T-DM1: a promising adjuvant therapy option for stage I HER2-positive breast cancer—interpreting ATEMPT trial results from a clinical perspective

Approximately 15–20% of breast cancers have overexpression and/or amplification of the human epidermal growth factor receptor 2 (HER2), a transmembrane glycoprotein epidermal growth factor receptor (EGFR) with tyrosine kinase activity (1,2). HER2-positive breast cancers are more aggressive and carry a higher risk of recurrence and poorer survival outcomes compared to HER2-negative breast cancers without adequate treatment (3,4). The introduction of HER2-targeted therapies has significantly improved the clinical outcomes of HER2-positive breast cancers by reducing relapse rates and extending survival (4,5). Randomized clinical trials have demonstrated that trastuzumab, a HER2-directed monoclonal antibody when combined with or administered after chemotherapy in localized disease, reduces the risk of recurrence by approximately 40–50% and improves overall survival (OS) (6-9). However, these trials predominantly included those with stage II or stage III HER2-positive breast cancers. While stage I (≤2 cm and lymph node-negative) HER2-positive breast cancers have a better prognosis and smaller absolute benefit from adjuvant systemic therapy compared to higher stages (stage II or III), recurrence rates ranging from 5–30%, with distant recurrence rate up to 14% in the absence of systemic therapy, highlight the importance of adjuvant systemic therapy for stage I HER2-positive breast cancers (10-12).

What is the current recommended systemic therapy regimen for stage I HER2-positive breast cancer? The APT (adjuvant paclitaxel and trastuzumab) trial (n=406 patients) established the combination of weekly paclitaxel and trastuzumab (TH) for 12 weeks, followed by trastuzumab (H) monotherapy for 9 months, with the addition of hormonal therapy for hormone receptor-positive tumors, as the current standard adjuvant systemic therapy for stage I HER2-positive breast cancers. The initial 3-year follow-up (published in 2015) showed a 3-year recurrence-free interval (RFI, defined as invasive local, regional, or distant recurrence, or any death from breast cancer) of 99.2% [95% confidence interval (CI): 98.4–100%] and a 3-year invasive disease-free survival (iDFS, defined as invasive local, regional, or distant recurrence, contralateral invasive breast cancer, or death from any cause) of 98.7% (95% CI: 97.6–99.8%). Long-term follow-up revealed a 10-year iDFS was 91.3% (95% CI: 88.3–94.4%), a 10-year RFI was 96.3% (95% CI: 94.3–98.3%), a 10-year breast cancer-specific survival (BSS) of 98.8% (95% CI: 97.6–100%), and a 10-year OS of 94.3% (95% CI: 91.8–96.8%). Based on these results, this regimen is widely accepted as the standard adjuvant systemic therapy. It is endorsed by all major guidelines, including the National Comprehensive Cancer Network and the European Society of Medical Oncology, for stage I (≤2 cm and lymph node-negative) HER2-positive cancers. While the regimen can also be used for cancers up to 3 cm, it is important to note that only 9% of patients in the trial had tumors between 2 and 3 cm (13,14).

Can we improve the remarkable outcomes of the paclitaxel and trastuzumab followed by trastuzumab (TH-H regimen from the APT trial) while minimizing side effects and optimizing health-related quality of life (QOL), especially with newer HER2-targeted therapies? Trastuzumab emtansine (T-DM1), a second-generation HER2-targeted agent, is an antibody-drug conjugate consisting of a HER2-directed monoclonal antibody linked to emtansine, a microtubule inhibitor (15). T-DM1 is used in locally advanced or metastatic HER2-positive breast cancer after prior treatment with trastuzumab and taxane, based on the EMILIA trial, and was approved by the Food and Drug Administration (FDA) for this indication in 2013 (16). It is also used as adjuvant therapy for localized (>1 cm tumor or lymph node positive) HER2-positive breast cancer with residual invasive cancer (detected pathologically in the breast and/or axillary lymph nodes) after neo-adjuvant trastuzumab and taxane-based therapy, based on the KATHERINE trial, and was FDA approved for this indication in 2019 (17).

The ATEMPT (Adjuvant Trastuzumab Emtansine Versus Paclitaxel Plus Trastuzumab for Stage I Human Epidermal Growth Factor Receptor 2-Positive Breast Cancer) trial by Tarantino et al. aimed to assess whether T-DM1 monotherapy offered lower toxicity than TH-H while maintaining clinically acceptable efficacy in stage I HER2-positive breast cancer. A total of 512 patients were randomized (3:1) to T-DM1 (n=384 patients, every 3 weeks for 17 cycles) or TH-H (n=128 patients, paclitaxel with trastuzumab weekly for 12 weeks, followed by trastuzumab every 3 weeks for 13 cycles), with adjuvant endocrine therapy if hormone receptor-positive in both arms. After a median follow-up of 5.8 years, T-DM1 showed excellent efficacy with a 5-year RFI of 98.3% (95% CI: 97–99.7%) with only 2 local recurrences and 3 distant recurrences; a 5-year iDFS of 97% (95% CI: 95.2–98.7%), a 5-year BSS of 99.4% (95% CI: 98.6–100%), and a 5-year OS of 97.8% (95% CI: 96.3–99.3%). Notably, the T-DM1 efficacy was consistent across all subgroups, including tumor size (<1 vs. ≥1 cm), hormone receptor status (positive vs. negative), HER2 immunohistochemistry (IHC) score (IHC 2+ vs. IHC 3+), and duration of receipt of T-DM1 (<6 vs. ≥6 months). This study, though not powered to compare the efficacy of T-DM1 with TH-H, as such a design was deemed unfeasible due to the low event rate in this population, the reported 5-year outcomes for the TH-H arm were: RFI of 93.2% (95% CI: 88.5–98.2%), iDFS of 91.1% (95% CI: 85.7–96.8%), BSS of 99% (95% CI: 97.2–100%), with wide confidence intervals reflecting lack of adequate power. Despite the limitations of cross-trial comparisons, the similar patient characteristics in the ATEMPT and APT trials suggest that T-DM1 achieves excellent long-term outcomes comparable to the TH-H regimen (18).

Given the impressive efficacy of T-DM1, how do its safety and tolerability compare with TH-H? The safety analysis of the ATEMPT trial revealed that the combined incidence of all clinically relevant toxicities (CRTs) was comparable between the two arms- 46% in the T-DM1 and 47% in the TH-H arm (P=0.83). CRTs were defined as grade ≥3 nonhematologic toxicity, grade ≥2 neurotoxicity, grade ≥4 hematologic toxicity, febrile neutropenia, any toxicity requiring dose delay or treatment discontinuation, or any serious adverse event. Although the combined rate of CRTs was similar, the type of toxicity differed significantly between the arms (Table 1). The TH-H arm had higher rates of ≥ grade 2 neuropathy, neutropenia, alopecia, diarrhea, gastroesophageal reflux disease (GERD), and infusion reactions, whereas ≥ grade 2 thrombocytopenia and elevated bilirubin were more common in the T-DM1 arm. Notably, treatment discontinuation due to toxicity was more frequent in the T-DM1 arm, with 61% of those who discontinued switching to trastuzumab to complete one year of treatment (19).

Among the patient-reported outcomes, those in the TH-H arm experienced a significantly greater decline in QOL from baseline to week 12 compared to the T-DM1 arm, as measured by the functional assessment of cancer therapy-breast cancer (FACT-B) score, with a 6-point decrease (P<0.01). Physical and psychological distress was also more pronounced in the TH-H arm during the first 12 weeks (P<0.01), coinciding with weekly paclitaxel dosing, and more patients in this arm missed work or reported work-related impairment at 3 and 12 weeks. At 18 months, T-DM1 showed superior QOL in women ≤50 years, with a mean FACT-B score difference of 6.48 (95% CI: 0.51–12.46) compared to TH-H, driven by improved social/family well-being and breast cancer-specific sub-scores. In women >50 years, T-DM1 was associated with better physical well-being and less activity impairment, though no differences in global QOL were observed (20).

Can novel prognostic or predictive biomarkers offer better prognostication and improve outcomes in stage I HER2-positive breast cancer? Despite favorable results in the ATEMPT and APT trials, a small number of recurrences occurred, irrespective of tumor size, HER2 IHC, or hormone receptor status, highlighting the limitations of standard clinicopathological features for prognostication and underscoring the need for novel biomarkers. To address this, the ATEMPT trial performed correlative analyses using the HER2DX risk score, multi-omic evaluations of HER2 heterogeneity, and thrombocytopenia predictors on the available samples. The HER2DX risk score, derived from a combination of clinical factors and genetic signatures related to immune features (IgG), tumor cell proliferation, and luminal differentiation, ranges from 0 to 100, with higher scores indicating higher relapse risk (21). The ATEMPT trial found that those with low HER2DX risk scores (0–50, 93.6% of those assessed) had significantly better RFI [98.1% vs. 81.8%, hazard ratio (HR), 0.10, P=0.01] and iDFS (96.3% vs. 81.8%, HR, 0.20, P=0.047) compared to those with high HER2DX risk scores (score of 50–100, only 6.4% of those assessed). In contrast, HER2 heterogeneity had no significant impact on recurrence or survival outcomes, and no germline genomic variants predicting the risk of thrombocytopenia or bleeding with T-DM1 were identified.

How should we decide between T-DM1 and TH-H for our stage I HER2-positive breast cancer patients in the clinic? T-DM1 is a compelling alternative to TH-H, offering notable advantages such as a lower risk of neuropathy, no ≥ grade 2 alopecia, improved QOL, decreased work-related impairment, and reduced neutropenia- all toxicities linked to paclitaxel. Furthermore, the absence of corticosteroid premedication with T-DM1 spares patients from corticosteroid-associated side effects, such as immunosuppression and hyperglycemia. T-DM1’s every-three-week dosing schedule also minimizes “time toxicity”, enhancing convenience compared to the weekly dosing required for TH-H during the first 12 weeks. These factors make T-DM1 particularly appealing to patients prioritizing QOL or seeking to avoid traditional chemotherapy. However, these benefits must be weighed against the significant financial toxicity of T-DM1, as its cost is substantially higher than TH-H, and its availability remains limited in underdeveloped countries. For those ineligible or unwilling to undergo paclitaxel-based systemic therapy, T-DM1 stands out as a favorable and effective option.

What are the future directions in adjuvant systemic therapy for stage I HER2-positive breast cancer?

• Can a shorter duration of HER2- directed therapy be used? A meta-analysis of four trials evaluating shorter trastuzumab durations (Short-HER: 9 weeks; PERSEPHONE, HORG, and PHARE: 6 months) in stage I–III HER2-positive breast cancer found that non-inferiority to 1 year of trastuzumab (in combination with chemotherapy) could not be established, with 1 year showing significantly improved OS (HR 1.28; 95% CI: 1.02–1.63; P=0.04) and iDFS (HR 1.24; 95% CI: 1.07–1.44; P=0.004) (22). However, subgroup analysis of this meta-analysis revealed no statistically significant difference in iDFS for node-negative patients (HR 1.15, 95% CI: 0.79–1.66, P=0.46), raising the question of whether a shorter duration of HER-2 directed treatment might be reasonable in stage I HER2 positive breast cancer? The ATEMPT trial demonstrated similar outcomes for those who received T-DM1 for <6 vs. ≥6 months, but 61% of those discontinuing <6 months transitioned to complete 1 year of treatment with trastuzumab (18). The ongoing ATEMPT 2.0 (NCT04893109) trial is evaluating this shorter course of T-DM1 for 6 cycles followed by trastuzumab for 11 cycles to determine if this allows for continued efficacy while reducing toxicity in stage I HER2-positive breast cancer.
• Can the adjuvant therapy regimens be de-escalated to a non-chemotherapy regimen? A randomized trial in older patients (70–80 years) with stage I-III HER2-positive breast cancer (of which stage I: 43.6%) found that trastuzumab monotherapy did not meet non-inferiority compared to trastuzumab with chemotherapy but showed only less than 1-month survival loss at 3 years, supporting trastuzumab monotherapy as a lower toxicity option for select patients (23). The ongoing ADEPT trial (NCT04569747) for stage I HER2-positive, hormone receptor-positive tumors is exploring a chemo-free regimen of trastuzumab, pertuzumab, and endocrine therapy. The ongoing IRIS trial (NCT04383275) is evaluating the efficacy and safety of capecitabine (oral chemotherapy) for 6 cycles + endocrine therapy (if hormone receptor-positive) + trastuzumab (cohort A: hormone receptor-positive and negative) and endocrine therapy + trastuzumab (cohort B: only hormone receptor-positive) in stage I HER2-positive breast cancer. These trials have the potential to expand tolerable adjuvant systemic therapy options for stage I HER2-positive breast cancer.
• Can the adjuvant therapy be tailored based on the recurrence risk? Similar to the ATEMPT trial (as discussed above), the APT trial showed that those with a high HER2DX risk score ≥32 had a higher 10-year recurrence risk (13.3% vs. 1.4% for those with a score <32), with 4.9% having scores ≥50 (14). The concordant results from both ATEMPT and APT trials highlight HER2DX risk score as a potential reliable prognostic tool for tailoring treatment in stage I HER2-positive breast cancer, though further exploration and prospective validation are needed. An accurate prognostic tool is crucial to enable treatment escalation with more effective adjuvant therapy for high-risk patients and de-escalation for low-risk patients.

While progress in de-escalating treatment for low-risk stage I HER2-positive breast cancer patients is promising, the equally critical need for tailored escalation in high-risk patients must not be overlooked. By moving beyond a one-size-fits-all approach and refining systemic therapy through ongoing and future trials incorporating prognostic and predictive biomarkers, we can optimize outcomes by minimizing toxicity and maximizing efficacy for all our patients.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gland Surgery. The article has undergone external peer review.

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