Meet The Professors: Pancreatic Cancer Edition, 2016 - Video 3534-year-old woman with an extensive family history of cancer is diagnosed with BRCA-mutated mPAC
7:17 minutes.
TRANSCRIPTION:
DR BEKAII-SAAB: So this is a young lady, 34-year-old mother of 2, came with a diagnosis of metastatic pancreas cancer, which she presented with high bilirubin, so it was involving the head. And it seems at the time of presentation, her disease was already in the liver. So you can imagine, a young mother, previously very active, devastated. She did have an extensive family history of cancer, including breast and uterine cancer, but no pancreas cancer. So the one thing that, of course, came to mind is that this sounds — in a patient like this, possibly related to a BRCA2 gene mutation. And we indeed did genetic testing, which revealed the mutation. But that takes a month or two to get all these results. In the meanwhile, we started her on — this is 1 instance where I was actually excited about modified FOLFIRINOX, because of not just the platinum, by the way. Irinotecan by itself has activity, because it’s a DNA-damaging agent. It does have activity in this group of patients. So you have really 2 agents that are working with you in this instance. So within 6 months, the patient actually went into complete response. All the liver lesions were gone. I mean, her CA 19-9 went from, I think, 900 to undetectable and remained so. Normalization of her CA 19-9; everything was great. She felt great. I mean, she was putting so much weight on, I had to push her to do more exercise. All she had was a little bit of Grade 1 neurotoxicity. We had a long discussion back and forth about what we do. And she requested that she wants to be done with therapy, which I thought was very reasonable given that it was a CR. She was feeling great, doing great. Also discussed possibly involving in one of the trials with a PARP inhibitor, but she really wanted to be off treatment. So we stopped treatment, and beyond that point her follow-up scans continued to show no evidence of disease. So the patient went to CR off treatment on a holiday, doing fantastic. DR LOVE: How long has it been now, since the — DR BEKAII-SAAB: More than a year. DR LOVE: So Margaret, any comments about the issue of BRCA germline mutations in pancreatic cancer? Not only treatment and outcomes with treatment, but in terms of screening? DR TEMPERO: Screening is a tough one. We do screen patients who have an inherited predisposition to getting pancreatic cancer, either because of the syndrome they’re in or in true pancreas cancer families. Unfortunately, what we’re finding in those families are a lot of benign premalignant tumors. It makes it difficult to know when to intervene, because it’s not like a colon polyp where you can just remove it. It’s a very complicated surgery. And some patients are developing invasive cancer in between screening, just as we sometimes see with breast cancer. So the jury’s still out about whether we can actually detect cancer early in this patient population. And, fortunately, because of large studies that are ongoing, there are biospecimens being collected. And there are some new biomarker panels that look like they’re pretty useful in detecting early-stage pancreatic cancer. So we’ll be able to apply those biomarker panels to the screening samples that were obtained as a part of screening. And we have the outcomes on those patients. And so we should be able to maybe take a different approach than just EUS or MRCP, which is what we’ve been using in the past. DR LOVE: And what’s known about the responses to chemotherapy, what kind of chemotherapy? Is this unusual or common to see what happened here? DR TEMPERO: What Tony described is pretty typical, actually. And you don’t actually have to use FOLFIRINOX. You may get the same bang for your buck with an easier-tolerated regimen like gemcitabine and cisplatin. And currently there’s a trial ongoing, particularly in the BRCA — these are with patients with known BRCA mutations, where they’re looking at gemcitabine and cisplatin in the control arm versus gemcitabine/cisplatin and a PARP inhibitor. DR LOVE: And how often do you see this? For example, at your center, where you have a high volume, how many patients a year come in with BRCA germline mutations in pancreatic cancer? DR TEMPERO: I would say about a half a dozen in our situation. DR LOVE: Really? Wow! DR TEMPERO: At Memorial Sloan Kettering, it’s a much bigger place than UCSF, and so they see probably 30 or 40. Any urban, dense area is going to see a fair number of these. But it’s really, really important for oncologists everywhere to think about inherited predisposition, because it has such an impact on the treatment. DR BROOKS: Earlier on, you mentioned BRCA-like. And I think about that in breast cancer. What specifically were you referring to? Were you talking about young age? Were you talking about family history? DR TEMPERO: No, no. I’m talking about a mutation pattern that involves the DNA repair pathways. DR BROOKS: So what specific mutations? DR TEMPERO: So it involves ATM. It involves PALB2. And some others. And it also is a gene expression that is associated with the BRCA mutation. So what we found in the ICGC data set is that if you had a BRCA mutation, you had a certain gene expression. So the gene and the gene expression, 2 separate things, but you had a different gene expression. So if you look at patients who have that gene expression, that adds in some more potential candidates for DNA-damaging agents. So that’s where you get to the 24%. So you have the known mutations. That gets you to about maybe 8% to 10%. And then you add in the ones that have a gene expression, typical of similar — like, BRCA-like, that gets you to 24%. DR BEKAII-SAAB: So that’s about one quarter of the patients. So that’s established already in other diseases: ovarian, for example, where you see — so the BRCAness or the BRCA-like is a larger chunk of patients. And they may not respond as well, but they do respond to these types of treatments. The more solid responses are with the BRCA1-2, PALB2. And again, whether germline or somatic, which is about — as Margaret mentioned, about 10% of the patients, ultimately. A couple of percent would be germline BRCA2, where you’ll be able to identify by family history or ethnic background. Ashkenazi Jews have a higher risk for BRCA2. I’ve seen multiple PALB2s, more so lately. But the somatic mutations are actually seen more often than the germline. And these are often missed, because they’re not part of a family history. But they do predict equally for a good response to platinums or even, arguably, to PARP inhibitors. |