Treatment Sequencing in BRCA-Mutated Pancreatic Cancer
James Cleary, MD, PhD, Dana-Farber Cancer Institute, Boston, Massachusetts, presents a case of a 63-year-old woman with metastatic pancreatic adenocarcinoma whose treatment highlights the impact of precision medicine.
The patient, found to have a germline BRCA2 mutation with biallelic loss, achieved a strong response to first-line platinum-based chemotherapy followed by durable disease control on maintenance olaparib for more than 3 years. This case underscores the importance of molecular testing to guide therapy selection, including platinum chemotherapy, PARP inhibitor maintenance, and emerging targeted approaches in pancreatic cancer.
Transcript:
Hello, my name is James Cleary. I am a medical oncologist at Dana-Farber Cancer Institute. Thank you very much for joining us today. The case we're going to be talking about today is of a patient with metastatic pancreatic cancer. What this case demonstrates is some of the improvements that have been made in the care of metastatic pancreatic cancer patients and how precision medicine is starting to transform this disease.
The case is a 63-year-old woman with a strong family history of breast and ovarian cancer who also has a personal history of breast cancer 10 years ago who presented with unintentional weight loss, jaundice, and epigastric pain. A CT scan showed a pancreatic head mass and multiple liver lesions. She ultimately underwent a liver biopsy, which showed pancreatic adenocarcinoma consistent with a pancreatobiliary primary.
Given her strong family history of cancer and also the fact that she had breast cancer 10 years ago, she underwent germline testing and was found to have a germline BRCA2 mutation. On tumor next generation sequencing, they again saw the BRCA2 mutation and they saw that the second copy of BRCA2 was lost. So she had biallelic loss of BRCA2. In addition to the biallelic loss of BRCA2, her NGS sequencing showed a KRAS G12D mutation, and two-copy loss of MTAP.
The patient was started on FOLFIRINOX chemotherapy and had a wonderful response. CT scans after 4 cycles and 8 cycles both showed a significant decrease in her metastatic liver lesions and pancreatic mass. However, after 4 months of FOLFIRINOX chemotherapy, the patient was very fatigued and asked for a break from chemotherapy. Because she had biallelic loss of BRCA and had such a wonderful response to the FOLFIRINOX chemotherapy, her oncology team elected to put her on a PARP inhibitor. And on that PARP inhibitor, she had a tremendous response. It was very durable, and she continued on the PARP inhibitor, olaparib, for over 3 years.
So to talk about this case, and the reason we designed the case this way, is it shows a patient with a BRCA2 mutation. And BRCA2 mutations are the most common of germline mutations that can cause pancreatic cancer. And BRCA2 mutations are also well known to cause breast, ovarian, pancreatic cancer, and also prostate cancer. But really, one of the reasons that BRCA2 mutations can influence the care of pancreatic cancer patients is a BRCA2 mutation really signifies increased sensitivity to platinum chemotherapy. And this case shows that well, that the patient just had a wonderful response to full FIRINOX chemotherapy.
So really an important teaching point is if you're taking a care of a patient with metastatic pancreatic cancer that has a BRCA1, BRCA2 or PALB2 mutation, you really want to give them first-line platinum-containing chemotherapy. And reasonable regimens include like this, FOLFIRINOX. In addition, though, giving gemcitabine and cisplatin also is a very good first-line regimen for these patients.
The second teaching point of this case is in patients who have a nice response to platinum chemotherapy and have either a BRCA1, BRCA2, or PALB2 mutation, you can think about doing maintenance PARP inhibition with drugs such as olaparib or rucaparib. Really, the thing you want to look for though is you want to make sure that the patient didn't have progressive disease on platinum chemotherapy. If their cancer progressed on platinum chemotherapy, a PARP inhibitor is not going to work.
The other thing we're learning more and more is that the patients who really respond to this are patients who have biallelic loss of BRCA or PALB2. And what we mean by biallelic loss is in one allele, you have a BRCA mutation and then the cancer deletes the other BRCA allele. In this case, the patient had a germline BRCA2 mutation, and then in the other allele, it was deleted. Basically, there was no functional BRCA2 in this patient's tumor. And since they're so BRCA2 deficient, that's why they're so platinum chemotherapy sensitive, and that's why they can have such a wonderful response to PARP inhibition.
Other things that this case shows is this patient has a KRAS G12D mutation. In pancreas cancer, the most common mutation is KRAS mutations. Over 90% to 95% of pancreatic cancer patients have a KRAS mutation. And out of the different KRAS mutations, KRAS G12D is the most common. And really there's a big revolution happening now in the care pancreatic cancer because now we're starting to get KRAS inhibitors. And these KRAS inhibitors, at least in clinical trials, have shown tremendous promise. And as a clinician on the first line, we can't wait to get these KRAS inhibitors FDA approved so we can start giving them to our patients.
The final thing in this case, again, just talking about molecular medicine and different targets for these patients is this patient has two-copy MTAP loss, and patients with two-copy MTAP loss might be susceptible and sensitive to an experimental medication called a PRMT5 inhibitor. And there's a lot of enthusiasm that while it's a little further behind in KRAS inhibitors that maybe over the next few years, we'll start seeing PRMT5 inhibitors becoming FDA approved.
In conclusion, really what this case shows is the importance of molecular medicine in pancreatic cancer and that this patient had a BRCA2 mutation and was very sensitive to platinum chemotherapy and also was able to benefit from maintenance PARP inhibition. And then an emerging molecular target is KRAS mutations as many KRAS inhibitors have shown great promise in clinical trials. Thank you very much for listening.
