Abstract C104: Dual primary pancreas cancers – Related or independent lesions?

Abstract

Abstract Background: Not infrequently, an apparent second pancreas ductal adenocarcinoma (PDAC) is identified either synchronously or metachronously. To date, it remains unclear whether these individual PDACs represent intrapancreatic metastases or a new primary PDAC. Here, we sought to understand the clinicogenomic features of this patient population to provide insights on the underlying biology and management implications. Methods: Memorial Sloan Kettering Cancer Center (MSK) institutional databases were searched for patients with two PDAC diagnoses and at least one pancreatic resection or patients who had undergone completion/total pancreatectomy and then manually curated. Detailed demographic and clinical information were abstracted from the medical record. Metachronous patients excluded if previous surgical margin positive for invasive or pre-invasive carcinoma. All patients were either consented to MSK IMPACT for somatic and germline sequencing (N=16), were approved for de-identified genomic analyses by IRB (N=3), or were excluded from genomic analysis (N=2). KRAS wild-type (WT) tumors were interrogated for targetable fusions with Archer FusionPlex solid tumor panel. Results: N=21 patients (pts) identified, N=6 synchronous, N=15 metachronous. Mean age at diagnosis of first PDAC (PDAC1): 67.1y (51.2–79.1y). PDAC risk factors: 52% (10/19) smoking history, 15% (2/13) with first degree relative with PDAC, 85% (11/13) with first degree relative with any malignancy, and 40% (8/20) with history of premalignant pancreas lesion. N=2 pts with pathogenic germline mutation in ATM. By morphology, 80% (4/5) of synchronous and 65% (11/17) of asynchronous lesions indistinguishable. Two lesions, both metachronous, demonstrated divergent histology while remaining cases demonstrated focal differences. Genomically, 40% (10/25) samples with mKRAS G12V, G12R (16%), G12D (12%), Q61H (8%), G12C (4%); 20% KRAS WT. Of available paired tumor samples, 71% (5/7) with identical KRAS alleles and additional driver mutations. N= 1 pt with different KRAS alleles also had divergent TP53 alleles and CDKN2A/B loss occur in metachronous lesions 14 m apart. N=1 pt with KRAS WT tumor had an actionable fusion involving FGFR2. For metachronous lesions, median interval PDAC1 to PDAC2: 5.1 y (1.1 – 15.2 y). At median follow-up of 7.2 y (0.2 – 15.4 y) from PDAC1, 90% (19/21) have undergone completion/total pancreatectomy and N=16 (76%) alive with 5-year survival rate of 93% (14/15). Conclusions: The clinical, pathologic, and genomic data strongly suggest that two PDAC, independent of disease interval, most often represent the same phylogenetic entity. KRAS allele variant adjudication was the single most important discriminator and was in concordance with other driver oncogenes. Pathogenic germline variants were rare and limited to gATM; notably no gBRCA/PALB2. Acknowledging the highly selected nature of this cohort, solitary intrapancreatic metastases demonstrate a more favorable biology and these patients may benefit from personalized management approaches beyond traditional paradigms. Citation Format: Joshua D. Schoenfeld, Hulya Sahan-Ozkan, Nadeem Bilani, Michael I. D'Angelica, William R. Jarnagin, Jeffrey Drebin, Diane Reidy-Lagunes, Alice C. Wei, Sree B. Chalasani, Anna M. Varghese, Fiyinfolu Balogun, Wungki Park, Kenneth H. Yu, Olca Basturk, Eileen M. O'Reilly. Dual primary pancreas cancers – Related or independent lesions? [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Pancreatic Cancer; 2023 Sep 27-30; Boston, Massachusetts. Philadelphia (PA): AACR; Cancer Res 2024;84(2 Suppl):Abstract nr C104.