Escalation or de-escalation of HER2-directed therapy requires special attention in HER2+ breast cancer


Sara A. Hurvitz, MD, discusses when de-escalation therapy may play a role in patients with HER2-positive breast cancer.

According to a presentation by Sara A. Hurvitz, MD, during the 21st Annual International Congress on the Future of Breast Cancer® West.1

“The outcomes of HER2-positive breast cancer have been dramatically improved with the advent of HER2-directed therapy,” said Hurvitz, professor of medicine and director of the breast oncology program at the University of California, Los Angeles. Angeles, during the presentation. “We can tell our patients [that] HER2-positive disease is associated with some of the best outcomes today. That said, we have to decide which patients are eligible for enhanced versus defused therapy. Almost all patients will receive some form of systemic therapy if they have HER2-positive disease.

Clinician discretion is the key to therapeutic escalation

Regarding treatment escalation for patients with high-risk HER2-positive breast cancer, Hurvitz noted that current evidence-based strategies point to different approaches depending on characteristics, including response to treatment. For example, she explained that the results from the Phase 3 KATHERINE trial (NCT01772472) support the adjuvant ado-trastuzumab emtansine (T-DM1; Kadcyla) for all patients with residual disease.

Intensification of therapy may be an option for those at high risk of recurrence or progression, but other factors may play into appropriate patient selection. Hurvitz said results from the Phase 3 ExteNET trial (NCT00878709) support the use of adjuvant neratinib (Nerlynx) in some patients with residual disease, adding that she would recommend this approach in hormone receptor positive patients at high risk, such as those with a high residual nodal load. However, she noted that this recommendation must be weighed against the potential toxicities of the diet.

In ExteNET, patients with HER2-positive early breast cancer were randomized 1:1 to receive either neratinib 240 mg daily for 1 year or placebo. All patients had been previously treated with trastuzumab (Herceptin). The primary endpoint of the trial was invasive disease-free survival (iDFS) and there was an extended 5-year follow-up for iDFS and overall survival (OS).2

“Keep in mind that this study did not enroll patients who had received pertuzumab (Perjeta) or T-DM1, Hurvitz said.”[Therefore] the relative benefits or absolute benefits of neratinib in patients who received these agents are not entirely clear. »

The trial results showed that the 5-year iDFS rates were 90.2% and 87.7% in the neratinib and placebo arms, respectively (HR, 0.73; 95% CI, 0. 57-0.92; P = 0.0008). A minimal benefit on OS was observed between the 2 arms (HR, 0.95; 95% CI, 0.74-1.21; P = 0.6914).

When broken down by hormone receptor status, a clearer benefit in terms of iDFS was seen in the neratinib arm. Patients with hormone receptor-positive disease had a 5-year SIDID rate of 91.2% when treated with neratinib compared to 86.8% in the placebo group (HR, 0.60; 95% CI, 0.43-0.83). Comparatively, in patients with disease without hormone receptors, the 5-year SFDi rates were 88.9% and 88.8%, respectively (HR, 0.95; 95% CI, 0.66- 1.35).

Additionally, in a subgroup analysis, greater iDFS benefit was reported in patients with hormone receptor-positive disease who had residual disease and who had been off adjuvant therapy for less than one year. by trastuzumab. In this subgroup, neratinib-treated patients had a 5-year iDFS rate of 85.0% versus 77.6% in placebo-treated patients (HR, 0.60; 95% CI , 0.33-1.07). In terms of OS, the 8-year rates were 91.3% and 82.2%, respectively (HR, 0.47; 95% CI, 0.22-0.92).

Hurvitz then described some ongoing studies of new approaches to treating high-risk diseases. Phase 3 of CompassHER2-RD (NCT04457596) is evaluating treatment with T-DM1 vs T-DM1 plus tucatinib (Tukysa) in patients with high-risk HER2-positive breast cancer. Additionally, the Phase 3 ASTEFANIA trial (NCT04873362) is investigating T-DM1 monotherapy versus the combination with atezolizumab (Tecentriq) in patients with node-positive, HER2-positive early breast cancer after standard neoadjuvant therapy.

De-escalation approach depends on tumor size and other aspects

In terms of treatment de-escalation in the neoadjuvant setting, Hurvitz clarified that systemic treatment is still needed for all patients with small HER2-positive tumors (

“One of the benefits of the neoadjuvant setting is that it gives us the opportunity to really feel comfortable omitting anthracyclines from our therapy because we can see if the treatment we chose has worked,” said Hurvitz.

In the Phase 2 TRYPHAENA study (NCT00976989), researchers evaluated 3 neoadjuvant treatment regimens in patients with locally advanced, inflammatory or early-stage HER2-positive breast cancer. Patients were randomized 1:1:1 to receive pertuzumab plus trastuzumab with 5-fluorouracil/epirubicin/cyclophosphamide (FEC) for cycles 1-3 and docetaxel for cycles 4-6; FEC for cycles 1-3 followed by pertuzumab plus trastuzumab with docetaxel for cycles 4-6 (THP); or 6 cycles of pertuzumab plus trastuzumab with docetaxel and carboplatin (TCHP).3

The results of the trial showed that the TCHP approach and the FEC to THP strategy led to similar results in terms of pathological complete response (pCR). Hurvitz said the longer-term disease-free survival (DFS) and progression-free survival (PFS) results tended toward the TCHP arm, meaning it was safer from a cardiac perspective.

Another trial, the phase 2 neoCARH study (NCT03140553), compared the efficacy of epirubicin/cyclophosphamide followed by docetaxel/trastuzumab (EC-TH) with that of docetaxel/carboplatin/trastuzumab (TCH). The study compared the combinations in the neoadjuvant setting in patients with HER2-positive breast cancer under HER2 blockade alone.4

Patients treated with TCH had a higher pCR rate than those who received EC-TH, 37.3% (95% CI, 25.8% to 50.0%) versus 55.9% (95 %, 43.3% to 67.9%), respectively (P = 0.032). Hurvitz also noted that the TCH diet produced better results in terms of adverse effects.

Hurvitz then pointed to the Phase 3 TRAIN-2 trial (NCT01996267) as the study that solidified the anthracycline-free approach in the neoadjuvant setting. In this trial, patients with HER2-positive stage II to III breast cancer were randomized 1:1 to receive FEC plus paclitaxel or paclitaxel, trastuzumab and carboplatin plus trastuzumab.5

“pCR rates were nearly equivalent in the 2 treatment arms, but more patients were able to complete the full year of trastuzumab in the no-anthracycline arm,” Hurvitz said. “There was more grade 3/4 febrile neutropenia in the anthracycline arm, and longer-term follow-up appears to be as good with the no-anthracycline arm [regimen] than the anthracycline-based diet.


  1. Hurvitz SA. Application for defused and intensified HER2-directed therapy in the curative setting. Introduced to : 21st Annual International Congress on the Future of Breast Cancer® West; July 29-33, 2022; San Diego, California.
  2. Chan A, Moy B, Mansi J, et al. Final Efficacy Results of Neratinib in Hormone Receptor Positive HER2-Positive Early-Stage Breast Cancer from the Phase III ExteNET Trial. Breast cancer clinic. 2021;21(1):80-91.e7. doi:10.1016/j.clbc.2020.09.014
  3. Schneeweiss A, Chia S, Hickish T, et al. Pertuzumab Plus Trastuzumab in Combination with Standard Neoadjuvant Anthracycline-Containing and Non-Anthracycline Chemotherapy Regimens in Patients With HER2-Positive Early Breast Cancer: A Randomized Phase II Cardiac Safety Study (TRYPHAENA) . Anne Oncol. 2013;24(9):2278-2284. doi:10.1093/announce/mdt182
  4. Gao HF, Wu Z, Lin Y, et al. Containing anthracycline versus neoadjuvant chemotherapy containing carboplatin in combination with trastuzumab for HER2-positive breast cancer: the neoCARH phase II randomized clinical trial. Ther Adv Med Oncol. 2021;13:17588359211009003. doi:10.1177/17588359211009003
  5. van Ramshorst MS, van der Voort A, van Werkhoven ED, et al. Neoadjuvant chemotherapy with or without anthracyclines in the presence of dual HER2 blockade for HER2-positive breast cancer (TRAIN-2): a multicenter, open-label, randomized, phase 3 trial. Lancet Oncol. 2018;19(12):1630-1640. doi:10.1016/S1470-2045(18)30570-9


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