ASCO Supports Expanded Adjuvant Therapy for Early Breast Cancer

OncologyLive, Vol. 19/No. 18, Volume 19, Issue 18

Patients with early-stage breast cancer facing a high risk of recurrence would benefit from the expanded use of adjuvant therapy, according to updated guidelines from the American Society of Clinical Oncology.

Neelima Denduluri, MD

Patients with early-stage breast cancer facing a high risk of recurrence would benefit from the expanded use of adjuvant therapy, according to updated guidelines from the American Society of Clinical Oncology (ASCO). The recommendations cover clinical scenarios for patients with residual invasive HER2-negative disease after surgery and those with HER2-positive tumors who are candidates for additional targeted therapy (Table).1

The ASCO guidelines are adapted from Cancer Care Ontario recommendations for selecting optimal treatment regimens. Neelima Denduluri, MD, co-chair of the ASCO expert panel that wrote the guidelines, said in a podcast that the focused update comes in response to seminal results from the CREATE-X (UMIN000000843), ExteNET (NCT00878709), and APHINITY (NCT01358877) trials.2 ASCO issued the update after reviewing data “that has the potential to impact practice of clinical medicine.”

For patients with HER2-positive tumors, the guideline covers 2 clinical situations. “The update focuses on women with early breast cancer who have HER2-positive disease and have had all their tumor removed, and it focuses on what is the appropriate adjuvant therapy for women with HER2-positive breast cancer and early breast cancer,” said Denduluri, a medical oncologist with Virginia Cancer Specialists in Arlington.

“The third topic that this guideline update covers is in women with HER2-negative disease who we’ve chosen to give preoperative therapy and, at the time of surgery, they have a residual cancer burden. For those patients, in the past, we never had a standard therapy that we can discuss with them.”

Specifically, the update delves into these questions:

• Should patients with early-stage HER2-negative breast cancer with residual invasive disease at surgery receive adjuvant capecitabine (Xeloda) following completion of standard preoperative anthracycline- and taxane-based combination chemotherapy in patients?

• Should patients with early-stage HER2-positive breast cancer receive 1 year of adjuvant pertuzumab (Perjeta) in addition to trastuzumab (Herceptin)-based combination chemotherapy?

Capecitabine in HER2-Negative Disease

• Should patients with early-stage HER2-positive breast cancer receive extended adjuvant therapy with neratinib (Nerlynx) following combination chemotherapy and trastuzumab-based adjuvant therapy?ASCO offered a moderate recommendation based on “intermediate” evidence in favor of adding adjuvant capecitabine following standard anthracycline- and taxane-based preoperative therapy for patients with early-stage HER2-negative breast cancer who have pathologic invasive residual disease at surgery (Figure).

The recommendation is based on data from CREATE-X (N = 910). That randomized phase III trial evaluated the effect of 6 to 8 cycles of adjuvant capecitabine on disease-free survival (DFS) and overall survival (OS) in patients with stage I-IIIB HER2-negative disease who received neoadjuvant anthracycline, taxane, or combined anthracycline and taxane therapy with curative intent.

The trial was stopped early after meeting its primary endpoint for DFS. At a median follow-up of 3.6 years, the 5-year DFS rate was 74.1% for the capecitabine arm versus 67.6% for the control arm (HR, 0.70; 95% CI, 0.53-0.92; P = .01). OS was also superior in the capecitabine arm (89.2% vs 83.6%; HR, 0.59; 95% CI, 0.39-0.90; P = .01). Patients with triple-negative breast cancer and hormone receptor—positive breast cancer also benefitted from capecitabine treatment.

Table. Updated ASCO Recommendations for Early-Stage Breast Cancer

The update also addresses women with HER2-negative disease who have residual cancer burden at the time of surgery despite receiving preoperative therapy. Those women are at increased risk for relapse, but data from the CREATE-X trial suggest that these patients derive benefit from the addition of adjuvant capecitabine. The panel concluded that adjuvant capecitabine was likely to benefit patients with triple-negative disease as well.

In patients with triple-negative disease, DFS was 69.8% versus 56.1% (HR, 0.58, 95% CI, 0.39 to 0.87) in favor of the capecitabine arm. Capecitabine was associated with superior OS (78.8% vs 70.3%; HR, 0.52; 95% CI, 0.30-0.90) and conferred a survival advantage to patients with hormone receptor—positive breast cancer.

“In triple-negative breast cancer, if a patient is not eligible for a clinical trial and they have a significant residual cancer burden after receiving traditional anthracycline- and taxane-containing neoadjuvant therapy, capecitabine gives them a significant option that improves survival,” Denduluri said. She cautioned that the dose of 1250 mg/m2 of capecitabine twice-daily used in CREATE-X, and the most common dosage used in the United States, is associated with increased toxicity, especially among patients 65 years and older.

Pertuzumab in HER2-Positive Disease

She added that, although capecitabine is generally well tolerated, physicians need to be aware that the dose used in the study may not be tolerated in every population. The expert panel concluded that patients with high-risk, early-stage, HER2-positive breast cancer can receive 1 year of adjuvant pertuzumab along with trastuzumab-based combination chemotherapy based on results from APHINITY. In the phase III clinical trial, 4805 patients who had undergone mastectomy or lumpectomy were assigned to a maximum of 18 weeks of standard adjuvant chemotherapy with trastuzumab (Herceptin) and placebo or trastuzumab and pertuzumab. Patients then continued their assigned regimen for 1 year.

After a median follow-up of 3.8 years, 3-year invasive DFS was 93.2% in the placebo group and 94.1% in the pertuzumab group (HR, 0.81; 95% CI, 0.66-1.00). The absolute overall invasive DFS benefit was 0.9%. Thirty-six percent of patients had hormone receptor—negative tumors and 63% had lymph node involvement.

Investigators found an absolute 3-year invasive DFS benefit of 1.8% among patients with nodepositive disease, with what appeared to be a numerically greater benefit associated with pertuzumab (92% vs 90.2%; HR, 0.77; 95% CI, 0.62-0.96). The invasive DFS rate for patients with node-negative cancer was 97.5% in the pertuzumab arm and 98.4% in the placebo arm (HR, 1.13; 95% CI, 0.68-1.86).

Among hormone receptor—negative patients, 8.2% in the pertuzumab group experienced invasive DFS events compared with 10.6% in the placebo group (HR, 0.76, 95% CI, 0.56-1.04). Investigators did not find a correlation between pertuzumab benefit and hormone receptor status.

The panel added that there are no data regarding the appropriate duration of pertuzumab treatment for patients who achieved a pathologic complete response following neoadjuvant pertuzumab.

Although both CREATE-X and APHINITY are positive trials, Denduluri said that the results were not as strong as the panel would have hoped, possibly because trastuzumab and chemotherapy are “excellent” therapies. As a result, many of the findings from the subgroup analyses were not statistically significant.

Figure. Illustration of Early-Stage Breast Cancer

Neratinib in HER2-Positive Disease

“That’s why, as a panel, we did add some qualifying statements to the guideline despite the lack of robust P values to discern if the subgroup of HER2-positive may benefit more from neratinib or the subgroup may benefit more from pertuzumab,” she added. “We couldn’t put that in the guideline. However, the expert panel did make some recommendations regarding which subpopulations that we thought would derive the most benefit from these agents.The panel recommended extended adjuvant therapy with neratinib following trastuzumab for patients with HER2-positive, hormone receptor— positive and node-positive disease based on data from ExteNET. The FDA approved neratinib in July 2017 in this setting. The European Commission approved a similar indication in September 2018.

In the phase III study, 2840 women who were within 2 years of completing adjuvant trastuzumab were randomly assigned to 1 year of neratinib (n = 1420) or placebo (n = 1420). After a median follow-up of 2 years, invasive DFS was 91.9% in the placebo arm and 94.2% in the experimental arm (HR, 0.66; 95% CI, 0.49-0.90; P = .008). A total of 2117 patients gave reconsent and were eligible for extended follow-up. At a median follow-up of 5 years, invasive DFS was 87.7% in the placebo arm compared with 90.2% in the neratinib arm (HR, 0.73; 95% CI, 0.57-0.92).

The benefit associated with neratinib was stronger among patients with ≥4 involved lymph nodes (HR, 0.67; 95% CI, 0.46-0.96), those treated with neratinib within 1 year of completion of trastuzumab (HR, 0.70; 95% CI, 0.54-0.90), and those with hormone receptor-positive tumors (HR, 0.60; 95% CI, 0.43-0.83).

Denduluri added that the caveat to this recommendation is that patients in ExteNET were pertuzumab-naïve. Moreover, when the trial was performed, investigators did not know that the node-negative population probably does well with chemotherapy and the standard 1 year of trastuzumab.

“Therefore, we think that the people who benefit most from the neratinib for a year, which is 240 mg a day, are those who have node-positive disease and those with hormone receptor—positive disease,” she said.

Forty percent of patients in ExteNET experienced grade 3 or 4 diarrhea; antidiarrheal prophylaxis was not required in that trial. Investigators are exploring the safety and tolerability of neratinib in patients ≥60 years with metastatic HER2- positive breast cancer in an ongoing phase II trial (NCT02673398).

Data from the ongoing, open-label phase II CONTROL trial presented at the 2017 San Antonio Breast Cancer Symposium examined the antidiarrheal medication loperamide in patients with HER2-positive disease who received neratinib for 1 year. Prophylaxis was administered during the first two 28-day treatment cycles.3

At the data cutoff, 137 patients had received prophylaxis with loperamide alone, 64 patients had received loperamide plus budesonide, and 120 patients had received loperamide plus colestipol.

The incidence of grade 3 diarrhea was 39.8% in ExteNET compared with 30.7% for loperamide monotherapy, 23.4% for loperamide/ budesonide, and 11.5% for loperamide/colestipol. There was 1 grade 4 event in ExteNET and none in CONTROL.


  1. Denduluri N, Chavez-MacGregor M, Telli ML, et al. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer: ASCO Clinical Practice Guideline focused update. J Clin Oncol. 2018;36(23):2433-2443. doi: 10.1200/JCO.2018.78.8604.
  2. Selection of optimal adjuvant chemotherapy and targeted therapy for early breast cancer [podcast]. ASCO Guidelines Podcast Series. May 22, 2018. Accessed August 17, 2018.
  3. Puma Biotechnology presents interim results of phase II CONTROL trial of neratinib in extended adjuvant treatment of HER2-positive early stage breast cancer at the 2017 San Antonio Breast Cancer Symposium [press release]. Los Angeles, CA: Puma Biotechnology; April 4, 2017. Accessed August 17, 2018.