C. Kent Osborne, MD

Insights From the 2017 San Antonio Breast Cancer Symposium

Question

What role do you see CDK 4/6 inhibition playing in the treatment of triple-negative breast cancer?

Answer

That’s a difficult one. Most of the clinical studies have been done in estrogen receptor (ER)-positive breast cancer for obvious reasons, because the estrogen pathway works in part through the cyclin D1 pathway, and so inhibiting that would make sense for ER-positive tumors.

For ER-negative tumors it is a little less obvious, although growth factor-induced proliferation pathways are active in ER-negative cells. There was a study presented at the 2017 San Antonio Breast Cancer Symposium (SABCS) that indicated CDK4/6 inhibitors inhibited insulin-like growth factor signaling regardless of ER-positive or ER-negative cells, so perhaps that suggests there might be some activity in ER-negative human tumors, although I think that remains to be seen.

Ultimately, I think the jury still out on triple-negative cancers as to what their role might be. There is some rationale, at least, for looking at it.

Question

One study presented at SABCS suggests that venous thromboembolism rates may be much higher among patients treated with a CDK 4/6 inhibitor. Why do you think this is, and might it be preventable?

Answer

Well, first of all, the rates were higher, but it was still a rare event. As I remember from the abstract, it was 1.3% or 1.4% of patients on the experimental arm and 0.4% on the other arm.

You have to remember that patients with metastatic breast and other cancers are more susceptible to venous thromboembolism and other clotting problems because tumors release more thrombogenic substances that probably result in an increased risk, particularly when patients are also on chemotherapy for some reason, so I’m not surprised that there would be an increased risk.

I can’t really explain why it would be higher in the CDK4/6 inhibitor group. It could be by chance, or maybe it has something to do with killing more tumor cells. As tumor cells are being killed or die, they may release more of these thromboplastic, thrombin-generating substances into the blood and maybe that could explain it. But I don’t think it’s a problem clinically so much because it is pretty rare event, even though it might be higher.

Preventing it? Maybe, although I don’t think anyone routinely puts patients on aspirin or one of the other anticoagulants. It would be something to think about, I suppose, but right now it’s not something that is a major problem in treating these patients.

Question

Do any particular studies presented at SABCS suggest which patients are most likely to benefit from CDK 4/6 inhibition?

Answer

I wish there was a biomarker that would predict with accuracy who was going to benefit and who wasn’t. There has been a big search for such a marker and no one has found one yet — but the search continues.

There were some clinical data in some of the studies that predicted a slightly higher chance of response, and those were more aggressive cancers clinically, such as the ER-positive but progesterone receptor-negative tumors, which tend to be more aggressive and have a higher proliferation rates, cancers with visceral liver metastases, and grade 3 tumors — so the more aggressive tumor types seem to have a greater relative benefit than less-aggressive tumors, although all of the groups have some benefit.

So, what we really need is an accurate biomarker. People have looked at the Rb pathway, they’ve looked at cyclin D1 amplification, and they have looked at many other factors and haven’t been able to pinpoint one yet that would give us the answer, but it is an extremely important question given the expense of these drugs. And although patients are relatively symptom-free, there are side effects to them that we need to consider.

There was one study of a single agent, abemaciclib, where it seemed to work even in Rb-negative tumors, which would contradict current thinking, but we still don’t know which tumors are more likely to become resistant, and which tumors are going to be de novo resistant before we start treatment. Those would be really important factors if we had them, but we’re not there yet.

It was suggested, and this was the conclusion of that paper, that abemaciclib may have a somewhat different mechanism of action, in addition to its inhibition of CDK 4/6, and they showed that it inhibits some other kinases, it increases apoptosis whereas some of the others seem to be more cytostatic. So this would suggest that at least one of the currently available CDK 4/6 inhibitors may inhibit other pathways or other kinases as well and gets around the Rb-negative genotype.

Question

Is there any role for CDK 4/6 inhibition in the neoadjuvant setting?

Answer

Not yet. I think it is being explored right now to see if it adds anything or increases the pathologic complete response rate, for instance. But right now I think that there is no use for it as a standard agent in the neoadjuvant setting.

Question

Are any other studies presented at SABCS likely to be practice-changing?

Answer

I think there were several. There was a paper presented addressing the issue of the duration of aromatase inhibitors, which compared 2 years extra beyond 5 years compared with 5 years and 2 was just as good as 5, so that would suggest that at least for aromatase inhibitors, if they are included in the endocrine adjuvant therapy, that maybe going beyond 7 years is not necessary and you can stop at 7.

Similarly, another study looked at the duration of bisphosphonates not just as bone preservation agents but also as adjuvant therapy for breast cancer. The study showed that the duration of 2 years was just as good as 5 years. So again, that would be an important observation that should make its way to the clinic and reduce the side effects of these agents while achieving the same benefit.

Another one was the use of the CDK 4/6 inhibitor, ribociclib, in the premenopausal patient. This was the first such study that I’m aware of using the CDK 4/6 inhibitors in younger patients and it seemed to work if used in the setting of ovarian suppression to make the patient postmenopausal. I think this will be an important change in our practice.

Another one that is sort of offbeat, but which confirms other studies, was about the use of acupuncture for aromatase inhibitor-induced joint stiffness and pain. There already have been a couple of studies looking at that and they have been positive, but there hasn’t been total consistency across studies so it may be somewhat dependent on who is doing the acupuncture and the actual points of acupuncture. This was a very well done study and was beneficial for joint stiffness and pain. These findings would lead me at least to use that technique more than I have been for both joint pain and stiffness. Other studies have also shown that acupuncture can relieve hot flashes in a significant proportion of patients.

The last one was additional work on the use of GnRH analogs in protecting the ovaries of women undergoing chemotherapy, and it does seem to work in a proportion of patients who want to preserve fertility. It offers an additional avenue to take in addition to other ways of fertility preservation in young patients who want to have a family after being treated for their breast cancer. Overall, I believe these are the research studies presented at the SABCS that might be practice changing.