In recent years, increased access to genetic testing has revealed that up to eight per cent of pancreatic cancer patients have an inherited mutation in one of three genes – BRCA2, BRCA1 and PALB2. Cancers arising in patients with germline mutations in one of these genes are thought to be more sensitive to treatment using platinums and PARP inhibitors, two drugs that kill cancer cells by taking advantage of their inability to repair damage in their DNA when the function of one of these genes is impaired.
This knowledge has paved the way for personalized treatments for patients with germline mutations in these genes. But despite some successes attributed to such treatments, important questions have remained unanswered: why do some patients carrying a germline mutation in one of these genes fail to respond to these drugs and why do some of patients respond better than others?
A new study by members of TFRI’s Enhanced Pancreatic Cancer Profiling for Individualized Care (EPPIC) research program published in Clinical Cancer Research (October 2020) provides insight into these questions, allowing doctors to better know which patients will benefit from these treatments. The research team, led by Dr. George Zogopoulos, treated and molecularly characterized patient tumours transplanted in mice, and analyzed these results together with tumour profiling and clinical data from patients with pancreatic cancer.
“Our study shows that testing for inherited mutations in BRCA1, BRCA2 and PALB2 alone is not sufficient to predict response to targeted drugs such as platinums and PARP inhibitors,” explains Dr. Yifan Wang, the paper’s first author who is a PhD student and a surgical resident at McGill University. “Some patients with a germline mutation in one of these genes may not develop pancreatic cancer because of their germline mutation. Instead, they develop pancreatic cancer from some other cause. In patients that develop pancreatic cancer because of the inherited mutation in these genes, the cancer undergoes additional molecular events that allows drugs, such as platinums and PARP inhibitors, to successfully kill the cancer cells.”
According to Dr. Wang, these additional molecular events give rise to molecular biomarkers or “fingerprints” that help predict treatment responses and clinical outcomes for patients with germline mutations in the BRCA1, BRCA2 or PALB2 genes. These molecular “fingerprints” include genomic hallmarks of homologous recombination deficiency (HRD), Ki67 index, tumour ploidy, and transcriptomic subtype.
“We can refine patient selection by incorporating testing that looks for evidence of these molecular “fingerprints” in the cancers themselves, which would help us determine exactly who would benefit from the use of platinums and PARP inhibitors,” said Dr. Wang.
A Preclinical Trial and Molecularly Annotated Patient Cohort Identify Predictive Biomarkers in Homologous Recombination–deficient Pancreatic Cancer
Yifan Wang, Jin Yong Patrick Park, Alain Pacis, Robert E. Denroche, Gun Ho Jang, Amy Zhang, Adeline Cuggia, Celine Domecq, Jean Monlong, Maria Raitses-Gurevich, Robert C. Grant, Ayelet Borgida, Spring Holter, Chani Stossel, Simeng Bu, Mehdi Masoomian, Ilinca M. Lungu, John M.S. Bartlett, Julie M. Wilson, Zu-Hua Gao, Yasser Riazalhosseini, Jamil Asselah, Nathaniel Bouganim, Tatiana Cabrera, Louis-Martin Boucher, David Valenti, James Biagi, Celia M.T. Greenwood , Paz Polak, William D. Foulkes, Talia Golan, Grainne M. O'Kane, Sandra E. Fischer, Jennifer J. Knox, Steven Gallinger, and George Zogopoulos
The study was partially funded by a Terry Fox Translational Research Program grant to Enhanced Pancreatic Cancer Profiling for Individualized Care (EPPIC)