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. 2024 Nov 1;30(21):4932-4942.
doi: 10.1158/1078-0432.CCR-24-1164.

Clinical and Genomic Features of Classical and Basal Transcriptional Subtypes in Pancreatic Cancer

Harshabad Singh  1   2   3 , Joanne Xiu  4 , Kevin S Kapner  1 , Chen Yuan  1   3 , Raja R Narayan  5 , Matthew Oberley  4 , Alex Farrell  4 , Rishi Surana  1   2   3 , Brandon M Huffman  1   2   3 , Kimberly Perez  1   2   3 , James M Cleary  1   2   3 , Alexander C Jordan  1   2   3   6 , Andressa Dias Costa  1   3 , Hannah L Williams  1   3 , Srivatsan Raghavan  1   2   3   6 , Benjamin Weinberg  7 , Michael J Pishvaian  8 , Rachna T Shroff  9 , Sanjay Goel  10 , Stephanie K Dougan  11   12 , Jonathan A Nowak  3   13 , David Spetzler  4 , George Sledge  4 , Brian M Wolpin  1   2   3 , Andrew J Aguirre  1   2   3   6
Affiliations

Clinical and Genomic Features of Classical and Basal Transcriptional Subtypes in Pancreatic Cancer

Harshabad Singh et al. Clin Cancer Res. .

Abstract

Purpose: Transcriptional profiling of pancreatic cancers has defined two main transcriptional subtypes: classical and basal. Initial data suggest shorter survival for patients with basal tumors and differing treatment sensitivity to FOLFIRINOX and gemcitabine plus nab-paclitaxel by transcriptional subtype.

Experimental design: We examined 8,743 patients with RNA sequencing from pancreatic cancers performed at Caris Life Sciences. Classical and basal subtypes were identified using purity independent subtyping algorithm on RNA sequencing, and two cohorts were analyzed: (i) the biomarker cohort included patients with complete molecular profiling data (n = 7,250) and (ii) the outcome cohort included patients with metastatic disease with available survival outcomes (n = 5,335). A total of 3,842 patients were shared between the two cohorts. Kaplan-Meier curves and Cox proportional hazards regression were used to assess patient survival.

Results: In the biomarker cohort, 3,063 tumors (42.2%) were strongly classical (SC) and 2,015 tumors (27.8%) were strongly basal (SB). SC and SB tumors showed strong associations with histologic phenotypes and biopsy sites. SB tumors had higher rates of KRAS, TP53, and ARID1A mutations, lower rates of SMAD4 mutation, and transcriptional evidence of epithelial-mesenchymal transition. Sixty of 77 cases (78%) maintained their transcriptional subtype between temporally and/or spatially disparate lesions. In the outcome cohort, the SB subtype was associated with shorter overall survival time, regardless of whether they received FOLFIRINOX or gemcitabine plus nab-paclitaxel as first-line chemotherapy. The mutant KRAS allele type was prognostic of outcomes; however, this impact was restricted to SC tumors, whereas all mutant KRAS alleles had similarly poor outcomes in SB tumors.

Conclusions: The SB subtype is a strong independent predictor of worse outcomes, regardless of the up-front chemotherapy regimen used. Clinical trials should further investigate pancreatic cancer transcriptional subtypes as a prognostic and predictive biomarker.

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Figures

Figure 1.
Figure 1.. Clinical features of strong classical and strong basal pancreatic cancer
(A) Cohort identification. Biomarker cohort has a total of 7,250 patients, and outcomes cohort includes 5,335 patients. A total of 3,842 patients are shared between the biomarker and outcomes cohort. (B) Differences in distribution of strong classical and strong basal transcriptional subtypes between histologic variants of pancreatic cancer. (C-D) Differences in distribution of strong classical and strong basal transcriptional subtypes between sites of disease in pancreatic cancer. Percentages do not add up to 100% since intermediate phenotypes (lean and likely basal/classical) are not depicted.
Figure 2.
Figure 2.. Genomic features of strong classical and strong basal pancreatic cancer
(A) Several recurrent oncogenic alterations in pancreatic cancer are significantly different between strong classical and strong basal tumors. (B) Differences in distribution of hotpot mutations in KRAS between strong classical and strong basal pancreatic cancer. (C) Rates of mutations in genes in the DNA damage repair pathway are not significantly different across classical and basal tumors.
Figure 3.
Figure 3.. Temporal and spatial stability of classical and basal transcriptional subtypes
Classical and basal subtypes were determined in 77 cases who had RNA-sequencing performed on two distinct lesions. In 40 cases, pancreatic primary, and a metastatic lesion was profiled (A). In 29 cases two different metastatic lesions were profiled (B) and in 8 cases two distinct biopsies from the pancreatic primary tumor were profiled (C). Cases are segregated by whether original transcriptional subtype is preserved or changed. Transcriptional subtype was considered to be maintained if tumors were in the same general category as the original biopsy, i.e. classical or basal irrespective of it being classified as strong, likely, or lean by PurIST.
Figure 4.
Figure 4.. Clinical impact of strong classical and strong basal transcriptional subtypes on outcomes and response to therapy
(A) Real-world overall survival of patients with metastatic strong classical (n = 2,118) and strong basal (n = 1,579) pancreatic cancer shows significantly worse survival in those with strong basal tumors (B-C) Real-world overall survival for patients with metastatic strong classical and strong basal tumors based on receipt of 1st line gemcitabine and nab-paclitaxel (B) or FOLFIRINOX (C) for metastatic disease. Irrespective of 1st line chemotherapy regimen utilized strong basal tumors have worse survival compared to strong classical tumors. (D) Real-world overall survival for the three most frequent hotspot mutations in KRAS: G12D, G12V, and G12R is displayed based on transcriptional subtype. KRAS alleles have no prognostic significance in strong basal tumors who have uniformly poor survival. In strong classical tumors KRAS G12D has worse survival compared to KRAS G12R. Strong classical tumors with KRAS G12V show a non-significant trend towards worse survival compared to KRAS G12R. SB: Strong Basal, SC: Strong Classical.
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