HER2-Directed Treatment Escalation or De-escalation Necessitates Careful Consideration in HER2+ Breast Cancer


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

Sara A. Hurvitz, MD

Sara A. Hurvitz, MD

Multiple patient characteristics, including risk level and tumor size, may play a role in determining whether to treat patients with HER2-positive breast cancer are candidates for escalated or deescalated HER2-directed therapy, according to a presentation by Sara A. Hurvitz, MD, during the 21st Annual International Congress on the Future of Breast Cancer® West.1

“Outcomes for HER2-positive breast cancer have substantially been improved with the advent of HER2-directed therapy,” Hurvitz, a professor of medicine and the director of the Breast Oncology Program at the University of California, Los Angeles, said during the presentation. “We can tell our patients [that] HER2-positive disease is associated with some of the best outcomes now. With that said, we must decide which patients are eligible for escalated therapy vs deescalated therapy. Almost all patients will receive some form of systemic therapy if they have HER2-positive disease.”

Clinician Discretion Is Key in Therapy Escalation

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

Escalating therapy may be an option for those who are at high-risk of recurrence or pregression, but other factors may play into the appropriate patient selection. Hurvitz said that findings from the phase 3 ExteNET trial (NCT00878709) support the use of adjuvant neratinib (Nerlynx) in select patients with residual disease, adding that she would recommend this approach in hormone receptor–positive patients who are high-risk, such as those with high residual nodal burden. However, she noted that this recommendation must be balanced against the potential toxicities of the regimen.

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

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

Findings from the trial 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 = .0008). A minimal benefit in OS was observed between the 2 arms (HR, 0.95; 95% CI, 0.74-1.21; P = .6914).

When broken down by hormone receptor status, a clearer benefit in terms of iDFS was observed in the neratinib arm. Patients with hormone receptor–-positive disease experienced a 5-year iDFS rate of 91.2% when treated with neratinib compared with 86.8% in the placebo arm (HR, 0.60; 95% CI, 0.43-0.83). Comparatively, among patients with hormone receptor–negative disease, the 5-year iDFS rates were 88.9% and 88.8%, respectively (HR, 0.95; 95% CI, 0.66-1.35).

Additionally, in a subgroup analysis, a greater iDFS benefit was reported among patients with hormone receptor–positive disease who had with residual disease and were less than a year removed from adjuvant treatment with trastuzumab. In this subgroup, patients who were treated with neratinib experienced a 5-year iDFS rate of 85.0% compared with 77.6% among patients who received placebo (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 went on to outline some ongoing studies of novel approaches to treating high-risk disease. The phase 3 CompassHER2-RD (NCT04457596) is evaluating treatment with T-DM1 vs T-DM1 plus tucatinib (Tukysa) among patients with high-risk, HER2-positive breast cancer. Moreover, the phase 3 ASTEFANIA trial (NCT04873362) is examining T-DM1 monotherapy vs in combination with atezolizumab (Tecentriq) in patients with node-positive, HER2-positive early breast cancer following standard neoadjuvant therapy.

De-escalation Approach Depends on Tumor Size, Other Aspects

In terms of therapy de-escalation in the neoadjuvant setting, Hurvitz clarified that systemic therapy is still necessary for all patients with small (< 1.5 cm) HER2-positive tumors. She also suggested that neoadjuvant therapy should be considered for patients with tumors 1.5 cm or greater and that in this setting pathologic response is prognostic and informs adjuvant therapy decision-making.

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

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

Findings from the trial showed that the TCHP approach and the FEC to THP strategy led to similar outcomes in terms of pathological complete response (pCR). Hurvitz said the longer-term disease-free survival (DFS) and progression-free survival (PFS) results trended 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 among patients with HER2-positive breast cancer under the single HER2 blockade.4

Patients treated with TCH displayed a superior pCR rate compared with those who received EC-TH, 37.3% (95% CI, 25.8%-50.0%) vs 55.9% (95% CI, 43.3%-67.9%), respectively (P = .032). Hurvitz also noted that the TCH regimen produced better outcomes in terms of adverse effects.

Hurvitz then emphasized that the phase 3 TRAIN-2 trial (NCT01996267) was the study that solidified the nonanthracycline approach in the neoadjuvant setting. In this trial, patients with stage II to III HER2-positive breast cancer were randomly assigned 1:1 to receive FEC plus paclitaxel or paclitaxel, trastuzumab, and carboplatin plus trastuzumab.5

“The pCR rates were virtually equivalent in the 2 treatment arms, but more patients were able to complete the full year of trastuzumab in the nonanthracycline arm,” Hurvitz said. “There was more grade 3/4 febrile neutropenia in the anthracycline arm, and the longer-term follow-up looks as good with the non-anthracycline [regimen] as the anthracycline-based regimen.”


  1. Hurvitz SA. Candidacy for de-escalated and escalated HER2-directed therapy in the curative setting. Presented at: 21st Annual International Congress on the Future of Breast Cancer® West; July 29-33, 2022; San Diego, CA.
  2. Chan A, Moy B, Mansi J, et al. Final efficacy results of neratinib in HER2-positive hormone receptor-positive early-stage breast cancer from the phase III ExteNET trial. Clin Breast Cancer. 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 anthracycline-free chemotherapy regimens in patients with HER2-positive early breast cancer: a randomized phase II cardiac safety study (TRYPHAENA). Ann Oncol. 2013;24(9):2278-2284. doi:10.1093/annonc/mdt182
  4. Gao HF, Wu Z, Lin Y, et al. Anthracycline-containing versus carboplatin-containing neoadjuvant chemotherapy 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 multicentre, open-label, randomised, phase 3 trial. Lancet Oncol. 2018;19(12):1630-1640. doi:10.1016/S1470-2045(18)30570-9
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