fusion was present almost exclusively in ACC patients. CTNNB1 was also a frequently detectable gene in ACC (13.6%), compared with PDAC (0.8%), ASC (0%), and ACP (4.0%). PTEN was a variant identified in 7.4% of ASC patients, being significantly more common than in PDAC patients (0.9%, p < 0.05). Furthermore, KMT2D was found in 12.0% of ACP patients, showing a trend toward a higher prevalence than in PDAC (1.8%) (Supplemental Table 1).

Figure 4 shows data on the MSI and TMB status among the four tumor types. These are biomarkers predicting the efficacy of immunotherapy [26, 27]. The proportion of MSI-H was 0.3% in PDAC, compared with 2.6% in ACC, 2.3% in ASC, and 0% in ACP, with no significant differences among the four groups (Fig. 4a). TMB-high (> 10 mutations/Mb) tumors were observed in 1.8% of PDAC, 7.9% of ACC, 2.3% of ASC, and 0% of ACP, with a slightly higher trend in ACC compared with PDAC (p = 0.18) (Fig. 4b). Additionally, the median TMB was 2.51 mutations/Mb for PDAC, 3.99 for ACC, 3.93 for ASC, and 1.78 for ACP, showing no significant difference among the four groups (Fig. 4c).

Fig. 4figure 4

MSI and TMB status among rare subtypes of pancreatic cancer and pancreatic ductal adenocarcinoma (PDAC). The distribution of a MSI status, b TMB status and c TMB load among the four tumor types are shown

Treatment response

Table 2 summarizes ORR and DCR of first-line FFX and GnP therapy for each tumor type. Among 1977 PDAC patients, ORRs of FFX and GnP were comparable, at 24.1 and 25.2%, respectively. DCR was 60.3% for FFX and 66.8% for GnP, being significantly higher for the latter (p = 0.006). By contrast, in ACC patients, FFX tended to lead to better ORR compared with GnP, approaching significance (61.5 vs. 23.5%, respectively, p = 0.06). In addition, DCR for FFX was elevated at 76.9%. ASC and ACP showed no noticeable differences in ORR and DCR between these two regimens.

Table 2 Overall response rate (ORR) and disease control rate (DCR) by the subtypes of pancreatic cancerTime to treatment failure

TTF of first-line FFX and GnP in each tumor group is shown in Fig. 5. In PDAC patients, the median TTF for FFX was 28.1 weeks (95%CI 25.0–30.9 weeks) vs. 28.0 weeks (95%CI 26.7–30.7 weeks) for GnP, resulting in very similar Kaplan–Meier curves (Fig. 5a). On the other hand, for patients with ACC, TTF was longer for FFX (median TTF, 42.3 weeks; 95%CI 15.7–189.9 weeks), whereas the median TTF for GnP was 21.0 weeks (95%CI 16.0–29.3 weeks, p = 0.004) (Fig. 5b). ASC patients showed a shorter median TTF on receiving both regimens without any differences; 16.0 weeks (95%CI 7.0–36.0 weeks) for FFX, and 18.1 weeks (95%CI 13.0–24.9 weeks) for GnP. In ACP patients, the median TTF for FFX was not reached (95%CI 40.4 weeks to not reached) and 22.1 weeks (95%CI 8.0–40.9 weeks) for GnP (Fig. 5c, d).

Fig. 5figure 5

Kaplan–Meier curves of time to treatment failure (TTF) according to first-line FOLFIRINOX (FFX) versus gemcitabine plus nab-paclitaxel (GnP) therapy. Data are shown for a pancreatic ductal adenocarcinoma (PDAC), b acinar cell carcinoma (ACC), c adenosquamous carcinoma (ASC), and d anaplastic carcinoma of pancreas (ACP) patients

Patients with HRR genes have been reported to show a more favorable response to platinum-containing regimens [28, 29]. Thus, we examined TTF of FFX and GnP among ACC patients according to the presence or absence of HRR genes (regarding the five representative genes mentioned in Fig. 3d). Among ACC patients with HRR genes, FFX showed significantly longer TTF compared with GnP (126.3 vs. 25.7 weeks, respectively; p = 0.04, Supplemental Fig. 1a). However, there was also a trend toward longer TTF of FFX compared with GnP in patients without HRR genes, being close to significance (42.3 vs. 20.7 weeks, respectively; p = 0.05, Supplemental Fig. 1b). Furthermore, we evaluated the treatment response by prevalence of BRAF fusion or CTNNB1 mutation, characteristic variants of ACC. Patients with BRAF fusion genes showed a significantly shorter duration of successful chemotherapy compared with those without them (15.7 vs. 30.1 weeks, respectively; p = 0.04, Supplemental Fig. 2a). There was no notable difference in TTF of chemotherapy depending on the presence or absence of CTNNB1 mutation (36.9 vs. 28.1 weeks, respectively; p = 0.74, Supplemental Fig. 2b).

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