scholarly journals EUS-FNA Biopsies to Guide Precision Medicine in Pancreatic Cancer: Results of a Pilot Study to Identify KRAS Wild-Type Tumours for Targeted Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Joanne Lundy ◽  
Marion Harris ◽  
John Zalcberg ◽  
Allan Zimet ◽  
David Goldstein ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Targeted Therapy ◽  
Pilot Study ◽  
Precision Medicine ◽  
Molecular Analysis ◽  
Single Agent ◽  
Locally Advanced ◽  
Disease Stage ◽  
Wild Type ◽  
Egfr Inhibition

BackgroundPancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer death and lacks effective treatment options. Diagnostic endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA) biopsies represent an appealing source of material for molecular analysis to inform targeted therapy, as they are often the only available tissue for patients presenting with PDAC irrespective of disease stage. However, EUS-FNA biopsies are typically not used to screen for precision medicine studies due to concerns about low tissue yield and quality. Epidermal growth factor receptor (EGFR) inhibition has shown promise in clinical trials of unselected patients with advanced pancreatic cancer, but has not been prospectively tested in KRAS wild-type patients. Here, we examine the clinical utility of EUS-FNA biopsies for molecular screening of KRAS wild-type PDAC patients for targeted anti-EGFR therapy to assess the feasibility of this approach.Patients and MethodsFresh frozen EUS-FNA or surgical biopsies from PDAC patient tumours were used to screen for KRAS mutations. Eligible patients with recurrent, locally advanced, or metastatic KRAS wild-type status who had received at least one prior line of chemotherapy were enrolled in a pilot study (ACTRN12617000540314) and treated with panitumumab at 6mg/kg intravenously every 2 weeks until progression or unacceptable toxicity. The primary endpoint was 4-month progression-free survival (PFS).Results275 patient biopsies were screened for KRAS mutations, which were detected in 88.3% of patient samples. 8 eligible KRAS wild-type patients were enrolled onto the interventional study between November 2017 and December 2020 and treated with panitumumab. 4-month PFS was 14.3% with no objective tumour responses observed. The only grade 3/4 treatment related toxicity observed was hypomagnesaemia.ConclusionsThis study demonstrates proof-of-principle feasibility to molecularly screen patients with pancreatic cancer for targeted therapies, and confirms diagnostic EUS-FNA biopsies as a reliable source of tumour material for molecular analysis. Single agent panitumumab was safe and tolerable but led to no objective tumour responses in this population.

Sequential neoadjuvant chemotherpy with nab-paclitaxel plus gemcitabine and FOLFIRINOX in locally advanced pancreatic cancer (LAPC): A PILOT study.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e15193-e15193 ◽  
Author(s):  
Volker Kunzmann ◽  
Ingo Hartlapp ◽  
Michael Scheurlen ◽  
Hermann Einsele ◽  
Justus Mueller ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Pilot Study ◽  
Neoadjuvant Chemotherapy ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Sensory Neuropathy ◽  
Disease Stage ◽  
Ductal Adenocarcinoma ◽  
Hematological Toxicity ◽  
Highly Active

e15193 Background: Nab-Paclitaxel (nab-P) + Gemcitabin (G) and FOLFIRINOX have both shown promising activity in metastatic pancreatic cancer (mPC). Our group has developed sequential usage of both regimens in order to exploit the stromal depletion effects of nab-P and increase global efficacy of chemotherapy in the neoadjuvant setting of LAPC. Methods: This pilot study evaluated patients with cytological/histological confirmed diagnosis of locally advanced pancreatic ductal adenocarcinoma without evidence of metastatic disease (stage III). nab-P+G was administered for 2 cycles (nab-P 125 mg/m2, G 1000 mg/ 2; on days 1, 8, 15; every 28 days) followed by 2 cycles of FOLFIRINOX (as reported by Conroy et al., NEJM 2011). Results: We report the preliminary analysis of 8 pts treated in our institution. Patients characteristics were M/F: 5/3; median age 63 (46-79); PS 0/1: 6/2. 3 pts (37%) had a biliary stent before starting treatment. All pts received the planned 4 cycles of neoadjuvant chemotherapy without dose reductions. There were no treatment-related deaths and none of pts stopped treatment due to toxicity. Grade 3-4 toxicities were neutropenia (50 %), nausea (12%), diarrhea (12%) and thrombopenia (25%). Grade 2-3 sensory neuropathy occured in 25% of pts. Prior nab-P+G did not result in increased hematological or non-hematological toxicity of FOLFIRINOX. Among the 8 patients evaluable so far, 5 partial responses (63%) and 3 stable disease (37%) have been observed, resulting in a disease control rate of 100%. After sequential chemotherapy 3 pts (37%) underwent radical surgical resection. Of note, all resected patients pts showed regression of the tumor (Evans Regression Score 2-4) with 1 patient fullfilling the criteria of a complete pathological remission (pCR). 4 pts received concomitant chemo-radiotherapy and 1 pt underwent an explorative laparotomy with evidence of occult (micronodular) peritoneal metastasis. Conclusions: Sequential neoadjuvant chemotherapy with nab-P+G and FOLFIRINOX seems to be highly active with manageable toxicity profile and may allow to achieve pCR in LAPC. These results are encouraging to test this approach in a prospective phase II trial.

scholarly journals Advanced pancreatic cancer: The standard of care and new opportunities

2018 ◽  
Author(s):  
Amrallah A. Mohammad
Keyword(s):  
Pancreatic Cancer ◽  
Mortality Rate ◽  
Cancer Treatment ◽  
Molecular Analysis ◽  
Therapeutic Approach ◽  
Locally Advanced ◽  
Advanced Pancreatic Cancer ◽  
Standard Of Care

Presentation of pancreatic cancer is localized, locally advanced or metastatic. With the later represented the main bulk (more than 80%). Despite the significant innovation in molecular analysis and therapeutic approach in many types of cancer in the last two decades, still the outcome of advanced pancreatic cancer is disappointing and the mortality rate approximately unchanged. In this mandated review we intended to highlight the standard of care and emerging agents for advanced pancreatic cancer treatment.

Masitinib plus gemcitabine as first-line treatment of pancreatic cancer with pain: Results from phase 3 study AB12005.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4018-4018
Author(s):  
Joel Ezenfis ◽  
Olivier Hermine ◽  
Keyword(s):  
Pancreatic Cancer ◽  
Statistical Significance ◽  
Locally Advanced ◽  
Disease Stage ◽  
Study Cohort ◽  
Line Treatment ◽  
First Line ◽  
Phase 3 ◽  
Risk Of Death ◽  
First Line Treatment

4018 Background: Masitinib (MAS) is a small molecule drug targeting mast cell and macrophage activity, innate immune cells that are critical components of the tumor microenvironment. Proof of concept that MAS in combination with gemcitabine (GEM) improved overall survival (OS) in pancreatic cancer (PC) patients (pts) with pain, was previously shown [doi 10.1093/annonc/mdv133]. The presence of pain in PC is thought to identify pts whose disease is driven in part by a pro-tumoral immune response. Methods: AB12005 was a prospective, placebo (PBO) controlled, double blind, randomized (2:1 MAS:PBO, stratified by disease stage, ECOG and geographic region) phase 3 trial, evaluating oral MAS (6.0 mg/kg/d) in combination with GEM (1000 mg/m²) against PBO plus GEM for the treatment of unresectable locally advanced PC (LAPC) and/or metastatic PC (mPC) pts with pain criteria; i.e. baseline visual analog scale of pain intensity (VAS) > 20 and/or pt treated with an opioid analgesics dose ≥1 mg/kg/d at baseline. Eligible pts were chemo-naïve with histologically or cytologically confirmed inoperable LAPC or mPC and an ECOG status ≤2. The estimated sample size was ̃330 pts to detect an OS hazard ratio (HR) of 0.68 (80% power, 2-sided α = 0.025) after 310 deaths. The study was successful if improvement in median OS (primary endpoint) relative to control reached a 2.5% level of statistical significance for either a targeted subgroup of LAPC with pain criteria, or the overall study cohort. Results: A total of 384 pts were enrolled (safety population n = 383; mITT n = 379; target subgroup n = 92). In the predefined subgroup of unresectable LAPC with pain, MAS-GEM (n = 62) showed significant benefit over PBO-GEM (n = 30) with median OS of 13.0 months (97.5% CI [11.0;18.0]) vs 11.2 months (97.5% CI [7.4;13.0]); p = 0.007. The HR was 0.46 (97.5% CI [0.2;0.9], p = 0.0047), corresponding to a significant 54% reduction in risk of death for MAS-GEM pts relative to control. Secondary analyses in the same subgroup were convergent with this primary outcome. Median PFS showed a 1.8 month between group difference in favor of MAS-GEM (p = 0.039), with a HR of 0.47 (97.5% CI [0.3;0.9], p = 0.014). The 12-month and 18-month OS rates showed a 1.3 fold and 3.4 fold improvement, respectively, in favor of MAS-GEM (53.2% and 33.9% for MAS-GEM vs 40.0% and 10% for PBO-GEM, respectively). In the overall population, comprising LAPC and mPC pts with pain, no survival benefit was observed; median OS for MAS-GEM (n = 244) was 6.9 months vs 8.0 months for PBO-GEM (n = 135); p = 0.461. The MAS-GEM combination was well tolerated with no sign of add-on toxicity. The proportion of patients presenting at least one adverse event (AE) or serious AE was respectively, 96.3% and 19.1% for MAS-GEM (n = 246) vs 99.3% and 21.3% for PBO-GEM (n = 136). Conclusions: The combination MAS (6.0 mg/kg/d) plus GEM may provide a new first line treatment option for unresectable LAPC pts with associated pain. Clinical trial information: NCT03766295.

scholarly journals Role of Stereotactic Body Radiotherapy in the Treatment of Elderly and Poor Performance Status Patients With Pancreatic Cancer

2017 ◽  
Vol 13 (3) ◽  
pp. 157-166 ◽  
Author(s):  
Lauren M. Rosati ◽  
Joseph M. Herman
Keyword(s):  
Pancreatic Cancer ◽  
Stereotactic Body Radiotherapy ◽  
Group Performance ◽  
Performance Status ◽  
Single Agent ◽  
Locally Advanced ◽  
Poor Performance ◽  
Tumor Control ◽  
Poor Performance Status ◽  
Patient Reported

Literature on the management of nonmetastatic pancreatic ductal adenocarcinoma in patients who are elderly or have poor performance status is sparse. The median survival of this unique cohort of patients is < 6 months, and most patients are only offered single-agent gemcitabine or supportive care. Recently, adding nanoparticle albumin-bound paclitaxel to gemcitabine was shown to improve survival of patients with metastatic disease with Eastern Cooperative Group performance status of 2. Although standard chemoradiotherapy provides long-term locoregional control in locally advanced pancreatic cancer, it is difficult for this group of patients to tolerate 6 weeks of therapy. Stereotactic body radiotherapy (SBRT) can be delivered in only 3 to 5 days, does not require concurrent chemotherapy, and has limited toxicity, and tumor control rates appear to be equivalent to or better than those achieved with standard chemoradiotherapy. Additionally, SBRT has been shown to improve cancer-related pain and patient-reported quality of life. Given the favorable toxicity profile, SBRT seems like an obvious choice for patients who are elderly, have multiple comorbidities, or have poor performance status. Herein, we review the literature on SBRT in this unique patient population and discuss future directions.

Differential tumor and normal mucosa biomarker modulation by epidermal growth factor receptor (EGFR) inhibition using erlotinib in oral cavity squamous cell carcinoma (OCSCC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 6077-6077
Author(s):  
C. Tsien ◽  
M. Nyati ◽  
D. Chepeha ◽  
F. Worden ◽  
J. Helman ◽  
...  
Keyword(s):  
Targeted Therapy ◽  
Surgical Resection ◽  
Locally Advanced ◽  
Immunohistochemical Analysis ◽  
Normal Mucosa ◽  
Preclinical Model ◽  
Published Data ◽  
Head Neck Cancer ◽  
Egfr Inhibition ◽  
Tumor Biopsies

6077 Background: Targeted therapy may improve the therapeutic index in locally advanced head neck cancer if differential EGFR inhibition in tumors compared to the normal mucosa is demonstrated. Based on prior published data, EGFR degradation is an important biomarker of cytotoxicity in a preclinical model. The aim of this pilot study was to determine if there are differences in biomarker modulation between tumor and the normal mucosa and confirm our initial preclinical findings regarding EGFR degradation. Methods: Patients with primary OCSCC requiring surgical resection had normal mucosa and tumor biopsies prior to a test course of erlotinib. Patients received one week of erlotinib 150 mg qd. Repeat tumor and normal mucosal biopsies were obtained at the time of surgical resection to evaluate the effect of the EGFR inhibitor on both tumor and the normal mucosa. Changes in known preclinical markers of EGFR activity (phospho, total EGFR, AKT, STAT3) were measured by immunoblotting assays. In addition, changes in distribution of these biomarkers were analyzed by immunohistochemical analysis. Results: 12 pts were enrolled; 7 pts with paired tumor and normal mucosa biopsies. Tumor specimens showed over-expression of EGFR compared to the normal mucosa (p = 0.005). Erlotinib treatment led to marked inhibition of both pEGFR and EGFR protein (p = 0.004 and p = 0.007, respectively) in tumor biopsies. In contrast, we found heterogeneity in EGFR inhibition in the normal mucosa following erlotinib. (p = 0.1 [pEGFR], and p = 0.07 [EGFR)]) We noted dramatic reduced levels of pSrc and pSTAT3 following erlotinib in tumors compared to untreated matched tumor samples. In addition, levels of p27 were enhanced. Conclusions: Differential EGFR inhibition in tumors compared to the normal mucosa, may suggest that the addition of EGFR inhibitors to chemo-RT or accelerated RT, whose dose limiting toxicity is acute mucositis, may select patients who will benefit from targeted therapy. Our results demonstrate that EGFR inhibition by erlotinib led to marked reduction in EGFR protein levels. EGFR degradation may be an important biomarker in selecting patients predicted to have a response to TKI. These results need further validation. No significant financial relationships to disclose.

The role of neoadjuvant chemotherapy in elderly patients with borderline or locally advanced pancreatic cancer: Is it safe and feasible?

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 685-685 ◽  
Author(s):  
Atsushi Oba ◽  
Christopher Hanyoung Lieu ◽  
Cheryl Lauren Meguid ◽  
Sarah Lindsey Davis ◽  
Alexis Diane Leal ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Elderly Patients ◽  
Combination Chemotherapy ◽  
Single Agent ◽  
Locally Advanced ◽  
Neoadjuvant Treatment ◽  
Advanced Pancreatic Cancer ◽  
Survival Advantage ◽  
Locally Advanced Pancreatic Cancer

685 Background: For borderline resectable (BRPC) or locally advanced pancreatic cancer (LAPC), neoadjuvant (NAT) FOLFIRINOX or gemcitabine plus nab-paclitaxel (GnP) are standard treatment options and these regimens have shown a survival advantage over single-agent gemcitabine. However, the role of these modern therapeutic regimens in elderly patients is debatable. In this analysis, we evaluated the outcomes of neoadjuvant treatment (NAT) with combination chemotherapy in elderly patients. Methods: 230 consecutive patients who underwent neoadjuvant treatment for BRPC/LAPC discussed and planned for NAT at the University of Colorado Cancer Center from January 2011 to March 2019 were reviewed. 214 patients who received FOLFIRINOX (n = 143) or GnP (n = 71) were eligible for analysis. We divided all patients into three groups ( < 70, 70-74, ≥75 years) and compared the short-term and long-term outcomes. Results: Of 214 patients, patients < 70 (n = 147) received FOLFIRINOX more frequently than the other groups (p < 0.001): FOLFIRINOX: 115 cases, GnP: 32 cases, 70-74 years (n = 33): FOLFIRINOX: 15 cases, GnP: 18 cases, and ≥75 years (n = 34): FOLFIRINOX: 13 cases, GnP: 21 cases. Resection rates were not statistically different between three groups ( < 70: 62%, 70-74: 70%, ≥75 years: 56%, p = 0.504). There was a slight trend towards worse survival in the two older groups (Median Survival Time [MST]: < 70: 23.2 mo., 70-74: 19.5 mo., ≥75 years: 17.6 mo., p = 0.075) The FOLFIRINOX group was superior to GnP group in all three groups (MST: < 70: 25.6 vs 18.2 mo., p = 0.017; 70-74: 33.2 vs 16.1mo., p = 0.029; ≥75 years: not reached vs 16.1 mo., p = 0.135). There were no toxic deaths or 30 day mortality after pancreatectomy in the study population. Conclusions: Neoadjuvant combination chemotherapy regimens were safe and feasible for elderly patients. Neoadjuvant therapy with FOLFIRINOX was associated with a survival advantage vs GnP and is an good option for fit and elderly patients ≥75 years.

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