CDK4/6 Inhibitors & Endocrine Therapy in Breast Cancer

Sara M. Tolaney, MD, MPH:This particular patient presented with asymptomatic metastatic disease. Although she did have visceral involvement with lung metastases, again, she was not symptomatic. And so, in this type of patient I do think using endocrine therapy with a CDK4/6 inhibitor would be a good decision and would certainly spare this patient chemotherapy-related toxicities.

I think there has been a change in our approach to treatment of patients now with metastatic hormone receptor—positive disease. In the past, when patients presented with visceral involvement, many oncologists would turn to chemotherapy up front. However, now that we’ve seen the very impressive progression-free survival seen by adding a CDK4/6 inhibitor to endocrine therapy, we see that these patients actually have a progression-free survival of around 24 to 28 months in the first-line setting, which is much longer than we typically see with chemotherapy up front.

We also see that these patients can achieve objective responses as high as 50% to 60% in the first-line setting, which again is higher than we typically see with chemotherapy. So I think it is important to try to use endocrine therapy and a CDK4/6 inhibitor as much as we can up front and really save chemotherapy for those patients who may have impending visceral crisis. For example, for a patient who may present with significantly elevated liver function tests or quadrant pain, those are patients for whom you may feel more comfortable using chemotherapy up front. But certainly, in a patient like this who’s asymptomatic, I think endocrine therapy with the CDK4/6 inhibitor is a good choice.

There are certainly a lot of factors that we need to take into account when making treatment decisions. And for a lot of these, I think oncologists just kind of have them in the back of their mind. Certainly looking at time from initial presentation to recurrence is an important factor. We know that those patients who recur many years after their original cancer often do better than those patients who recur soon after their initial presentation.

We know that patients who have higher-grade tumors also tend to have a worse prognosis than those with lower-grade tumors. Certainly those patients with visceral involvement also tend to have worse outcomes than those without visceral involvement. So I think we’re playing all these factors in when making a treatment decision. Certainly we’re also factoring in how sensitive we think this patient will be to endocrine therapy. Is this a patient who relapsed within a year of being on adjuvant endocrine treatment? Or is this a patient who seemed to have endocrine-sensitive disease and recurred after discontinuation of endocrine therapy years later? And so I think one has to factor all these things into account when deciding treatment approaches.

We do know that adding CDK4/6 inhibitors to endocrine therapy is associated with a progression-free survival advantage, with almost all trials in the first-line setting showing hazard ratios of about 0.55 very consistently. So we do know it will keep their disease controlled for longer. What we don’t know is whether or not there’s an overall survival benefit to using a CDK4/6 inhibitor in the first-line setting.

We do have data from PALOMA-3 that did look at survival in the second-line setting, and we did find that, overall, there was a trend toward survival advantage in the overall population. That was about a 7-month difference in overall survival. But very interestingly, when they looked at those patients with endocrine-sensitive disease—so those patients, for example, who did not recur within their first 2 years of being on adjuvant endocrine therapy or patients who at least were on first-line therapy in the metastatic setting for over 6 months—those endocrine-sensitive patients did have a statistically significant improvement in overall survival with a difference of about 10 months. So I think we’re learning that these agents really do change the natural history of metastatic ER [estrogen receptor]—positive disease. I think we’re all eagerly awaiting the survival data in the first-line setting, many of us thinking it may be positive. So I think there is a clear advantage to using these agents.

Transcript edited for clarity.

Case: A 58-Year-Old Woman With Metastatic ER+ Ductal Carcinoma

• 58-year-old woman with estrogen-receptor-positive (ER+), progesterone-receptor-negative (PR-), HER2-negative (HER2-) invasive ductal carcinoma (IDC) of L breast; she completed adjuvant anastrozole for 5 years
• Now, 13 months later, she presents with 4 small (<1.0 cm) asymptomatic lesions in the left lung and mediastinal and hilar lymphadenopathy.
• Mediastinoscopy was performed and confirmed ER+ PR- Her2- carcinoma
• ECOG PS: 0
• The patient was started on abemaciclib + fulvestrant