Decreasing Treatment in HER2-Positive Breast Cancer: Doing More With Less

HER2 is a transmembrane receptor tyrosine kinase in the EGFR family that is amplified or overexpressed in approximately 20% of breast cancers.¹ Historically, this subtype has been associated with biologically aggressive tumors, presenting worse progression-free survival and overall survival (OS). However, the discovery of HER2-targeted therapies, such as the humanized monoclonal antibody trastuzumab (Herceptin; Genentech, Inc), has improved outcomes in this patient population; survival rates are now comparable with those of patients with hormone receptor–positive disease.²

In early-stage disease, joint analysis of NSABP B-31 and NCCTG N9831 data showed that adding trastuzumab to chemotherapy led to a 37% relative improvement in OS and a 40% improvement in disease-free survival (DFS).³ The addition of pertuzumab (Perjeta; Genentech, Inc), which binds to HER2 at a different epitope, increased rates of pathologic complete response (pCR) and resulted in modest improvements in invasive DFS, particularly in higher-risk, node-positive disease.⁴

The TRYPHAENA trial (NCT00976989) evaluated dual HER2 blockade with trastuzumab and pertuzumab combined with a nonanthracycline regimen. Similar pCR and DFS rates were observed compared with an anthracycline-containing regimen. The nonanthracycline arm contained docetaxel (Taxotere), carboplatin, trastuzumab (Herceptin), and pertuzumab (Perjeta; TCHP) for 6 cycles. Given that HER2-targeted therapies have an increased risk of cardiac dysfunction, especially with the addition of anthracyclines, TCHP provided a less cardiotoxic option.⁵

Findings from the KRISTINE trial (NCT02131064) helped further define this approach by comparing ado-trastuzumab emtansine plus pertuzumab (T-DM1 + P) with TCHP. The primary end point (pCR) was higher in patients receiving TCHP than in those receiving T-DM1 + P.⁶

Data from the APHINITY trial (NCT01358877) further confirmed the benefit of adding adjuvant pertuzumab to trastuzumab in patients with node-positive, HER2-positive early-stage breast cancer.⁷ At present, TCHP is widely used in patients with higher-risk HER2-positive disease, particularly those with node-positive or high-risk node-negative disease.⁸

These pivotal trials investigated HER2-targeted therapy in patients with high-risk node-negative or node-positive disease.

• NEOSPHERE (NCT00545688) included patients with stage II, stage III, or inflammatory breast cancer.⁹
• TRYPHAENA included patients with operable, locally advanced, or inflammatory breast cancer and a primary tumor greater than 2 cm.⁵
• KRISTINE included patients with stage II or III disease.⁶

In APHINITY, patients with node-positive disease benefited most from the addition of pertuzumab, with no significant benefit seen in the node-negative subgroup at 8 years.⁷

There was previously no standard treatment for stage I HER2-positive disease. The APT trial addressed this gap by enrolling patients with tumors of 3 cm or less and no lymph node involvement beyond a single micrometastatic node.

Patients received weekly paclitaxel for 12 weeks with trastuzumab every 3 weeks to complete 1 year. This regimen demonstrated a low recurrence risk (< 2% at 3 years) and is now considered an option in low-risk stage I HER2-positive breast cancer.¹⁰

Other trials are advancing the approach further by excluding chemotherapy altogether. ATEMPT (NCT01853748) and ADEPT (NCT04569747) are evaluating chemotherapy-free approaches for patients with stage I HER2-positive breast cancer.^11-13 ATEMPT, a randomized phase 2 trial, compared adjuvant T-DM1 to paclitaxel plus trastuzumab (TH) in patients with stage I HER2-positive breast cancer. Although the trial was not powered for efficacy, 5-year outcomes were similar between T-DM1 and TH (recurrence risk, 98.3% vs 93.3%; OS, 97.8% vs 97.9%).

Toxicity profiles were similar between groups, with patient-reported outcomes favoring T-DM1. Data suggest that T-DM1 may be an option for patients ineligible for TH.

ATEMPT 2.0 will compare the toxicity profiles of 6 cycles of T-DM1 followed by subcutaneous trastuzumab vs TH. This trial will assess whether an abbreviated course of T-DM1 maintains efficacy and reduces toxicity compared with the standard TH regimen.¹² ADEPT may give patients with hormone receptor–positive, HER2-positive disease a chemotherapy-free regimen with combination subcutaneous trastuzumab and pertuzumab plus endocrine therapy.¹³ Both ATEMPT 2.0 (NCT04893109) and ADEPT are currently recruiting.

ADAPT (NCT01817452) is a large, multicohort umbrella trial that aims to identify patients suitable for de-escalation without compromising efficacy and to reduce overtreatment and exposure to toxicity. The HER2-positive, hormone receptor–negative cohort demonstrated higher rates of pCR with neoadjuvant trastuzumab and pertuzumab plus weekly paclitaxel than without paclitaxel. Dual blockade without chemotherapy yielded lower pCR rates but favorable outcomes in select patients. These patients were node-negative, strongly HER2-positive (immunohistochemistry 3+), and responded early to therapy.¹⁴ This chemotherapy-free approach may be an option for strongly HER2-positive, node-negative patients who are unable to tolerate chemotherapy.

Recently, the neoCARHP trial (NCT04858529) reassessed the need for carboplatin in patients with HER2-positive, stage II to III breast cancer. Neoadjuvant taxane, trastuzumab, and pertuzumab (THP) demonstrated noninferior efficacy with lower toxicity than the current standard-of-care regimen, TCHP, which includes carboplatin.¹⁵

The CompassHER2-pCR trial (NCT04266249) is evaluating whether neoadjuvant paclitaxel, trastuzumab, and pertuzumab can allow omission of additional chemotherapy after surgery in patients with HER2-positive stage II to IIIA breast cancer. The findings may provide further support for a less toxic chemotherapy regimen that does not compromise efficacy. In addition, a high HER2DX genomic assay score was associated with higher pCR rates in patients treated with neoadjuvant THP in a high-risk subset of patients with HER2-positive early-stage breast cancer.¹⁶ This may help refine patient selection for de-escalated therapy.

HER2-targeted therapy has transformed HER2-positive breast cancer from a poor-prognosis disease to one with substantially improved survival and recurrence outcomes. It may be possible to de-escalate chemotherapy and decrease toxicity exposure without compromising efficacy in select patients. The HER2 treatment landscape continues to evolve as numerous trials investigate further de-escalation strategies.

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12. A randomized phase II trial of adjuvant trastuzumab emtansine (T-DM1) followed by subcutaneous trastuzumab versus paclitaxel plus subcutaneous trastuzumab for stage I HER2-positive breast cancer (ATEMPT 2.0). ClinicalTrials.gov. https://clinicaltrials.gov/study/NCT04893109

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15. Gao HF, Li W, Wu Z, et al. De-escalated neoadjuvant taxane plus trastuzumab and pertuzumab with or without carboplatin in HER2-positive early breast cancer (neoCARHP): a multicentre, open-label, randomised, phase 3 trial. J Clin Oncol. 2025;43(suppl 17):LBA500. doi:10.1200/JCO.2025.43.17_suppl.LBA500

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