TY - JOUR
T1 - Genomic Biomarkers Associated with Response to Induction Chemotherapy in Patients with Localized Pancreatic Ductal Adenocarcinoma
AU - Ecker, Brett L.
AU - Tao, Alice J.
AU - Janssen, Quisette P.
AU - Walch, Henry S.
AU - Court, Colin M.
AU - Balachandran, Vinod P.
AU - Crane, Christopher H.
AU - D'Angelica, Michael I.
AU - Drebin, Jeffrey A.
AU - Peter Kingham, T.
AU - Soares, Kevin C.
AU - Iacobuzio-Donahue, Christine A.
AU - Vakiani, Efsevia
AU - Gonen, Mithat
AU - O'Reilly, Eileen M.
AU - Varghese, Anna M.
AU - Jarnagin, William R.
AU - Wei, Alice C.
N1 - Publisher Copyright:
© 2023 American Association for Cancer Research.
PY - 2023/4/10
Y1 - 2023/4/10
N2 - Purpose: There is increasing use of neoadjuvant chemotherapy in the management of localized pancreatic ductal adenocarcinoma (PDAC), yet there are few validated biomarkers to guide therapy selection. We aimed to determine whether somatic genomic biomarkers predict response to induction FOLFIRINOX or gemcitabine/nab-paclitaxel. Experimental Design: This single-institution cohort study included consecutive patients (N ¼ 322) with localized PDAC (2011-2020) who received at least one cycle of FOLFIRINOX (N ¼ 271) or gemcitabine/nab-paclitaxel (N ¼ 51) as initial treatment. We assessed somatic alterations in four driver genes (KRAS, TP53, CDKN2A, and SMAD4) by targeted next-generation sequencing, and determined associations between these alterations and (1) rate of metastatic progression during induction chemotherapy, (2) surgical resection, and (3) complete/major pathologic response. Results: The alteration rates in driver genes KRAS, TP53, CDKN2A, and SMAD4 were 87.0%, 65.5%, 26.7%, and 19.9%, respectively. For patients receiving first-line FOLFIRINOX, SMAD4 alterations were uniquely associated with metastatic progression (30.0% vs. 14.5%; P ¼ 0.009) and decreased rate of surgical resection (37.1% vs. 66.7%; P < 0.001). For patients receiving induction gemcitabine/nab-paclitaxel, alterations in SMAD4 were not associated with metastatic progression (14.3% vs. 16.2%; P ¼ 0.866) nor decreased rate of surgical resection (33.3% vs. 41.9%; P ¼ 0.605). Major pathologic response was rare (6.3%) and not associated with type of chemotherapy regimen. Conclusions: SMAD4 alterations were associated with more frequent development of metastasis and lower probability of reaching surgical resection during neoadjuvant FOLFIRINOX but not gemcitabine/nab-paclitaxel. Confirmation in a larger, diverse patient cohort will be important before prospective evaluation of SMAD4 as a genomic biomarker to guide treatment selection.
AB - Purpose: There is increasing use of neoadjuvant chemotherapy in the management of localized pancreatic ductal adenocarcinoma (PDAC), yet there are few validated biomarkers to guide therapy selection. We aimed to determine whether somatic genomic biomarkers predict response to induction FOLFIRINOX or gemcitabine/nab-paclitaxel. Experimental Design: This single-institution cohort study included consecutive patients (N ¼ 322) with localized PDAC (2011-2020) who received at least one cycle of FOLFIRINOX (N ¼ 271) or gemcitabine/nab-paclitaxel (N ¼ 51) as initial treatment. We assessed somatic alterations in four driver genes (KRAS, TP53, CDKN2A, and SMAD4) by targeted next-generation sequencing, and determined associations between these alterations and (1) rate of metastatic progression during induction chemotherapy, (2) surgical resection, and (3) complete/major pathologic response. Results: The alteration rates in driver genes KRAS, TP53, CDKN2A, and SMAD4 were 87.0%, 65.5%, 26.7%, and 19.9%, respectively. For patients receiving first-line FOLFIRINOX, SMAD4 alterations were uniquely associated with metastatic progression (30.0% vs. 14.5%; P ¼ 0.009) and decreased rate of surgical resection (37.1% vs. 66.7%; P < 0.001). For patients receiving induction gemcitabine/nab-paclitaxel, alterations in SMAD4 were not associated with metastatic progression (14.3% vs. 16.2%; P ¼ 0.866) nor decreased rate of surgical resection (33.3% vs. 41.9%; P ¼ 0.605). Major pathologic response was rare (6.3%) and not associated with type of chemotherapy regimen. Conclusions: SMAD4 alterations were associated with more frequent development of metastasis and lower probability of reaching surgical resection during neoadjuvant FOLFIRINOX but not gemcitabine/nab-paclitaxel. Confirmation in a larger, diverse patient cohort will be important before prospective evaluation of SMAD4 as a genomic biomarker to guide treatment selection.
UR - http://www.scopus.com/inward/record.url?scp=85151575240&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85151575240&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-22-3089
DO - 10.1158/1078-0432.CCR-22-3089
M3 - Article
C2 - 36795432
AN - SCOPUS:85151575240
SN - 1078-0432
VL - 29
SP - 1368
EP - 1374
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 7
ER -