Breaking Down CDK4/6 Resistance in ER+/ HER2- Breast Cancer

Nicholas C. Turner, MD, PhD

Multiple pivotal studies have led to CDK4/6 inhibitors such as ribociclib (Kisqali), abemaciclib (Verzenio), and palbociclib (Ibrance) becoming the standard of care for women with metastatic ER-positive/HER2-negative breast cancer. But these agents aren’t effective in all patients, said Nicholas C. Turner, MD, PhD.

Speaking at the 11th European Breast Cancer Conference in Barcelona, Spain, Turner, a consultant medical oncologist with The Royal Marsden Hospital NHS Trust, explained how tumors resist treatment with CDK4/6 inhibitors and how that resistance can be overcome.¹

“We’ve learned a lot about what can drive resistance to CDK4/6 inhibitors, which by themselves block progression from G1 through to S phase. But both estrogen receptor signaling and alternative cyclin-dependent kinases can both promote G1/S entry despite CDK4/6 inhibition,” he said. “We can therefore augment CDK4/6 inhibitors by combining [them] with endocrine therapy, but also, potentially, by targeting other cyclin-dependent kinases by [in turn] targeting the key signal transduction pathways that are important in the cell.

“In ER-positive breast cancer, of course, we know that the PI3K/mTOR pathway is critical, and that augments the efficacy of CDK4/6 inhibitors, leading to much more durable cell-cycle arrest.”

INTRINSIC RESISTANCE

Intrinsic resistance is a function of incomplete cell cycle arrest, which occurs when CDK4/6 inhibitors are administered alone rather than in combination with endocrine therapy, Turner explained.

He said that cyclin-dependent kinases 4 and 6 and cyclin D1, which activates these kinases, are critical to the growth of ER-positive breast cancer. ER-positive disease is dependent on cyclin D1, and amplification promotes the expression of cyclin D1 in about 20% of ER-positive breast cancers. Cyclin D1 is also one of the key targets of the estrogen receptor itself, promoting activation of CDK4 and CDK6.

“You get some rescue of the effects of inhibiting CDK4/6 by another cyclin dependent kinase, [CDK2], and this can be partially activated by cyclin D1,” he said. “If you then combine endocrine therapies with CDK4/6 inhibitors, you get a much more substantial effect.”

Turner added that endocrine therapy itself blocks the expression of cyclin D1, which enhances the efficacy of CDK4/6 by blocking this partial effect that cyclin D1 can activate CDK2.

“When we’re using a CDK4/6 inhibitor, we should be combining it with an effective endocrine therapy to maximize the effect of endocrine therapies,” he said.

The effect of CDK2 will not be significant for most patients with ER-positive cancers, according to Turner.

He pointed to results from the phase II neoMONARCH trial, which showed that neoadjuvant abemaciclib (Verzenio) in combination with anastrozole induced complete cell cycle arrest, as measured by Ki-67, for 67.8% of patients with HR-positive/ HER2-negative early stage breast cancer.²

Complete cell cycle arrest, which was defined as a Ki-67 index of <2.7% at 2 weeks, was the primary endpoint of the study. For those treated with abemaciclib alone, 57.7% of patients achieved cell cycle arrest compared with 14.3% for anastrozole alone.

&ldquo;In the majority of patients, their tumors start off very sensitive to these combinations of endocrine therapy and CDK4/6 inhibition,&rdquo; he said. &ldquo;The majority of tumors show a substantial drop in proliferation when you use this combination.&rdquo;

The abemaciclib combination yielded a geometric mean change in Ki-67 from baseline to day 15 of —92.86%. For abemaciclib alone, there was a 90.52% reduction. With anastrozole alone, there was a mean geometric reduction of 62.78%. For the combination versus abemaciclib or anastrozole alone, there was a geometric mean ratio of 0.19 (90% CI, 0.13-0.28;P<.001).

Turner added that there is a small number of ER-positive/ HER2-negative breast cancers that appear to have intrinsic resistance to these combinations, but investigators do not yet know definitively what biological factors might be driving those tumors.

A phase II study of palbociclib and anastrozole for patients with stage II/III ER-positive breast cancer found that patients who demonstrated resistance to both treatments of the combination were found to have high expression of cyclin E1 and CDKN2D, of the P16 family, in their tumors.³However, the sample size in the study was small, and larger studies are needed to validate these findings.

Turner is looking forward to further trial results due later this year that might provide insight to the mechanism of resistance.

ACQUIRED RESISTANCE

Clinical evidence looking at acquired resistance to CDK4/6 inhibitors is slim, but Turner said that more trial results will be coming later this year. At present, preclinical evidence, mostly from cell lines and patient-derived xenograft models, is more robust.

When his lab took ER-positive breast cancer cells lines and made them resistant to CDK4/6 inhibitors, investigators found that some cell lines lost RB1, the main target of CDK4/6. Others, however, acquired very high expression of cyclin E1, the cyclin that activates CDK2. In this cell line, the tumor acquired amplification of cyclin E1 as a driver of resistance to CDK4/6 inhibitors.⁴

Similar findings were noted with the use of patient-derived xenografts of ER-positive breast cancer. The tumors initially responded well to treatment with ribociclib before developing acquired resistance, Turner said.

Many of these tumors demonstrated RB1 loss. Other models showed the tumor acquiring inactivating RB1 mutations at progression, making the tumor intrinsically resistant to CDK4/6 inhibition. Turner said that this process appears to be relatively rare in patients. Future study results should help to clarify how often these mutations occur at progression.

Overexpression of CDK6 has also been implicated as a driver of acquired resistance to CDK4/6 inhibition, as it is a target of these agents. In a study of cell line models that were exposed to abemaciclib, the investigators found that cell lines that had amplification of CDK6 showed an increase in CDK6 expression and were not as responsive to CDK4/6 inhibition.⁵

OVERCOMING RESISTANCE

Results from previous studies suggest that PI3 kinase inhibitors may be the key to overcoming resistance to CDK4/6 inhibitors.

Turner noted that PI3 kinase inhibitors have demonstrated synergy in several studies with CDK4/6 inhibitors.⁴Findings from a 2014 study published in Cancer Cell, for instance, showed that inPIK3CA-mutated breast cancers, the combination of ribociclib and the alpha-specific PI3K inhibitor alpelisib (BYL719) improved initial responses and overcame acquired resistance.⁶

However, he added that &ldquo;the triplet of combining endocrine therapy, CDK4/6, and PI3 kinase inhibitors is more effective than any of the doublets in the lab.&rdquo;

Triplet therapy has the added advantage of preventing acquired resistance. Results from a study performed in Turner&rsquo;s lab with xenograft models showed that in a tumor that progressed after initially responding to ribociclib, administering a PI3 kinase inhibitor induced more durable complete responses.

&ldquo;The challenges with these inhibitors is they&rsquo;re difficult to take to the clinic. These combinations are challenged by toxicity in the clinic,&rdquo; Turner went on to say. &ldquo;We&rsquo;re going to wait to see, from the phase II studies, [if] some tolerable, effective combinations come out."

References:

1. Turner N. Resistance to CDK4/6 inhibitors. Presented at: the 2018 European Breast Cancer Conference; March 21-23, 2018; Barcelona, Spain.
2. Martin M, Hurvitz SA, Chan D, et al. Final results of neoMONARCH: a phase 2 neoadjuvant study of abemaciclib in postmenopausal women with hormone receptor positive (HR+), HER2 negative breast cancer (BC). Presented at: the 2017 San Antonio Breast Cancer Symposium; Dec. 5-9, 2017. Abstract PD5-01. sabcs.org/Portals/SABCS2016/Documents/SABCS-2017-Abstracts.pdf.
3. Ma CX, Gao F, Luo J, et al. NeoPalAna: neoadjuvant palbociclib, a cyclin-dependent kinase 4/6 inhibitor, and anastrozole for clinical stage 2 or 3 estrogen receptor-positive breast cancer.Clin Cancer Res.2017;23(15):4055-4065. doi: 10.1158/1078-0432. CCR-16-3206.
4. Herrera-Abreu MT, Palafox M, Asghar U, et al. Early adaptation and acquired resistance to CDK4/6 inhibition in estrogen receptor-positive breast cancer [erratum in Cancer Res. 2016;76(19):5907].Cancer Res.2016;76(8):2301-2313. doi: 10.1158/0008- 5472.CAN-15-0728.
5. Yang C, Li Z, Bhatt T, et al. Acquired CDK6 amplification promotes breast cancer resistance to CDK4/6 inhibitors and loss of ER signaling and dependence.Oncogene.2017;36(16):2255-2264. doi: 10.1038/onc.2016.379.
6. Vora SR, Juric D, Kim N, et al. CDK 4/6 inhibitors sensitize PIK3CA mutant breast cancer to PI3K inhibitors.Cancer Cell.14;26(1):136-49. doi: 10.1016/j.ccr.2014.05.020.