Genomic Assays Continue to Individualize Treatment for HR+ Breast Cancer

Sayeh Lavasani, MD, MS

Genomic assays are painting a clearer picture of which patients with hormone receptor (HR)—positive breast cancer can receive endocrine therapy alone or do require the addition of chemotherapy, said Sayeh Lavasani, MD, MS.

For example, in the pivotal TAILORx trial, patients were stratified by risk using the Oncotype DX assay, which is a 21-gene assay. Patients in the low-risk group received endocrine therapy alone while patients in the high-risk group received endocrine therapy and chemotherapy, and patients in the intermediate-risk group were randomized to either approach. At a median follow-up of 7.5 years, the use of endocrine therapy alone was deemed noninferior to endocrine therapy and chemotherapy in terms of invasive disease-free survival (iDFS; HR, 1.08; 95% CI, 0.94-1.24; P = .26).¹

Additionally, the MINDACT trial utilized the 70-gene MammaPrint assay to demonstrate the noninferiority of endocrine therapy alone in patients who were considered clinically high risk but genomically low risk. Results did not show an improvement in iDFS with the combination of chemotherapy and endocrine therapy (HR, 0.78; 95% CI, 0.50-1.21; P = .27).²

Lavasani, an assistant professor of clinical medicine in the Department of Medical Oncology and Therapeutic Research at City of Hope, said that unanswered questions still remain in this space, particularly with how to treat node-positive patients. The upcoming results of the RxPONDER study (NCT01272037), which looked at patients with an Oncotype DX score of <25 and 1 to 3 positive lymph nodes, will look to address this challenge.

In an interview during the 2019 OncLive^® State of the Science Summit™ on Breast Cancer, Lavasani discussed the application of gene assays in the management of patients with HR-positive breast cancer, as well as ongoing research in this space.

OncLive: What are the key genomic assays being used in this space?

Lavasani: [There is] genomic profiling, which includes Oncotype DX and MammaPrint assays. [In my presentation], I focused on the Oncotype DX 21-gene assay and the update of the TAILORx study that was reported at the 2018 ASCO Annual Meeting and published in the New England Journal of Medicine. That showed that patients with an Oncotype DX recurrence score of 11 to 25, they were randomized to receive endocrine therapy with or without chemotherapy. The outcome for both groups was the same. iDFS was the primary endpoint, and there was no difference in iDFS in either group.

For patients younger than age 50, they did slightly better with chemotherapy if their Oncotype DX score was 21 to 25. In patients with an Oncotype DX score of 16 to 20, there was a slight improvement with chemotherapy. However, in general, the study did not show any benefit with adding chemotherapy to this patient population.

The MINDACT study was a randomized, controlled trial on MammaPrint testing. These were patients who were clinically high risk, but genomically low risk. The MammaPrint, or 70-gene assay, did not show increased risk in this patient population, and they were randomized to receive endocrine therapy with or without chemotherapy. The results of this study did not show any improvement in outcome for patients who received chemotherapy. Therefore, this would change the recommendation for almost 50% of patients because they fall into the category of high clinical risk and low genomic risk. We can avoid chemotherapy in these patients. The MINDACT study included node-positive patients as well.

Based on the results of these trials, what unanswered questions remain?

There are definitely questions that need to be answered. For node-positive patients, we still don't know what to do regarding Oncotype DX. We do have some retrospective data that support doing Oncotype DX in patients who have 1 to 3 positive lymph nodes, but we are waiting for the results of the RxPONDER study. That is for patients who have an Oncotype DX score of <25, and they were randomized to receive endocrine therapy with or without chemotherapy. We don't yet have the data for this study.

Are Oncotype DX and MammaPrint the only available assays in this space?

We have multiple other assays available in the market, such as EndoPredict, PAM50 (Prosigna), and Breast Cancer Index (BCI). These assays are all mentioned under the National Comprehensive Cancer Network (NCCN) guidelines, but Oncotype DX is actually endorsed by the NCCN. Both Oncotype DX and MammaPrint have category 1 evidence behind them. For BCI, it can predict a late recurrence for patients with breast cancer, so its purpose is a bit different.

For patients who still benefit from chemotherapy, have any de-escalation approaches been studied?

De-escalation involves looking at these genomic tests and deciding whether patients need adjuvant chemotherapy or not. For HR-positive, HER2-negative patients, if we decide they need chemotherapy based on these assays, we basically use [standard] chemotherapy for them. If they are low risk, we can avoid giving unnecessary chemotherapy to a lot of patients by utilizing these genomic assays.

Is there discrepancy between the chemotherapy regimens utilized across practices?

It is a pretty gray area overall for HR-positive patients. If they have more than 3 positive lymph nodes, [data have] shown that patients would benefit from an anthracycline-based approach. Usually our standard approach is dose-dense [doxorubicin and cyclophosphamide followed by paclitaxel], but for patients whose Oncotype DX score is not super high, we can definitely use a combination of docetaxel and cyclophosphamide.

What else from your presentation would you like to add?

I also spoke about the use of adjuvant chemotherapy, [administering] 10 years of tamoxifen versus 5 years, and the multiple studies looking at 10 years of aromatase inhibitors (AIs) or extending AI for 5 more years. There is, of course, the risk versus benefit of doing this with the AI, so that will be a big topic of conversation. There is also the topic of adding bone-targeted agents for postmenopausal patients with HR-positive disease, just to reduce the risk of recurrence.

What patients need from extended therapy?

The patient population that will benefit from extended AI are the node-positive patients. ASCO updated the guideline for adjuvant endocrine therapy about 6 months ago. That is the recommendation for patients who are node-positive: they should definitely consider these patients for 10 years of AI or overall extended AI. For patients overall, when we extend AI for 5 more years, we are definitely seeing the risk of developing new breast cancer and contralateral breast cancer. This has been reported in recent studies. This is very important because [we want to avoid the risk of developing new breast cancer].

How beneficial are bone-targeted agents in practice?

At City of Hope, we are definitely using bone-targeted agents in postmenopausal patients who are HR-positive, especially if they have osteopenia or osteoporosis. Even without having any bone condition or bone loss, if they are going on an AI, we usually consider them for zoledronic acid. We give this therapy every 6 months for up to 3 years. Of course, denosumab (Xgeva) is an alternative for this setting.

References

1. Sparano JA, Gray RJ, Makower DF, et al. Adjuvant chemotherapy guided by a 21-gene expression assay in breast cancer. N Engl J Med. 2018;379(2):111-121. doi: 10.1056/NEJMoa1804710.
2. Cardoso F, van't Veer LJ, Bogaerts J, et al. 70-Gene signature as an aid to treatment decisions in early-stage breast cancer. N Engl J Med. 2016;375:717-729. doi: 10.1056/NEJMoa1602253.