HR+ Breast Cancer Studies Explore Escalation, De-Escalation Strategies

Stephanie L. Graff, MD

Recent studies have demonstrated that escalation and de-escalation approaches, with chemotherapy, endocrine therapy, and CDK4/6 inhibitors, are areas of research moving to the forefront in hormone receptor (HR)—positive breast cancer, explained Stephanie L. Graff, MD.

For example, data from the phase III TAILORx trial demonstrated that adjuvant endocrine therapy had noninferior outcomes compared with adjuvant chemoendocrine therapy in patients with HR-positive/HER2-negative, node-negative early-stage breast cancer who have an intermediate risk of distant recurrence based on their Oncotype DX Breast Recurrence Score (HR, 1.08; 95% CI, 0.94-1.24; P = .26).¹

More recently, at the 2018 San Antonio Breast Cancer Symposium (SABCS), results were presented for the phase III TAM-01 trial, which examined the efficacy of low-dose tamoxifen at 5 mg versus placebo in patients with atypical ductal carcinoma (ADH), lobular carcinoma in situ (LCIS), and estrogen receptor (ER)—positive or ductal carcinoma in situ (DCIS) of unknown origin. Data showed that the addition of low-dose tamoxifen significantly reduced the risk of new and recurrent disease after surgery.²

Additionally, the CDK4/6 inhibitors abemaciclib (Verzenio), ribociclib (Kisqali), and palbociclib (Ibrance), which are all approved by the FDA in the metastatic breast cancer setting, are now being evaluated in the high-risk adjuvant setting in the monarchE (NCT03155997), NATALEE (NCT03701334), and PALLAS (NCT02513394) studies, respectively.

“There are a lot of interesting opportunities around the idea of escalation and de-escalation of care,” said Graff, director of the Breast Program at the Sarah Cannon Cancer Institute of HCA Midwest Health, and associate director of the Breast Cancer Research Program at Sarah Cannon Research Institute.

OncLive: What are the updates in escalation and de-escalation of care for patients with HR-positive breast cancer?

In an interview during the 2019 OncLive^® State of the Science Summit^TM on Breast Cancer, Graff discussed the latest updates on escalation and de-escalation of therapy in patients with HR-positive breast cancer.Graff: On the heels of the TAILORx trial, which we saw at the 2018 ASCO Annual Meeting, we saw that a lot of women won’t need chemotherapy to treat their breast cancer—which is a huge opportunity for us to de-escalate care. That is also going on in the background with lots of discussion around what the right length of adjuvant endocrine therapy is. Should we take it for 5 years? Should we take it for 2 years? Does it matter if patients receive 10 years of an aromatase inhibitor (AI) or 5 years of tamoxifen followed by 5 years of an AI? There is a lot of interesting thought happening.

Were there any updates from the 2018 SABCS related to these strategies?

What factors are you looking at to determine the optimal dosage and length of treatment for a patient with DCIS?

Then, there are some emerging clinical trials of the CDK4/6 inhibitors in the adjuvant setting for patients with locally advanced HR-positive breast cancer. We are moving those drugs out of the metastatic setting and into the earlier-stage setting.One of the things that really interested me at the 2018 SABCS was data looking at the use of tamoxifen for women with DCIS or the higher-risk, precancerous lesions—such as LCIS or atypical ductal hyperplasia. It asks the question of tamoxifen at 5 mg versus no therapy; again, this was almost a prevention sort of thing. The standard dose of tamoxifen has been 20 mg, but we know this comes with a lot of side effects that can be kind of scary, such as thromboembolic disease and uterine carcinoma. Looking at this 5 mg dose, we saw a big benefit compared with nothing. It gives us, again, an opportunity to de-escalate where something is better than nothing, in those patients with stage 0 DCIS who perhaps are worried about side effects. This gives us a real opportunity to still offer something.All sorts of things are going to factor into our decision around what the right dose of tamoxifen is for women with DCIS. Of course, the trial was not randomized to the standard dose versus 5 mg; it was 5 mg versus nothing. Often in DCIS, we'll now use the AIs, which we know are a little bit better than tamoxifen.

Could you expand on the research with CDK4/6 inhibitors in the adjuvant setting?

What other therapies are being explored in this setting?

Looking back at the TAILORx trial, are there any unanswered questions that remain from those data?

Therefore, there are a lot of questions. You are looking at the patient’s age, what symptoms or adverse events (AEs) they have on this medication, what other health factors they have that increase their risks of having AEs, and the features of their DCIS—its grade, how it was managed surgically, and whether or not [they received] radiation. You’re using all of that to formulate the best strategy.We know that those drugs make a huge difference in the metastatic setting for women with HR-positive breast cancer in combination with an AI or fulvestrant (Faslodex). Therefore, all of the trials are looking at CDK4/6 inhibitors in combination with an AI for women with high-risk, HR-positive breast cancer. It is mostly [being] looking at in large tumors or lymph node—positive tumors. All of the trials are looking at abemaciclib, palbociclib, and ribociclib for about 2 years followed by the full 5 to 10 years of an AI. We will look to see if it decreases recurrence in those patients and ultimately survival.There are a lot of looks at checkpoint inhibitors, but those are largely reserved in the triple-negative breast cancer space. There is some early work being done in HER2-positive breast cancer. We haven’t seen the checkpoint inhibitors move into the HR-positive space; it is a little bit less immune mediated and less immune structured to the cancer cells themselves. We will see if that’s something that emerges on the horizon.TAILORx was really practice-affirming for me. Most medical oncologists in this country are using a threshold of around 25 to determine chemotherapy versus no chemotherapy, but what helped solidify is that younger women may have a higher risk. We saw that, in younger women under the age of 50, the cutoff of 25 is a little bit fuzzier and there is room to drop that line down in the younger population.

One of the big questions that arose out of TAILORx, for me, is around the issue of escalation and de-escalation. We saw that patients with scores of over 25, despite the fact that everyone with a score of over 25 in that trial received chemotherapy, still had a 13% risk of cancer recurrence at 5 to 9 years. This tells us that chemotherapy plus endocrine therapy in those high-risk scores are not enough; those are the patients for whom I’m thinking more about the CDK4/6 inhibitor adjuvant trials that are ongoing.

What do you hope the field will achieve by the end of 2019?

The other question is that, because 25 was such a “black and white line” for women over the age of 50, it makes you wonder about the [patients with] 26 to 31 [scores]. It may be that, for older women, there is room to hedge that line farther up. Again, we would need some prospective randomized data to look at that or some deeper analysis, but it raises the question about if that needs to be such a black and white line for older women, particularly the elderly.Looking though the horizon for 2019, we are waiting on the RxPONDER trial, which is looking at the 21-Gene Recurrence Score in lymph node—positive breast cancer. There is increasing evidence that the genomic profiles continue to have a role in lymph node–positive breast cancer that biology matters just as much as stage, so we're anxiously awaiting those results.

We are continuing to see more and more data emerge for immunotherapy across all subtypes of breast cancer. As a breast oncologist, I feel that we’re a little bit late to the immunotherapy “party.” Therefore, I’m excited to see more and more of that arsenal that we use in breast cancer treatment. There is a lot that I am excited about with the CDK4/6 inhibitors in the adjuvant setting, as those are moving forward for those high-risk, ER-positive breast cancers.

References

1. Sparano JA, Gray RJ, Wood WC, et al. TAILORx: phase III trial of chemoendocrine therapy versus endocrine therapy alone in hormone receptor-positive, HER2-negative, node-negative breast cancer and an intermediate prognosis 21-gene recurrence score. J Clin Oncol. 2018;36(suppl; abstr LBA1). doi: 10.1200/JCO.2018.36.18_suppl.LBA1?af=R.
2. De Censi A, Puntoni M, Gonzaga AG, et al. Randomized trial of low dose tamoxifen to prevent recurrence of breast intraepithelial neoplasia. In: Proceedings from the 2018 San Antonio Breast Cancer Symposium; December 4-8, 2018; San Antonio, TX. Abstract GS03-01.