Managing HER2+ Early Breast Cancer: A Focus on Target Therapy


New breast cancer diagnoses account for 31% of annual cancer diagnoses among women in the United States.1 Among those diagnoses, HER2 overexpression is observed in 25% to 30% of cases. Historically, HER2-positive (HER2+) breast cancer was considered an aggressive subtype and was associated with a poor prognosis; however, the emergence of HER2-targeted therapies such as trastuzumab has considerably improved disease-free survival (DFS) and overall survival (OS).2,3 In a rapidly evolving treatment paradigm, strategies have shifted focus from traditional anthracycline-based regimens to more targeted therapies.

Neoadjuvant Treatment

The combination of an anthracycline-based chemotherapy plus an HER2-targeted treatment has been the cornerstone of neoadjuvant treatment for patients with HER2+early breast cancer; however, concerns over cardiotoxicity—especially with chemotherapy plus trastuzumab—have prompted a shift towards alternative regimens. The randomized, phase 3 TRAIN-2 study (NCT01996267) investigated the use of neoadjuvant anthracycline-based or non–anthracycline-based chemotherapy plus HER2-targeted agents for patients with stage II and III HER2+ breast cancer.4 Results of a secondary analysis of the study demonstrated a 3-year event-free survival (EFS) of 92.7% (95% CI, 89.3%-96.2%) in the anthracycline group and 93.6% (95% CI, 90.4%-96.9%) in the non-anthracycline group. Additionally, a decline in left ventricular ejection fraction was higher in patients who received an anthracycline-based chemotherapy versus patients who did not (7.7% vs 3.2%; P = .04). Based on comparable efficacy outcomes, the results of the TRAIN-2 study supported the transition from anthracycline-based to non–anthracycline-based regimens for patients with HER2+early-stage breast cancer.4

Additionally, emerging research indicates that dual HER2 blockade involving agents like trastuzumab and lapatinib provides superior DFS and OS benefits compared to single agent anti-HER2 therapy for patients with HER2+ early breast cancer. The combination of trastuzumab plus pertuzumab given in the neoadjuvant and adjuvant settings has been shown to increase pathological complete response (pCR) rates and reduce recurrence risk. Dual blockade is also less commonly associated with cardiotoxicity than are chemotherapy combinations.5

Adjuvant Treatment

Following neoadjuvant treatment, adjuvant therapy decisions are increasingly guided by the response to initial treatment such as pCR. The National Comprehensive Cancer Network guidelines recommend that patients who achieve pCR receive 12 months of anti-HER2 therapy agents such as trastuzumab.6 In the HERA trial (NCT00045032), there was no established benefit seen with more than 12 months of treatment.7 Additionally, fewer incidents of cardiotoxicity were seen with 12 vs 24 months of trastuzumab therapy.

Recent long-term follow-up data from the KATHERINE trial (NCT01772472) demonstrated the efficacy of ado-trastuzumab emtansine (T-DM1) for the treatment of patients with HER2+ early breast cancer with residual invasive disease who did not achieve pCR with neoadjuvant therapy.8 Findings presented at the 2023 San Antonio Breast Cancer Symposium (SABCS) showed improved invasive DFS (iDFS) and OS among 239 patients treated with T-DM1 as compared with results for the 148 patients given standard trastuzumab. At a median follow-up of 8.4 years, an iDFS event occurred in a higher percentage of patients in the trastuzumab arm than in the T-DM1 arm (32.2% vs 19.7%, respectively) (hazard ratio, 0.54; 95% CI, 0.44-0.66; P < .0001). The OS data also favored T-DM1 at the 8.4-year mark, with a total of 89 patients (12%) experiencing an OS event in the T-DM1 arm compared with 126 patients (17%) in the trastuzumab arm (hazard ratio, 0.66; 95% CI, 0.51-0.87; P = .0027). No new safety signals emerged in the 8.4-year follow-up.9

Escalation and De-Escalation Strategies

Recently, strategies involving escalation and de-escalation of HER2-targeted therapies have been investigated based on patient risk and response.10 Escalation strategies have been explored in trials including APHINITY (NCT01358877) and ExtenNET (NCT00878709).11,12 In the phase 3 APHINITY trial, the addition of pertuzumab to adjuvant trastuzumab plus chemotherapy was evaluated in patients with HER2+ breast cancer. The results demonstrated an 8-year OS of 92.7% in patients treated with pertuzumab compared with 92.0% in patients treated with placebo. Additionally, the 8-year iDFS was 88.4% in the pertuzumab arm versus 85.8% in the placebo arm. With no statistically significant difference in OS, further follow-up is needed to determine potential survival benefit with the addition of pertuzumab.11 Investigators associated with the ExteNET trial assessed the use of neratinib, an irreversible pan-HER tyrosine kinase inhibitor (TKI), in patients who received treatment for 1 year after treatment with trastuzumab. The 8-year OS rates were 90.1% (95% CI, 88.3%-91.6%) with neratinib use versus 90.2% (95% CI, 88.4%-91.7%) with placebo. Overall, the results of the ExteNET trial showed comparable OS for neratinib and placebo given in the extended adjuvant setting to patients with early-stage HER2+ breast cancer.12

In an effort to reduce the overall use of chemotherapy to treat patients with HER2+ early-stage breast cancer, de-escalation strategies have been explored in current and ongoing trials using pCR as an end point. In the phase 2, randomized, open-label WSG-ADAPT-HER2+/HR– trial (NCT01817452), the impact of neoadjuvant pertuzumab plus trastuzumab with or without weekly paclitaxel on pCR with in hormone receptor–negative/HER2+ early breast cancer is being investigated. Investigators have reported similar results with both treatment arms with no significant differences in iDFS, relapse-free survival (RFS), locoregional RFS, distant DFS, or OS with the addition of paclitaxel.13 The results showed that pCR was associated with enhanced iDFS (hazard ratio, 0.14; 95% CI, 0.03-0.64; P = .011).Additional de-escalation strategies are currently being studied in ongoing trials such as CompassHER2-pCR (NCT04266249), DECRESCENDO (NCT04675827), and ATEMPT (NCT01853748).

Future Strategies

The treatment landscape of HER2+ early-stage breast cancer is rapidly evolving and shifting from traditional chemotherapy towards more targeted, personalized approaches. Agents that include trastuzumab deruxtecan, tucatinib, pembrolizumab, and atezolizumab are being studied in trials such as DESTINY-Breast05 (NCT04622319) and DESTINY-Breast11 (NCT05113251) to hopefully offer even more effective and personalized treatments. With ongoing research and trials, future strategies are likely to further improve patient outcomes, reducing the burden of this challenging disease.


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  4. van der Voort A, van Ramshorst MS, van Werkhoven ED, et al. Three-year follow-up of neoadjuvant chemotherapy with or without anthracyclines in the presence of dual ERBB2 blockade in patients with ERBB2-positive breast cancer: a secondary analysis of the TRAIN-2 randomized, phase 3 trial. JAMA Oncol. 2021;7(7):978-984. doi:10.1001/jamaoncol.2021.1371
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  6. NCCN. Clinical Practice Guidelines in Oncology. Breast cancer, version 5.2023. Updated December 5, 2023. Accessed December 12, 2023.
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  8. Loibl S, Huang CS, Mano MS, et al. Adjuvant trastuzumab emtansine in HER2-positive breast cancer patients with HER2-negative residual invasive disease in KATHERINE. NPJ Breast Cancer. 2022;8:106. doi:10.1038/s41523-022-00477-z
  9. Loibl S, Mano M, Untch M, et al. Phase III study of adjuvant ado-trastuzumab emtansine vs trastuzumab for residual invasive HER2-positive early breast cancer after neoadjuvant chemotherapy and HER2-targeted therapy: KATHERINE final IDFS and updated OS analysis. Abstract presented at: 2023 San Antonio Breast Cancer Symposium; December 5-9, 2023; San Antonio, TX. Abstract GS03-12. American Association for Cancer Research. Accessed December 19, 2023.
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  11. Loibl S, Jassem J, Sonnenblick A, et al. VP6-2022: Adjuvant pertuzumab and trastuzumab in patients with early HER-2 positive breast cancer in APHINITY: 8.4 years' follow-up. Ann Oncol. 2022; 33(9):986-987. doi:10.1016/j.annonc.2022.06.009
  12. Holmes FA, Moy B, Delaloge S, et al; ExteNET Study Group. Overall survival with neratinib after trastuzumab-based adjuvant therapy in HER2-positive breast cancer (ExteNET): A randomised, double-blind, placebo-controlled, phase 3 trial. Eur J Cancer. 2023;184:48-59. doi:10.1016/j.ejca.2023.02.002
  13. Nitz U, Gluz O, Graeser M, et al; WSG-ADAPT Investigators. De-escalated neoadjuvant pertuzumab plus trastuzumab therapy with or without weekly paclitaxel in HER2-positive, hormone receptor-negative, early breast cancer (WSG-ADAPT-HER2+/HR–): survival outcomes from a multicentre, open-label, randomised, phase 2 trial. Lancet Oncol. 2022;23(5):625-635. doi:10.1016/S1470-2045(22)00159-0
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Rebecca A. Shatsky, MD, an expert on breast cancer
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