Robert L. Coleman, MD:I think in this case, what we see is a patient who has had a good response to therapy. I say that because, after the completion of her frontline approach, she did not have overt evidence of progression. Sometimes, we have a better signal than this, because patients are left with disease that we monitor and, after the completion of their therapy, the disease is gone. So, that’s kind of a clear signaldisease was there, disease is gone—that the treatment had an effect.
In this scenario, the patient was left with no visible residual disease and she was given 3-weekly paclitaxel with carboplatin. In that time period while she was on therapy, no new disease occurred. She didn’t develop ascites; there were no new masses. So, at the end of the primary assessment we found that she was considered clinically NED (no evidence of disease), but whether or not she was actually sensitive or responsive to platinum is really not known, because we don’t have a marker.
Just about 4 to 5 months after she completed therapy, while we were observing her CA 125 and having her come in for serial exams, she noticed some new symptoms, and the symptoms were familiar. That’s always a problem, and patients are very acutely aware of this. These symptoms were familiar because they were associated with when she was diagnosed, so she promptly presented to her physician. They examined her, drew a CA 125, and noticed that it had gone from where her nadir was which was at a normal level—to a very elevated level. And, of course, identifying the disease on reimaging was a disappointing, but not unexpected, finding of the disease.
This patient has distribution of the disease, seen by her CAT scan, in the areas that she had had it before. This is probably the result of many factors. One of the aspects of this disease that we’re trying very hard to understand is the role of the cancer stem cell population that would necessarily be resident after the completion of therapy. And so, it’s not so uncommon to see that these would recur in a similar area, because that’s where you’d expect these kind of tumor cells to still be deposited.
In this case, she has this disease occur, and the fact that it occurred over 5 months in a way that can be measurable would suggest that the tumors were probably growing even though she was still on therapy. It takes time for a human cancer cell to divide and for enough of them to divide to become measurable. And in this case, the patient presented with relatively large amounts of disease after a relatively short period of time. This is outside of what we would consider the usual outcome, but it’s unfortunately something we do see in about a quarter of patients.
If you look at studies to see what the population outcomes are from frontline therapy, especially ones that have an R0 resection like this patient had, you would have said that it was likely50% or better—that she would have a progression-free survival of 16 to 18 months, maybe even longer. That’s the bell-shaped curve, and so for someone to recur within a 5-month window after completing frontline therapy—especially with no evidence of disease at that time—suggests that the biology of this tumor is somewhat different than those other patients, and that speaks to the slightly unusual aspect of this case.
So, the question is whether or notBRCAmutation would alter the form of therapy. I think the short answer to that is probably not at this point, but it does raise a number of really interesting questions. One of the questions, and I think one of aspects ofBRCAmutation that we have understood before, was why these patients as a population did very well. Their life expectancies were longer, and their responsiveness to platinum was better than what we saw in the general population. For many, there was the thought that maybe platinum sensitivity was a surrogate forBRCAmutation or dysfunction, sothese agents that we’re targeting towards theBRCApatients, the PARP inhibitorswe could use platinum-sensitivity as a surrogate for them.
But here we have the case of a woman who had very good surgery, and she had a relatively short time to develop bulky disease. The sense of whether or not she’s platinum sensitive and whether or not that’s a surrogate for BRCA function probably doesn’t strongly exist in her. It doesn’t necessarily mean that I wouldn’t use itI just probably wouldn’t use it at this point directly. The concept there is that, if the tumor was vulnerable because it had lacked functioningBRCAgenes, we would have expected the frontline setting to be much more positive than it was.
One aspect I think of, in understanding why she didn’t respond as well, goes back to trying to understand what is happening in the microenvironment of that tumor cell that is actually making it not sensitive to the platinum. And so, if she’s not had a lot of exposure to chemotherapy to actually induce what we would be considering, I think of an aspect like reversion mutation in the tumor. So, that’s why I wouldn’t necessarily exclude it; I just probably wouldn’t use it right away. I would tuck that away for a later point, when I might want to use it as a form of therapy.
Transcript edited for clarity.