Adjuvant Trials Demonstrate High Clinical Impact in Breast Cancer

Maryam Nemati Shafaee, MD, discusses the pivotal trials in breast cancer that were reported at the 2018 ASCO Annual Meeting.

Maryam Nemati Shafaee, MD

Clinical trial findings that were presented at the 2018 ASCO Annual Meeting could have a significant impact on patients with early-stage breast cancer in the adjuvant setting, explained Maryam Nemati Shafaee, MD.

For example, in the phase III TAILORx trial, adjuvant endocrine therapy demonstrated noninferiority to adjuvant chemoendocrine therapy in women with hormone receptor (HR)—positive/HER2-negative, nodenegative, early-stage breast cancer with an intermediate risk of distant recurrence (HR, 1.08; 95% CI, 0.94-1.24 P = .26).1

Following the study, Shafaee said that physicians can “safely say that this patient population does not need chemotherapy.”

Moreover, in the phase III PERSEPHONE trial, 4088 women with HER2-positive early breast cancer were randomized to receive trastuzumab (Herceptin) for 6 months (n = 2043) or 12 months (n = 2045). At a 5-year follow-up, the 4-year disease-free survival (DFS) rate was 89.8% and 89.4% with the 12-month and 6-month schedules, respectively (HR, 1.07; 90% CI, 0.93-1.24; P = .01).2

Although the trial demonstrated noninferiority with the shorter duration of therapy, Shafaee warned against its adoption into practice since other similar trials were negative.

Additionally, the 72-month follow-up analysis of the ABCSG-18 trial showed a DFS benefit with adjuvant denosumab (Xgeva) for postmenopausal women with early HR-positive breast cancer (HR, 0.823; 95% CI, 0.69-0.98; P = .026) per Cox proportional hazards regression analysis.3

In the trial, 3425 women receiving an aromatase inhibitor were randomized to receive 60 mg of denosumab (n = 1712) or placebo (n = 1713) every 6 months. In the denosumab group, DFS was 89.2% at 5 years (95% CI, 87.6-90.7) and 80.6% at 8 years (95% CI, 78.1-83.1). In patients randomized to placebo, DFS was 87.3% at 5 years (95% CI, 85.7-89.0) and 77.5% at 8 years (95% CI, 74.8-80.2).

Following these studies, Shafaee said that more data are needed if precision oncology is to continue to transform the field of breast cancer.

OncLive: What were the main updates in breast cancer from the 2018 ASCO Annual Meeting?

In an interview during the 2018 OncLive® State of the Science Summit™ on Breast Cancer, Shafaee, an assistant professor, at the Lester & Sue Smith Breast Center, Duncan Cancer Center, Baylor College of Medicine, discussed the pivotal trials in breast cancer that were reported at the 2018 ASCO Annual Meeting.Shafaee: The first is the TAILORx trial and the second is the PERSEPHONE trial. There are 2 adjuvant denosumab trials that I also spoke about. TAILORx was a study with a very high clinical impact.

There was an earlier paper of a subgroup in the trial that looked at the Oncotype DX Recurrence Risk Score between 0 and 10 [for those who received] endocrine therapy alone. They reported that if the Oncotype DX results showed a number between 0 and 10 in women with early-stage node-negative estrogen-receptor (ER)— positive breast cancer, then you can omit chemotherapy.

In the trial, they looked at recurrence score in the intermediate range between 11 and 25 in post- and premenopausal women. They looked at chemotherapy plus endocrine therapy versus endocrine therapy alone. The endpoint that they looked at was invasive disease-free survival (iDFS).

In this patient population, they reported that, especially in women aged over 50 years with an intermediate-risk score between 11 and 25, chemotherapy is essentially unnecessary. iDFS was pretty much the same between the group who received endocrine therapy and those who received chemotherapy plus endocrine therapy. We can safely say that this patient population does not need chemotherapy.

What did we learn from the PERSEPHONE trial?

When it comes to premenopausal women or those aged 50 years and younger, it is a little bit different. In this patient population, there was improvement in the outcomes seen in that range, especially between 16 and 20 and 20 and 25. There was about a 7% improved outcome or reduced recurrence risk in the range of 20 to 25. It’s not as clear as it is for patients aged over age 50.For PERSEPHONE, researchers looked at DFS in patients with early-stage, HER2-positive breast cancer who would need adjuvant trastuzumab therapy. They looked at 12 months versus 6 months of trastuzumab, which comes to 18 doses versus 9 doses of therapy. They wanted to know whether the 6-month duration was noninferior to the 12-month duration. They reported that the 6-month duration was noninferior to the 12-month duration of trastuzumab.

Are the results of PERSEPHONE enough to sway the standard?

What were the 2 adjuvant trials with denosumab?

There was a case where we saw a patient with mild cardiomyopathy from adjuvant trastuzumab. Even though the ejection fraction recovered, she had already received 9 doses. Did I want to challenge her and give her more? Based on these results, we talked about maybe not continuing to the 12 months. It’s not yet incorporated into the National Comprehensive Cancer Network (NCCN) guidelines, so it has to be approached with caution. The results were quite significant, so I would like to see what happens in the future.I would like to see what the expert panel decides on the NCCN guidelines update. We do know that there were 2 other studies—the HERA study and HORG study—that looked at 6 months versus 12 months of trastuzumab therapy in the adjuvant setting. Comparing the results of PERSEPHONE study with the prior results that had been reported would be interesting to see.The ABCSG-18 study looked at the use of denosumab in acute 6-month dosing in women with HR-positive breast cancer; these women received aromatase inhibitors in the adjuvant setting. They administered the drug every 6 months to see whether it decreases the risk of recurrent disease. We already knew that it decreases the risk of fractures in this patient population, but the endpoint of this trial was different. It showed that it could be an alternative.

Currently, the guidelines recommend using bisphosphonates. In the United States, we have been using zoledronic acid for this patient population. In 2017, a paper came out in the Journal of Clinical Oncology recommending adjuvant bisphosphonate, zoledronic acid, or clodronic acid. There were no convincing data at the time about denosumab. This study suggested that denosumab may be an alternative to zoledronic acid. The study used 60 mg of acute 6-month dosing and showed that it may be a good option.

The D-CARE study also looked at denosumab in a different dose-intense schedule. Their endpoint was bone metastasis-free survival. They did not show improvement with denosumab in a dose-intense approach versus placebo. We cannot necessarily compare them together because the patient populations were different; the way the medication was given was different, and their endpoints were different.

What area of research would you like to see addressed?

What I took away from these studies is that adjuvant denosumab may be an alternative for women who have HR-positive disease or are receiving aromatase inhibitors. There are always issues of cost and coverage that come into question. In that case, the decision should be made by the primary oncologist. I would like to see how the NCCN guidelines incorporate these results in the future.There are of course unanswered questions. In women aged 50 years or younger with an intermediate-risk score, which population are we going to treat with chemotherapy versus endocrine therapy? It would be nice to know which patients would be able to receive de-escalated therapy and could avoid chemotherapy. That would be a more targeted precision oncology approach.

Going forward with adjuvant therapy with trastuzumab, we know that 9 weeks is good, and we know 6 months is good. Maybe 6 months and 12 months are the same, but is there an optimum duration for adjuvant trastuzumab?


  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).
  2. Earl HM, Hiller L, Vallier A-L, et al. PERSEPHONE: 6 versus 12 months (m) of adjuvant trastuzumab in patients (pts) with HER2 positive (+) early breast cancer (EBC): randomised phase 3 non-inferiority trial with definitive 4-year (yr) disease-free survival (DFS) results. J Clin Oncol. 2018;36(suppl; abstr 506).
  3. Gnant M, Pfeiler G, Steger GG, et al. Adjuvant denosumab in early breast cancer: disease-free survival analysis of 3,425 postmenopausal patients in the ABCSG-18 trial. J Clin Oncol. 2018;36(suppl; abstr 500).