Association of Matrix Metalloproteinase 7 Expression With Pathologic Response After Neoadjuvant Treatment in Patients With Resected Pancreatic Ductal Adenocarcinoma

Abstract

IMPORTANCEThe use of neoadjuvant therapy (NAT) in resectable pancreatic ductal adenocarcinoma (PDAC) remains controversial. A favorable pathologic response (complete or marked tumor regression) to NAT is associated with better outcomes in patients with resected PDAC. The role of NAT for early systemic control compared with immediate surgical resection for PDAC is under investigation. In the era of precision medicine, biomarkers for patient selection and prediction of therapy response are crucial.OBJECTIVE To evaluate the use of assessment for protein expression on fine-needle aspiration (FNA) biopsy specimens in predicting pathologic response to NAT in treatment-naive patients. DESIGN, SETTING, AND PARTICIPANTSThis was a single-institution prognostic study from a high-volume center for pancreatic cancer. All specimens were obtained between January 1, 2009, and December 31, 2018, with a median (SE) follow-up of 20.2 (1.4) months. Analysis of the data was performed from October 1, 2019, to April 30, 2021. Targeted RNA sequencing of frozen FNA biopsy specimens from a discovery cohort of 23 patients was performed to identify genes with aberrant expression that was associated with patients' pathologic response to NAT. Immunohistochemical staining was performed on an additional 80 FNA biopsy specimens to assess expression of matrix metalloproteinase 7 (MMP-7) and its association with pathologic response. Receiver operating characteristic curves for prediction of favorable pathologic response were determined. RESULTSIn the discovery cohort (12 [52.1%] male; 3 [13.0%] Black and 20 [86.9%] White), RNA sequencing showed that lower MMP-7 expression was associated with favorable pathologic response (College of American Pathologists system scores of 0 [complete response] and 1 [marked response]). In the validation cohort (40 [50.0%] female; 9 [11.3%] Black and 71 [88.7%] White), patients with negative MMP-7 expression were significantly more likely to have a favorable pathologic response (odds ratio, 21.25; 95% CI, 6.19-72.95; P = .001). Receiver operating characteristic curves for prediction of favorable pathologic response from multivariable Cox proportional hazards regression modeling showed that MMP-7 expression increased the area under the curve from 0.726 to 0.906 (P < .001) even after stratifying by resectability status. The positive predictive value and negative predictive value of MMP-7 protein expression on FNA biopsy specimens in predicting unfavorable pathologic response (scores of 2 [partial response] or 3 [poor or no response]) were 88.2% and 73.9%, respectively.CONCLUSIONS AND RELEVANCE Assessment of MMP-7 expression on FNA biopsy specimens at the time of diagnosis may help identify patients who would benefit the most from NAT.

Targeted therapy for pancreatic ductal adenocarcinoma: Mechanisms and clinical study

“…In a discovery cohort of 23 patients, the study found that that lower expression of matrix metalloproteinase 7 ( MMP7 ) was associated with more favorable pathologic response, which is a strong surrogate for outcomes of PDAC patients. 15 The finding was confirmed in a validation cohort of 80 patients: patients with negative MMP7 immunohistochemistry staining were significantly more likely to have a more favorable pathologic response to NAT (odds ratio 21.25, 95% CI 6.19–72.95, p = 0.001). These results show great promise for use of RNA sequencing and proteomic analysis to identify targets that can predict NAT response.…”

“…More recently, Shoucair et al. 15 used targeted RNA sequencing of frozen FNA biopsy specimens to identify genes with atypical expression that were associated with patient response to NAT. In a discovery cohort of 23 patients, the study found that that lower expression of matrix metalloproteinase 7 ( MMP7 ) was associated with more favorable pathologic response, which is a strong surrogate for outcomes of PDAC patients.…”

“… 6 , 13 , 14 NAT is currently recommended by the National Comprehensive Cancer Network (NCCN) for patients with borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC). 15 , 16 …”

Obstructive sleep apnea predicts pathologic response to neoadjuvant therapy in resected pancreatic ductal adenocarcinoma

“…Using the current tumor regression grading system according to the College of American Pathologists (CAP), favorable PR was defined as a CAP score of 0 or 1, and unfavorable PR as a CAP score of 2 or 3. 2 In the analyzed cohort of patients who underwent NAT and resection for PDAC (n = 334) (Figure 1A and Table S1), OSA was significantly associated with male sex, resectable disease stage at diagnosis, shorter duration of NAT, increased tumor size, lymphovascular and perineural invasion, R1 margin, and unfavorable PR to NAT. In addition, OSA was an independent predictor of unfavorable PR in this study.…”

“…A growing body of evidence suggests that neoadjuvant therapy (NAT) improves surgery candidacy as well as postoperative outcomes in these patients, particularly in patients with a favorable pathologic response (PR). 2 There is, however, a lack of predictors of response to therapy before surgical resection.…”