PALB2 Mutated Pancreatic Adenocarcinoma | IJCCD

Lee, Jonathan; O'Connor, Catherine; Harrold, Emily; Richards, Allison; Velez-Cortes, Florencia; Moss, Drew; Schoenfeld, Joshua; Singhal, Anupriya; Thummalapalli, Rohit; Schwartz, Carly; Alagesan, Brinda; Larsen, Mary; Balogun, Fiyinfolu; Varghese, Anna; Yu, Kenneth; Kelsen, David; Park, Wungki; Mandelker, Diana; Stadler, Zsofia; O'Reilly, Eileen

doi:10.53876/001a.129565

Conference Abstracts - 5th Binaytara Precision Oncology Summit: Redefining Cancer Treatment with Molecular Targeted Strategies

Vol. 5, Issue Supplement 1, 2025 · S1-2

Clinico-genomic Characterization of PALB2-Mutated Pancreatic Adenocarcinoma

Jonathan Lee, MD MSc,Catherine O'Connor, BS,Emily Harrold, MBBCh,Allison Richards, PhD,Florencia Velez-Cortes, PhD,Drew Moss, MD,Joshua Schoenfeld, MD PhD,Anupriya Singhal, MD PhD,Rohit Thummalapalli, MD,Carly Schwartz, BS,Brinda Alagesan, MD PhD,Mary Larsen, MSN RN,Fiyinfolu Balogun, MD PhD,Anna Varghese, MD,Kenneth Yu, MD,David Kelsen, MD,Wungki Park, MD MS,Diana Mandelker, MD PhD,Zsofia Stadler, MD,Eileen O'Reilly, MD FASCO

pancreatic cancerhomologous recombinationtargeted therapy

Submission received: 2025-07-13 / Accepted: 2025-08-27 / Published: 2025-09-26

CCBY-SA-4.0

Publication: IJCCDhttps://doi.org/10.53876/001a.129565

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Background

Pancreatic adenocarcinoma (PDAC) with germline (g) or somatic (s) mutations in BRCA1/2 and PALB2 exhibit unique molecular characteristics and predict response to platinum-based chemotherapy and PARP inhibition. However, distinct features of PALB2 and PDAC are not well described. Herein, we characterize distinct clinico-genomic features of patients (pts) with g/s PALB2 and PDAC.

Methods

Institutional databases and cBioPortal were queried to identify pts with g/sPALB2 and PDAC. Pts with PALB2 variants of unknown significance (VUS) were excluded (annotation from OncoKb, ClinVar). Demographic data and clinical outcomes were abstracted from the medical record. Detailed mutational analysis obtained from cBioPortal. Zygosity determined with FACETS. Progression-free survival (PFS) and overall survival (OS) were estimated with the Kaplan-Meier Method.

Results

N=29 pts with pathogenic/oncogenic g/sPALB2 and PDAC identified between 2011-2024. N=25 (86%) gPALB2 (+/- sPALB2)and N=4 (14%) sPALB2 (no gPALB2); N=13 sPALB2 excluded as VUS. Median age (range): 57 years (38-78) gPALB2 and 63 years (43-73) sPALB2. N=23 (79%) white; N=16 (55%) female. Stage IV at diagnosis: N=11 (44%) gPALB2; N=2 (50%) sPALB2 cohort.

In the gPALB2 cohort (N= 25), 4 (16%) had a personal history of cancer (N=2 thyroid, N=1 uterine, N=1 CLL) and N=17 (68%) had a family history of cancer (N=7 breast/prostate/ovarian, N=1 pancreas).

KRAS and TP53 variants co-occurred in 84% and 36% of gPALB2 and 50% and 50% of sPALB2 cases, respectively. N=9 (56%) of patients with a gPALB2 mutation showed biallelic loss of PALB2 (N=6 by LOH, N=3 somatic LOH). None of the four patients in the sPALB2 cohort (negative gPALB2) had biallelic loss. Median TMB (mt/Mb): 4.10 (0.80-9.10) gPALB2; 3.85 (2.00-5.80) sPALB2.

For stage IV gPALB2 (N= 11), median PFS 4.2 months (95% CI 2.4, NR) and median OS 12 months (95% CI 5.5, NR). N=10 (90%) received platinum therapy, with N=6 in the first-line setting. Durable disease control on PARPi was observed for patients with gPALB2 and sPALB2, including N=1 sPALB2 with 7 months on 4th-line olaparib and N=1 gPALB2 with 6 months on 6th-line olaparib.

Conclusion

gPALB2 and sPALB2 mutations are seen in a small % of PDAC. gPALB2 PDAC presents earlier and is linked to a family history of cancer. gPALB2 compared to sPALB2 had higher biallelic loss; oncogenic sPALB2 are uncommon. Identification of g/sPALB2 has implication for therapeutics and screening. Loss of heterozygosity, TMB, telomeric allelic imbalance, large-scale state transitions, and implications for treatment will be presented.