Genomics Guide Treatment Escalation, De-Escalation in HR+ Breast Cancer

Stephanie L. Graff, MD

Based on the findings from the MINDACT trial, MammaPrint, which is an assay created to collectively assess 70 genes, was successfully shown to select women at a low risk of recurrence who may not benefit from adjuvant chemotherapy—specifically, those with low-volume, low-grade, and well-differentiated disease.¹

These findings were echoed in the phase III TAILORx trial, in which women with early-stage, HR-positive/HER2-negative breast cancer and an intermediate Oncotype DX Breast Recurrence Score were able to forgo chemoendocrine therapy and opt for endocrine therapy alone without compromising outcomes.²

However, Graff explained that not all patients are able to pursue de-escalated approaches and cautioned that those with extended nodal involvement still require intensive chemotherapy regimens, and potentially extended adjuvant endocrine therapy.

“The question now is whether moving [CDK4/6 inhibitors] earlier can help decrease the risk of a metastatic recurrence for someone with a high-risk, locally advanced breast cancer,” said Graff. “All 3 agents available to use right now—palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio)—are in trials in the adjuvant space for patients with high-risk breast cancer.”

OncLive: What is known about escalation and de-escalation in early-stage, HR-positive breast cancer?

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, Graff, director, Breast Program, Sarah Cannon Cancer Institute, associate director, Breast Cancer Research Program, Sarah Cannon Research Institute, discussed these data surrounding escalation and de-escalation in patients with early-stage, HR-positive breast cancer.Graff: Over the last couple of years, we've received a couple of updates. One came from the TAILORx trial, which showed that not all women in that population need chemotherapy. And, with genomic profiling, there's an opportunity to better select those who would benefit from chemotherapy and those who can safely avoid the toxicity of added treatment.

Following the success seen with CDK4/6 inhibitors in the metastatic setting, is there a rationale to explore them in the adjuvant space?

How are CDK4/6 inhibitors being explored in the neoadjuvant setting?

Which patients are not eligible for de-escalation approaches?

Are there other agents being explored in the neoadjuvant or adjuvant settings?

We have also had many updates on who needs extended adjuvant endocrine therapy beyond the 5-year mark. The takeaway from the extended adjuvant endocrine therapy discussion is that it needs to be a personalized decision for each patient and each physician, based on the stage of disease and other profiles that can help us predict who needs to stay on those medications.CDK4/6 inhibitors have shown great promise in the metastatic setting with a median duration of response of 22 to 24 months. All of the trials [examining them in the adjuvant setting] have nuances in how they're defining a high-risk population. For example, the monarchE study is looking at abemaciclib and incorporating Ki-67 in that population; this trial also has a separate cohort that’s just for patients with node-positive disease. A trial with ribociclib is about to open and is going to look at patients with HR-positive, lymph node—positive breast cancer as well. It will be interesting to then try to compare those studies and figure out which patient is a good candidate for which drug.CDK4/6 inhibitors have been looked at in the neoadjuvant setting to try to predict responsiveness. That hasn't become a mainstream approach for several different reasons, but we did get some great corollary science out of those trials to help us better understand who the patients are that respond. It [gives us] another opportunity to look at those patients who are very clear responders to CDK4/6 inhibitors in the neoadjuvant setting. Then, we can try to produce a genomic signature that could select who should get them in that setting and be spared chemotherapy. Certainly, [this holds true] if the results of the adjuvant CDK4/6 inhibitors trials are positive.The patients who we do not have the opportunity to de-escalate therapy in at this point are those with biologically aggressive cancers. It remains a question of how to best define those. We know from MINDACT and TAILORx that there are genomic profiles that can help select those patients. All of the trials that are done in the lymph node—positive space, even trials like RxPONDER—which we’re still waiting to see results of—are selecting women with what we consider low-volume, lymph node–positive breast cancer. These are women with 1 to 3 positive lymph nodes. At this point, women with HR-positive breast cancer who have 4 or more lymph nodes still need that chemotherapy backbone, even an aggressive chemotherapy backbone with an anthracycline.Immunotherapy is undergoing early evaluation in the neoadjuvant and adjuvant settings. We haven't classically considered HR-positive breast cancer to be a very immunogenic cancer. All of these trials have different chemotherapy backbones to try to produce immunogenicity in those tumors and achieve a better response to immunotherapy. We'll have to see what the most successful platform is. They're all very small volume trials that are trying to build that immunogenicity model, so that we understand what to bring forward into phase III trials.

References

1. Cardoso F, van’t Veer LJ, Bogaerts J, et al. 70-gene signature as an aid to treat- ment decisions in early-stage breast cancer. N Engl J Med. 2016;375(8):717-729. doi: 10.1056/NEJMoa1602253.
2. Sparano JA, Gray RJ, Wood WC, et al. TAILORx: phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-neg- ative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score. J Clin Oncol. 2018;36 (18 suppl; abstr LBA1). doi: 10.1200/ JCO.2018.36.18_suppl.LBA1.

A greater understanding of the genomics of patients with hormone receptor (HR)—positive breast cancer is enabling physicians to offer more personalized de-escalated and escalated treatment strategies for those with lower-risk disease or at a high risk of recurrence, explained Stephanie L. Graff, MD.