Arterial Administration of DNA Crosslinking Agents with Restraint of Homologous Recombination Repair by Intravenous Low-Dose Gemcitabine Is Effective for Locally Advanced Pancreatic Cancer

(1) Background: Pretreatment by Rad51-inhibitory substances such as gemcitabine followed by arterial chemotherapy using antineoplastic agents causing DNA crosslink might be more beneficial for patients with locally advanced pancreatic cancers than conventional treatments. The efficacy of arterial administration of DNA crosslinking agents with pretreatment of intravenous low-dose gemcitabine for patients with unresectable locally advanced or metastatic pancreatic cancer (LAPC or MPC) is evaluated. (2) Methods: A single-arm, single-center, institutional review board-approved prospective study was conducted between 2005 and 2015. Forty-five patients (23 LAPC, 22 MPC) were included. Patients received a weekly low dose of gemcitabine intravenously for three weeks followed by arterial administration of mitomycin C and epirubicin hydrochloride at tumor-supplying arteries on the fifth or sixth week. This treatment course was repeated at 1.5-to-2-month intervals. Overall survival (OS), local progression-free survival (LPFS), and therapeutic response were evaluated. LAPC or MPC were divided according to treatment compliance, excellent or poor (1 or 2), to subgroups L1, L2, M1, and M2. (3) Results: OS of LAPC and MPC were 23 months and 13 months, respectively. The OS of LAPC with excellent treatment compliance (subgroup L1, 10 patients) was 33 months with 31 months of LPFS, and four patients (40%) had a complete response (CR). The OS of the L1 subgroup was significantly longer than those of other subgroups L2, M1, and M2, which were 17 months, 17 months, and 8 months, respectively. As Grade 3 adverse effects, severe bone marrow suppression, interstitial pneumonitis, and hemolytic uremic syndrome were observed in six (13.0%), three (6.5%), and three (6.5%) patients, respectively. (4) Conclusions: Arterial DNA crosslinking with the systemic restraint of homologous recombination repair can be a new treatment option for LAPC.

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PO-1047: GemOx with low-dose RT and SBRT for locally advanced pancreatic cancer: a prospective trial

Radiotherapy and Oncology ◽

10.1016/s0167-8140(21)01064-1 ◽

2020 ◽

Vol 152 ◽

pp. S557

Author(s):

B. Meduri ◽

G. Aluisio ◽

E. D'Angelo ◽

M. Vernaleone ◽

C. Tata ◽

...

Keyword(s):

Pancreatic Cancer ◽

Low Dose ◽

Locally Advanced ◽

Prospective Trial ◽

Advanced Pancreatic Cancer ◽

Locally Advanced Pancreatic Cancer

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A Phase II Study of Fixed-Dose Rate Gemcitabine Plus Low-Dose Cisplatin Followed by Consolidative Chemoradiation for Locally Advanced Pancreatic Cancer

International Journal of Radiation Oncology*Biology*Physics ◽

10.1016/j.ijrobp.2007.01.005 ◽

2007 ◽

Vol 68 (3) ◽

pp. 809-816 ◽

Cited By ~ 86

Author(s):

Andrew H. Ko ◽

Jeanne M. Quivey ◽

Alan P. Venook ◽

Emily K. Bergsland ◽

Elizabeth Dito ◽

...

Keyword(s):

Pancreatic Cancer ◽

Dose Rate ◽

Phase Ii ◽

Low Dose ◽

Phase Ii Study ◽

Locally Advanced ◽

Advanced Pancreatic Cancer ◽

Locally Advanced Pancreatic Cancer ◽

Fixed Dose ◽

Fixed Dose Rate

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Defects in homologous recombination repair genes are associated with good prognosis and clinical sensitivity to DNA-damaging agents in pancreatic cancer: A case report

Molecular and Clinical Oncology ◽

10.3892/mco.2018.1588 ◽

2018 ◽

Author(s):

Amir Sonnenblick ◽

Aviad Zick ◽

Myriam Maoz ◽

Sherri Cohen ◽

Luna Kadouri ◽

...

Keyword(s):

Pancreatic Cancer ◽

Case Report ◽

Homologous Recombination ◽

Good Prognosis ◽

Homologous Recombination Repair ◽

Clinical Sensitivity ◽

Dna Damaging Agents ◽

Recombination Repair ◽

Repair Genes

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Homologous recombination repair gene mutations in Chinese pancreatic ductal adenocarcinoma patients.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e16234 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e16234-e16234

Author(s):

Nengwen Ke ◽

Maolin Yan ◽

Xu Che ◽

Yu Cheng ◽

Zheng Wang ◽

...

Keyword(s):

Pancreatic Cancer ◽

Homologous Recombination ◽

Pancreatic Ductal Adenocarcinoma ◽

Checkpoint Inhibitors ◽

Gene Mutations ◽

Ductal Adenocarcinoma ◽

Homologous Recombination Repair ◽

Common Mutation ◽

Wild Type ◽

Recombination Repair

e16234 Background: Pancreatic cancer (PC) is a highly malignant tumor with poor prognosis. Among them, pancreatic ductal adenocarcinoma (PDAC) accounts for 80-90% of pancreatic cancer. While, the treatment of PDAC has always been a clinical challenge. PDAC with mutations in homologous recombination repair (HRR) genes such as BRCA are particularly sensitive to platinum agents. The POLO study has shown that Olaparib was efficient and well-tolerated as maintenance therapy in patients with germline BRCA1/2 mutation and a metastatic PDAC controlled after a platinum-based induction chemotherapy. However, investigation of prevalence of HRR gene mutations in Chinese PDAC patients need to be well defined. Methods: Formalin-fixed, paraffin-embedded (FFPE) tumor tissues and matching blood samples from PDAC patients were collected and sequenced using next-generation sequencing (NGS) targeting 450 cancer genes. Genomic alterations and tumor mutational burden (TMB) values were assessed. The association of HRR gene mutations with TMB was assessed. The testing was carried out by OrigiMed (Shanghai, China) witch a College of American Pathologists accredited and Clinical Laboratory Improvement Amendments certified laboratory. Using targeted capture genomic sequencing, we assessed 98 PDAC patients for germline and somatic loss-of-function mutations in 14 genes, including BRCA1, BRCA2, and 12 other genes in the HR pathway. Results: In total, 98 PDAC patients were recruited including 48 females and 50 males with a median age of 58 (range 35-84). The most frequently mutated genes were KRAS (94%), TP53 (74%), CDKN2A (36%), SMAD4 (27%), GATA6 (9%) and ATM (5%). Mutation rates varied in pancreatic cancer signaling pathway: WNT (35.71%), PI3K (11.22%), HRR (11.22%), NOTCH (3.06%), FGF (2.04%). 2.04% (2/98) patients had high TMB (defined as ≥10 muts/Mb) with a median of 2.2 muts/Mb (0-47 mus/Mb). 34.69% (34/98) of the patients had one or more actionable genetic mutations. We identified that 11.2% (11/98) patients had at least one mutation in HRR genes. The most frequently mutated HRR genes were ATM (50%), BRCA1 (16.7%), BRCA2 (25%) and PALB2 (8.3%). The most common mutation type in HRR-related gene was truncation (75%, 9/12). HRR-related germline mutations in BRCA (71.43%, 5/7), ATM (28.57%, 2/7) were detected in seven patients, six of them with cancer related family history. We confirmed that patients with HRR mutations were younger than wild type HRR (52.6 years vs. 59.3 years, p < 0. 05). We demonstrated that patients with HRR mutations had a significantly higher TMB than patients with wild type HRR (median TMB: 3.4 vs. 1.8 muts/Mb, p < 0. 05). Conclusions: HRR gene alterations occurred in 11.2% of Chinese PDAC patients HRR pathway alterations are relatively frequent in PDAC patients and consideration for biomarker-enriched clinical trials with PARP, immune checkpoint inhibitors, and novel combinations are warranted.

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