The American Cancer Society reports a 5-year relative survival rate for metastatic BC of 27% based on women diagnosed between 2009 and 2015 [3]. Although patients with HR-positive disease have longer survival, statistics show us that long-term survival for stage IV disease is quite uncommon [4]. Here we report an unusual patient with a more than 9-year survival after being diagnosed with bone metastasis from primary right-sided BC, who later developed liver metastases and a non-Hodgkin lymphoma that had to be treated with bendamustine and rituximab.
The use of multiple lines of HT before resorting to chemotherapy in patients with HR-positive and HER2-negative advanced disease is recommended by National Comprehensive Cancer Network (NCCN) and European School of Oncology (ESO)-European Society of Medical Oncology (ESMO) current treatment guidelines for breast cancer [5, 6]. After failure of three lines of HT, multiple lines of systemic therapy can be used to palliate BC considering risks and benefits [6].
CDK4/6i (abemaciclib, palbociclib and ribociclib) are typically employed and have the best efficacy if given in the front-line therapy in patients with HR-positive, HER-negative BC. Literature has demonstrated that patients who received CDK4/6i plus HT versus HT alone as the first-line setting had longer progression-free survival, but they were not available when our patient presented in 2010 [7,8,9,10]. Palbociclib plus letrozole was her 6th line of therapy.
Abemaciclib is the only CDK4/6i approved for single-agent use in the subsequent-line therapy of metastatic HR-positive and HER2-negative BC [11]. However, NCCN Clinical Practice Guidelines and 4th ESO-ESMO International Consensus Guidelines for BC state that a second-line CDK4/6i should not be tried after failure of the first-line use of these agents due to lack of data supporting this practice. Since our patient maintained a good performance status and desired more therapy after four HT regimens, including letrozole and palbociclib, and more than five chemotherapy regimens, it seemed reasonable to try abemaciclib due to lack of other good options and a significant interval since prior exposure to a CDK4/6 inhibitor. Since the patient started this therapy, additional data emerged from multiple institutions indicating activity of abemaciclib after failure of palbociclib in a prior line of therapy [12,13,14,15] as summarized in Table 2. The purpose of this report is to raise awareness about this option and to allude to this lack of complete cross-resistance between the two CDK4/6 inhibitors.
Table 2 Systematic literature search of abemaciclib post-palbociclib therapy in BC patients After 10 lines of therapy, our patient had a good response with abemaciclib alone, remaining on this treatment for almost 16 months, while palbociclib plus HT had controlled her disease for only 5 months.
Mariotti et al. described metastatic BC patients who responded to abemaciclib after previous exposure to palbociclib. They reported 19 patients who received a mean of 5.6 prior therapies, including palbociclib plus HT (fulvestrant or letrozole), before trying abemaciclib in combination with HR or as a single agent. Four cases (21%) had longer progression-free survival (PFS) on abemaciclib compared to prior palbociclib PFS, and although no partial or complete response was observed, 33% had stable disease [15].
Evidence for giving abemaciclib as a single agent in subsequent lines of therapy of refractory HR-positive and HER2-negative metastatic BC is found in the MONARCH 1 trial [11]. Abemaciclib demonstrated positive anti-tumor activity in 26 patients of a total of 132 who previously progressed on or after HT and chemotherapy. MONARCH 1 excluded patients previously treated with CDK4/6i; however, our patient was previously exposed to palbociclib and progressed on it, but she still had good clinical benefit from abemaciclib. Additionally, we administered more than five chemotherapy regimens in the metastatic setting in our patient, while MONARCH 1 administered no more than two lines of chemotherapy during metastatic disease.
It is important to discuss why our patient might have responded to abemaciclib despite failing palbociclib. There are some structural differences between abemaciclib and the other two CDK4/6i, palbociclib and ribociclib. Besides being considered agents from the same drug class, it is known that abemaciclib has greater selectivity for CDK4 than for CDK6 and that it can inhibit other kinases which are not inhibited by the other two CDK4/6i, such as CDK9/7/2/1, GSK3α/β and CAMK2γ/δ. It is suggested that inhibition of these kinases by abemaciclib overcomes known mechanisms of resistance to CDK4/6 inhibition. Moreover, these agents have some differences in pharmacokinetics. Abemaciclib has the ability to induce cell death and apoptosis and arrest in the G2 phase of the cell cycle, and it is the most effective inhibitor of CDK4/6. Nonetheless, the three agents seem to have similar anti-tumor activity [16].
Navarro-Yepes et al. suggested a differential mechanism of resistance to abemaciclib versus palbociclib. Western blot analysis revealed dose-dependent downregulation of ERα, Rb, p-Rb and p27 in palbociclib-resistant cells, which were only partially cross-resistant to abemaciclib. Also, a key mediator of DNA repair (Rad51) was downregulated only in abemaciclib-resistant cells. The authors examined the combination of abemaciclib plus niraparib, a PARP inhibitor, in organoid cultures created from patient-derived xenograft (PDX) models with surrogate palbociclib-resistance cells, and found significantly reduced viability, number and density of these organoids. In vivo, with the same PDX models, the treatment reduced the rate of tumor growth and increased survival [17].
Among metastatic BC patients, there are clearly some exceptional cases, such as this patient who remained fully functional and a productive member of society, that deserve consideration from their providers. Besides the heavy treatment with chemotherapy regimens and the previous exposure to another CDK4/6i, abemaciclib showed a 16-month response and 11-month longer PFS than palbociclib-based therapy. This lack of complete cross-resistance between these two CDK4/6i should be better investigated.
The US Food and Drug Administration approved the first CDK4/6i, palbociclib, less than 5 years ago, and now we see ongoing trials to find more uses for these agents [18]. There are some ongoing studies that will generate prospective data regarding response to CDK4/6i after failure in a prior line of therapy. The MAINTAIN trial (NCT02632045) will investigate whether there is continued benefit for remaining on a CDK4/6i at the time of switching to anti-estrogen therapy in a randomized open-label trial [19]. Another study, a phase II trial with 100 participants in a single group assignment, will determine the role of continuing palbociclib treatment in combination with another type of HT (fulvestrant) after disease progression with palbociclib plus an aromatase inhibitor (NCT02738866) [20].
Investigations into the use of CDK4/6i with novel drugs can also be found. The TRINITI-1 study (NCT02732119), a single-arm open-label trial, is looking to determine whether ribociclib in combination with everolimus and exemestane is effective in treating men and postmenopausal women with HR+, HER2– locally advanced or metastatic BC following progression on a CDK4/6i [21]. Initial results of TRINITI-1 were already presented, and it achieved its primary efficacy end point with clinical benefit and tolerability [22]. The PACE trial (NCT03147287) is a phase II research study which is recruiting patients with metastatic HR-positive HER2-negative BC to evaluate the activity of fulvestrant alone, fulvestrant and palbociclib, or fulvestrant, palbociclib and avelumab combined, in participants who previously stopped responding to prior palbociclib and HT. Trials are ongoing and results are expected [23].