Intact SMAD-4 is a predictor of increased locoregional recurrence in upfront resected pancreas cancer receiving adjuvant therapy

Hunter C. Gits; Amy H. Tang; William S. Harmsen; William R. Bamlet; Rondell P. Graham; Gloria M. Petersen; Thomas C. Smyrk; Amit Mahipal; Roman O. Kowalchuk; Jonathan B. Ashman; William G. Rule; Dawn Owen; Michelle A. Neben Wittich; Robert R. McWilliams; Thorvardur Halfdanarson; Wen Wee Ma; Terence T. Sio; Sean P. Cleary; Mark J. Truty; Michael G. Haddock; Christopher L. Hallemeier; Kenneth W. Merrell

doi:10.21037/jgo-21-55

Intact SMAD-4 is a predictor of increased locoregional recurrence in upfront resected pancreas cancer receiving adjuvant therapy

Hunter C. Gits, Amy H. Tang, William S. Harmsen, William R. Bamlet, Rondell P. Graham, Gloria M. Petersen, Thomas C. Smyrk, Amit Mahipal, Roman O. Kowalchuk, Jonathan B. Ashman, William G. Rule, Dawn Owen, Michelle A. Neben Wittich, Robert R. McWilliams, Thorvardur Halfdanarson, Wen Wee Ma, Terence T. Sio, Sean P. Cleary, Mark J. Truty, Michael G. HaddockChristopher L. Hallemeier, Kenneth W. Merrell

Research output: Contribution to journal › Article › peer-review

Abstract

Background: Previous reports suggest that intact SMAD4 expression is associated with a locally aggressive pancreas cancer phenotype. The objectives of this work were to determine the frequency of intact SMAD4 and its association with patterns of recurrence in patients with upfront resected pancreas cancer receiving adjuvant therapy. Methods: A tissue microarray was constructed using resected specimens from patients who underwent upfront surgery and adjuvant gemcitabine with no neoadjuvant treatment for pancreas cancer. SMAD4 expression was determined by immunohistochemical staining. Associations of SMAD4 expression and clinicopathologic parameters with clinical outcomes were evaluated using Cox proportional hazard models. Results: One hundred twenty-seven patients were included with a median follow up of 5.7 years. Most patients had stage ≥ pT3 tumors (75%) and pN1 (68%). All patients received adjuvant gemcitabine, and 79% of patients received adjuvant chemoradiotherapy. Ten (8%) patients had intact SMAD4 expression. Grade was the only clinicopathologic parameter statistically associated with SMAD4 expression (P=0.05). Median overall survival was 2.1 years. On univariate analysis, SMAD4 expression was associated with increased locoregional recurrence (hazard ratio 7.0, P<0.01, 95% confidence interval: 2.8–18.0) but not distant recurrence (P=0.06) or overall survival (P=0.73). On multivariable analysis, SMAD4 expression (hazard ratio 9.6, P<0.01, 95% confidence interval: 3.7–24.8) and adjuvant chemoradiotherapy (hazard ratio 0.3, P=0.01, 95% confidence interval: 0.1–0.8) were associated with higher and lower locoregional recurrence, respectively. Conclusions: In patients with upfront resected pancreas cancer, SMAD4 expression was associated with an increased risk of locoregional recurrence. Prospective evaluation of the frequency of SMAD4 expression and validation of its predictive utility is warranted.

Original language	English (US)
Pages (from-to)	2275-2286
Number of pages	12
Journal	Journal of Gastrointestinal Oncology
Volume	12
Issue number	5
DOIs	https://doi.org/10.21037/jgo-21-55
State	Published - Oct 2021

Keywords

Chemoradiotherapy (CRT)
Mothers against decapentaplegic homolog 4 (SMAD4)
Pancreas cancer
Patterns of recurrence
Tissue microarray (TMA)

ASJC Scopus subject areas

Oncology
Gastroenterology

Access to Document

10.21037/jgo-21-55

Cite this

Gits, H. C., Tang, A. H., Harmsen, W. S., Bamlet, W. R., Graham, R. P., Petersen, G. M., Smyrk, T. C., Mahipal, A., Kowalchuk, R. O., Ashman, J. B., Rule, W. G., Owen, D., Neben Wittich, M. A., McWilliams, R. R., Halfdanarson, T., Ma, W. W., Sio, T. T., Cleary, S. P., Truty, M. J., ... Merrell, K. W. (2021). Intact SMAD-4 is a predictor of increased locoregional recurrence in upfront resected pancreas cancer receiving adjuvant therapy. Journal of Gastrointestinal Oncology, 12(5), 2275-2286. https://doi.org/10.21037/jgo-21-55

Gits, HC, Tang, AH, Harmsen, WS, Bamlet, WR, Graham, RP , Petersen, GM, Smyrk, TC, Mahipal, A, Kowalchuk, RO, Ashman, JB, Rule, WG, Owen, D, Neben Wittich, MA, McWilliams, RR, Halfdanarson, T, Ma, WW, Sio, TT, Cleary, SP, Truty, MJ , Haddock, MG , Hallemeier, CL & Merrell, KW 2021, 'Intact SMAD-4 is a predictor of increased locoregional recurrence in upfront resected pancreas cancer receiving adjuvant therapy', Journal of Gastrointestinal Oncology, vol. 12, no. 5, pp. 2275-2286. https://doi.org/10.21037/jgo-21-55

@article{a7b8331ecdbc49bfa5a436f2f3f43d39,

title = "Intact SMAD-4 is a predictor of increased locoregional recurrence in upfront resected pancreas cancer receiving adjuvant therapy",

abstract = "Background: Previous reports suggest that intact SMAD4 expression is associated with a locally aggressive pancreas cancer phenotype. The objectives of this work were to determine the frequency of intact SMAD4 and its association with patterns of recurrence in patients with upfront resected pancreas cancer receiving adjuvant therapy. Methods: A tissue microarray was constructed using resected specimens from patients who underwent upfront surgery and adjuvant gemcitabine with no neoadjuvant treatment for pancreas cancer. SMAD4 expression was determined by immunohistochemical staining. Associations of SMAD4 expression and clinicopathologic parameters with clinical outcomes were evaluated using Cox proportional hazard models. Results: One hundred twenty-seven patients were included with a median follow up of 5.7 years. Most patients had stage ≥ pT3 tumors (75%) and pN1 (68%). All patients received adjuvant gemcitabine, and 79% of patients received adjuvant chemoradiotherapy. Ten (8%) patients had intact SMAD4 expression. Grade was the only clinicopathologic parameter statistically associated with SMAD4 expression (P=0.05). Median overall survival was 2.1 years. On univariate analysis, SMAD4 expression was associated with increased locoregional recurrence (hazard ratio 7.0, P<0.01, 95% confidence interval: 2.8–18.0) but not distant recurrence (P=0.06) or overall survival (P=0.73). On multivariable analysis, SMAD4 expression (hazard ratio 9.6, P<0.01, 95% confidence interval: 3.7–24.8) and adjuvant chemoradiotherapy (hazard ratio 0.3, P=0.01, 95% confidence interval: 0.1–0.8) were associated with higher and lower locoregional recurrence, respectively. Conclusions: In patients with upfront resected pancreas cancer, SMAD4 expression was associated with an increased risk of locoregional recurrence. Prospective evaluation of the frequency of SMAD4 expression and validation of its predictive utility is warranted.",

keywords = "Chemoradiotherapy (CRT), Mothers against decapentaplegic homolog 4 (SMAD4), Pancreas cancer, Patterns of recurrence, Tissue microarray (TMA)",

author = "Gits, {Hunter C.} and Tang, {Amy H.} and Harmsen, {William S.} and Bamlet, {William R.} and Graham, {Rondell P.} and Petersen, {Gloria M.} and Smyrk, {Thomas C.} and Amit Mahipal and Kowalchuk, {Roman O.} and Ashman, {Jonathan B.} and Rule, {William G.} and Dawn Owen and {Neben Wittich}, {Michelle A.} and McWilliams, {Robert R.} and Thorvardur Halfdanarson and Ma, {Wen Wee} and Sio, {Terence T.} and Cleary, {Sean P.} and Truty, {Mark J.} and Haddock, {Michael G.} and Hallemeier, {Christopher L.} and Merrell, {Kenneth W.}",

year = "2021",

month = oct,

doi = "10.21037/jgo-21-55",

language = "English (US)",

volume = "12",

pages = "2275--2286",

journal = "Journal of Gastrointestinal Oncology",

issn = "2078-6891",

publisher = "Pioneer Bioscience Publishing Company (PBPC)",

number = "5",

}

TY - JOUR

T1 - Intact SMAD-4 is a predictor of increased locoregional recurrence in upfront resected pancreas cancer receiving adjuvant therapy

AU - Gits, Hunter C.

AU - Tang, Amy H.

AU - Harmsen, William S.

AU - Bamlet, William R.

AU - Graham, Rondell P.

AU - Petersen, Gloria M.

AU - Smyrk, Thomas C.

AU - Mahipal, Amit

AU - Kowalchuk, Roman O.

AU - Ashman, Jonathan B.

AU - Rule, William G.

AU - Owen, Dawn

AU - Neben Wittich, Michelle A.

AU - McWilliams, Robert R.

AU - Halfdanarson, Thorvardur

AU - Ma, Wen Wee

AU - Sio, Terence T.

AU - Cleary, Sean P.

AU - Truty, Mark J.

AU - Haddock, Michael G.

AU - Hallemeier, Christopher L.

AU - Merrell, Kenneth W.

PY - 2021/10

Y1 - 2021/10

N2 - Background: Previous reports suggest that intact SMAD4 expression is associated with a locally aggressive pancreas cancer phenotype. The objectives of this work were to determine the frequency of intact SMAD4 and its association with patterns of recurrence in patients with upfront resected pancreas cancer receiving adjuvant therapy. Methods: A tissue microarray was constructed using resected specimens from patients who underwent upfront surgery and adjuvant gemcitabine with no neoadjuvant treatment for pancreas cancer. SMAD4 expression was determined by immunohistochemical staining. Associations of SMAD4 expression and clinicopathologic parameters with clinical outcomes were evaluated using Cox proportional hazard models. Results: One hundred twenty-seven patients were included with a median follow up of 5.7 years. Most patients had stage ≥ pT3 tumors (75%) and pN1 (68%). All patients received adjuvant gemcitabine, and 79% of patients received adjuvant chemoradiotherapy. Ten (8%) patients had intact SMAD4 expression. Grade was the only clinicopathologic parameter statistically associated with SMAD4 expression (P=0.05). Median overall survival was 2.1 years. On univariate analysis, SMAD4 expression was associated with increased locoregional recurrence (hazard ratio 7.0, P<0.01, 95% confidence interval: 2.8–18.0) but not distant recurrence (P=0.06) or overall survival (P=0.73). On multivariable analysis, SMAD4 expression (hazard ratio 9.6, P<0.01, 95% confidence interval: 3.7–24.8) and adjuvant chemoradiotherapy (hazard ratio 0.3, P=0.01, 95% confidence interval: 0.1–0.8) were associated with higher and lower locoregional recurrence, respectively. Conclusions: In patients with upfront resected pancreas cancer, SMAD4 expression was associated with an increased risk of locoregional recurrence. Prospective evaluation of the frequency of SMAD4 expression and validation of its predictive utility is warranted.

AB - Background: Previous reports suggest that intact SMAD4 expression is associated with a locally aggressive pancreas cancer phenotype. The objectives of this work were to determine the frequency of intact SMAD4 and its association with patterns of recurrence in patients with upfront resected pancreas cancer receiving adjuvant therapy. Methods: A tissue microarray was constructed using resected specimens from patients who underwent upfront surgery and adjuvant gemcitabine with no neoadjuvant treatment for pancreas cancer. SMAD4 expression was determined by immunohistochemical staining. Associations of SMAD4 expression and clinicopathologic parameters with clinical outcomes were evaluated using Cox proportional hazard models. Results: One hundred twenty-seven patients were included with a median follow up of 5.7 years. Most patients had stage ≥ pT3 tumors (75%) and pN1 (68%). All patients received adjuvant gemcitabine, and 79% of patients received adjuvant chemoradiotherapy. Ten (8%) patients had intact SMAD4 expression. Grade was the only clinicopathologic parameter statistically associated with SMAD4 expression (P=0.05). Median overall survival was 2.1 years. On univariate analysis, SMAD4 expression was associated with increased locoregional recurrence (hazard ratio 7.0, P<0.01, 95% confidence interval: 2.8–18.0) but not distant recurrence (P=0.06) or overall survival (P=0.73). On multivariable analysis, SMAD4 expression (hazard ratio 9.6, P<0.01, 95% confidence interval: 3.7–24.8) and adjuvant chemoradiotherapy (hazard ratio 0.3, P=0.01, 95% confidence interval: 0.1–0.8) were associated with higher and lower locoregional recurrence, respectively. Conclusions: In patients with upfront resected pancreas cancer, SMAD4 expression was associated with an increased risk of locoregional recurrence. Prospective evaluation of the frequency of SMAD4 expression and validation of its predictive utility is warranted.

KW - Chemoradiotherapy (CRT)

KW - Mothers against decapentaplegic homolog 4 (SMAD4)

KW - Pancreas cancer

KW - Patterns of recurrence

KW - Tissue microarray (TMA)

UR - http://www.scopus.com/inward/record.url?scp=85118366963&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=85118366963&partnerID=8YFLogxK

U2 - 10.21037/jgo-21-55

DO - 10.21037/jgo-21-55

M3 - Article

AN - SCOPUS:85118366963

SN - 2078-6891

VL - 12

SP - 2275

EP - 2286

JO - Journal of Gastrointestinal Oncology

JF - Journal of Gastrointestinal Oncology

IS - 5

ER -

Intact SMAD-4 is a predictor of increased locoregional recurrence in upfront resected pancreas cancer receiving adjuvant therapy

Abstract

Keywords

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this