Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial

Pishvaian, Michael J.; Blais, Edik M.; Brody, Jonathan R.; Lyons, Emily; DeArbeloa, Patricia; Hendifar, Andrew Eugene; Mikhail, Sam; Chung, Vincent; Sahai, Vaibhav; Sohal, Davendra; Bellakbira, Sara; Thach, Dzung C.; Rahib, Lola; Madhavan, Subha; Matrisian, Lynn M.; Petricoin, Emanuel F.

doi:10.1016/s1470-2045(20)30074-7

Cited by 393 publications

(341 citation statements)

References 26 publications

Supporting

Mentioning

329

Contrasting

Unclassified

Order By: Relevance

“…Furthermore, results of the TAPUR trial (NCT02693535), reported at this year's ASCO meeting, show that olaparib monotherapy had significant antitumor activity in heavily pretreated pancreatic cancer patients with germline (disease control in 5/12 patients) or somatic (disease control in 3/16 patients) BRCA1/2-inactivating mutations [28]. These findings are in agreement with results from a retrospective analysis of the Know Your Tumor (KYT) registry trial [29], which found that patients with pancreatic cancer whose tumors harbor targetable molecular alterations, like BRCA1/2 mutations, and who received molecularly matched therapy had a significantly longer median OS than similar patients who did not receive molecularly matched therapy.…”

Section: Targeted Therapysupporting

confidence: 74%

“…As seen in the case of BRCA mutations which convey susceptibility towards PARP inhibitors, genetic screening prior to treatment allows for the identification of distinct patient populations and more precise therapy. Pishvaian et al [29] showed that the median OS of patients with advanced PDAC harboring targetable genetic alterations and receiving matched therapy is 1 year longer than of those with actionable alterations receiving unmatched therapy, or those without targetable alterations. No other therapeutic modality had an impact of this magnitude, showing that molecular profiling together with matched targeted therapy is clearly the most promising clinical directive.…”

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Precision Therapy of Pancreatic Cancer: From Bench to Bedside

Ciecielski¹,

Berninger²,

Algül³

2020

Visc Med

View full text Add to dashboard Cite

Background: Pancreatic ductal adenocarcinoma (PDAC), with a mortality rate of 94% and a 5-year-survival rate of only 8%, is one of the deadliest cancer entities worldwide, and early diagnostic methods as well as effective therapies are urgently needed. Summary: This review summarizes current clinical procedure and recent developments of oncological therapy in the palliative setting of metastatic PDAC. It further gives examples of successful, as well as failed, targeted therapy approaches and finally discusses promising ongoing research into the decade-old question of the “undruggability” of KRAS. Key Messages: Bench-driven concepts change the clinical landscape from “one size fits all” towards precision medicine. With growing insight into the molecular mechanisms of pancreatic cancer the era of targeted therapy in PDAC is gaining a new momentum.

show abstract

Section: Targeted Therapysupporting

confidence: 74%

Section: Resultsmentioning

confidence: 99%

Precision Therapy of Pancreatic Cancer: From Bench to Bedside

Ciecielski¹,

Berninger²,

Algül³

2020

Visc Med

View full text Add to dashboard Cite

show abstract

“…Differently from conventional PDAC, if appropriately selected based on their individual genomic and molecular features, these special PDAC subtypes can be treated with specific therapeutic strategies (see Table 1 for a list of selected ongoing trials with agents targeting molecular aberrations that are enriched in KRAS wild type PDAC), representing an important step towards the establishment of precision oncology for patients with pancreatic cancer [ 71 ]. As exemplified by the recently reported “Know Your Tumor” initiative experience in PDAC [ 72 ], only a minority of patients might currently benefit from extended molecular profiling (46 out of 1223–4% - profiled patients received matched therapy in their experience). That said, the evidences reviewed and discussed on these topics may call for a complementation of PDAC histological diagnosis with routine determination of KRAS mutational status, followed by comprehensive molecular profiling of KRAS wild-type cases.…”

Section: Clinical Considerations and Conclusionmentioning

confidence: 99%

KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities

Luchini

Paolino

Mattiolo

et al. 2020

J Exp Clin Cancer Res

View full text Add to dashboard Cite

Pancreatic ductal adenocarcinoma (PDAC) is a deadly disease, whose main molecular trait is the MAPK pathway activation due to KRAS mutation, which is present in 90% of cases. The genetic landscape of KRAS wild type PDAC can be divided into three categories. The first is represented by tumors with an activated MAPK pathway due to BRAF mutation that occur in up to 4% of cases. The second includes tumors with microsatellite instability (MSI) due to defective DNA mismatch repair (dMMR), which occurs in about 2% of cases, also featuring a high tumor mutational burden. The third category is represented by tumors with kinase fusion genes, which marks about 4% of cases. While therapeutic molecular targeting of KRAS is an unresolved challenge, KRAS-wild type PDACs have potential options for tailored treatments, including BRAF antagonists and MAPK inhibitors for the first group, immunotherapy with anti-PD-1/PD-L1 agents for the MSI/dMMR group, and kinase inhibitors for the third group. This calls for a complementation of the histological diagnosis of PDAC with a routine determination of KRAS followed by a comprehensive molecular profiling of KRAS-negative cases.

show abstract

“…Pancreatic cancer continues to have a poor 5-year survival rate despite its rising incidence [20,21]. By 2030, it is estimated to become the second leading cause of cancer related deaths [5].…”

Section: Discussionmentioning

confidence: 99%

Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

Hua

Liu

et al. 2020

Preprint

View full text Add to dashboard Cite

Background: Pancreatic ductal adenocarcinoma (PDAC) is a growing cause of cancer-related mortality worldwide. Kallikrein-related peptidase 8 (KLK8) has potential clinical values in many cancers. However, the clinicopathological significances of KLK8 in PDAC remain unknown. Methods: The relationship of KLK8 to clinicopathological features of PDAC was investigated based on public databases. KLK8 expression was examined in human PDAC tissues. Cell proliferation and apoptosis were evaluated in KLK8-overexpressed human pancreatic cancer cell lines Mia-paca-2 and Panc-1. The related signaling pathways of KLK8 involved in pancreatic cancer progression were analyzed by gene set enrichment analysis (GSEA) and further verified in in vitro studies. Results: KLK8 was up-regulated in tumor tissues in the TCGA-PAAD cohort, and was an independent prognostic factor for both overall survival and disease-free survival of PDAC. KLK8 mRNA and protein expressions were increased in PDAC tissues compared with para-cancerous pancreas. KLK8 overexpression exerted pro-proliferation and anti-apoptotic functions in Mia-paca-2 and Panc-1 cells. GSEA analysis showed that KLK8 was positively associated with PI3K-Akt-mTOR and Notch pathways. KLK8-induced pro-proliferation and anti-apoptotic effects in Mia-paca-2 and Panc-1 cells were attenuated by inhibitors for PI3K, Akt, and mTOR, but not by inhibitor for Notch.Conclusion: KLK8 overexpression exerts pro-proliferation and anti-apoptotic functions in pancreatic cancer cells via PI3K/Akt/mTOR pathway. Upregulated KLK8 in PDAC predicts poor prognosis and may be a potential therapeutic target for PDAC.

show abstract

Overall survival in patients with pancreatic cancer receiving matched therapies following molecular profiling: a retrospective analysis of the Know Your Tumor registry trial

Cited by 393 publications

References 26 publications

Precision Therapy of Pancreatic Cancer: From Bench to Bedside

Precision Therapy of Pancreatic Cancer: From Bench to Bedside

KRAS wild-type pancreatic ductal adenocarcinoma: molecular pathology and therapeutic opportunities

Upregulation of KLK8 Predicts Poor Prognosis in Pancreatic Cancer

Contact Info

Product

Resources

About