NEW YORK – Patients with TP53-mutated pancreatic ductal adenocarcinoma, or PDAC, may respond better to adjuvant treatment with the chemotherapy drug gemcitabine (Gemzar) than patients with TP53-wildtype tumors, according to a new study published in Clinical Cancer Research.
Although the study's authors noted that their findings will need to be validated through further research, the potential for TP53 to serve as a predictive and prognostic biomarker for PDAC indicates the rise of precision medicine in a patient population that has previously seen limited treatment advances.
"Translational research approaches have not been able yet to define relevant predictive or prognostic biomarkers in PDAC," wrote the study authors, led by Marianne Sinn and Carsten Denkert from the Berlin Institute of Health. "This may be one of the main reasons for the lack of survival improvement by precision medicine so far."
In this translational study, researchers in Germany used next-generation sequencing (NGS) on previously collected PDAC tissue samples to assess the relationship between the tumors' driver mutations and patients’ survival outcomes. Using these data in combination with functional genomic analyses performed in an NGS and RNASeq dataset of 146 pancreatic tumors from The Cancer Genome Atlas (TCGA), they deduced that TP53 mutations were a positive predictive factor for gemcitabine efficacy.
Specifically, the researchers found a "strong and significant benefit from gemcitabine" in patients with TP53-mutated PDAC tumors. In the observation group, on the other hand, TP53 mutations were an adverse prognostic factor.
The tissue samples used for this study and the accompanying data were initially gathered during the randomized, Phase III CONKO-001 trial, which compared adjuvant gemcitabine (six cycles in an outpatient setting) versus observation alone following surgical PDAC resection with a curative intent. CONKO-001’s results established adjuvant treatment with gemcitabine following surgical resection as standard of care for patients with PDAC.
Newer adjuvant chemotherapy regimens, including gemcitabine-capecitabine combinations and FOLFIRINOX, have changed the treatment algorithm slightly in the years since CONKO-001 showed gemcitabine's efficacy, the study authors note, pointing out that these more recent advancements may limit the direct influence of this translational study on current clinical practice. Even so, the researchers said that, to their knowledge, this study is the first NGS analysis of PDAC after surgical resection and adjuvant therapy, and that it may pave the way for further applications of precision medicine in PDAC.
"The sensitivity of TP53mut PDAC to gemcitabine in CONKO-001 provides a lead for further mechanistic investigations," they wrote.
CONKO-001 enrolled 368 patients between July 1998 and December 2004. Due to the retrospective nature of the study, the fact that CONKO-001 was a community-based study, and the insufficient amount of tissue or tumor contents in some of the samples, the researchers for this translational study were only able to successfully sequence tumor samples from 101 patients. The subgroup’s characteristics were nonetheless comparable to the overall study population.
The method of NGS was a customized sequencing panel designed with Ion AmpliSeq Designer based on mutation data of pancreatic cancer from the COSMIC database.
In these 101 usable samples, the researchers analyzed 37 genes. They identified the most common mutations: mutations in the TP53 gene — which was present in 60 percent of the CONKO cohort — along with mutations in KRAS, present in 75 percent; in SMAD4, present in 10 percent; in CDKNA2, present in 9 percent; and in SWI/SNF, present in 12 percent. Importantly, the incidence of these mutations were significantly lower than those found in TCGA. The researchers acknowledge this as a limitation of their study, pointing out that the difference could be due to the lower sensitivity of the NGS analysis performed in the formalin-fixed paraffin embedded samples from the CONKO cohort.
Again, the researchers noted that further investigations will be needed in additional cohorts before their findings can be introduced into clinical practice. But, going forward, the findings suggest a role for TP53 mutations as a predictive marker in PDAC treated with gemcitabine, according to the authors, and represents progress toward precision medicine in a notoriously aggressive cancer with just a 5 percent five-year survival rate across all stages.