T-DM1 Shows Promise With Low Recurrence Rates in HER2-Positive Breast Cancer

Patients with stage I HER2-positive breast cancer had effective long-term outcomes after 1 year of adjuvant trastuzumab emtansine (T-DM1), with high HER2DX risk scores predicting higher risk of recurrence, according to new data from the ATEMPT trial (NCT01852748).¹

Recurrence rates for patients with stage I HER2-positive breast cancer are between 5% toand30%. The international guidelines were based on the APT trial (NCT00542451) that found after 12 weeks, adjuvant paclitaxel (Herceptin) combined with 1 year of trastuzumab (TH regimen) resulted in a 10 year invasive disease-free survival of 91.3% in patients with small node-negative HER2-positive tumors.

The study authors of the APT trial concluded, “Adjuvant paclitaxel and trastuzumab is a reasonable treatment standard for patients with small, node-negative, HER2-positive breast cancer. The HER2DX genomic tool might help to refine the prognosis for this population.”²

Currently, T-DM1 is approved for the adjuvant treatment of patients with HER2-positive breast cancer with residual invasive disease following neoadjuvant therapy or with metastatic disease where it has shown similar efficacy with lower toxicity compared with trastuzumab plus taxane treatment.¹

Methods

The ATEMPT trial was designed as a multicenter, randomized, investigator-initiated phase 2 study. Patients who underwent breast cancer surgery within the past 90 days were randomized 3:1 to receive T-DM1 or TH. After 12 weeks of T-DM1 or the conclusion of paclitaxel therapy, adjuvant radiation therapy and endocrine therapy could be initiated.

Clinically relevant toxicities were monitored and defined as nonhematologic toxicity (grade ≥ 3), neurotoxicity (grade ≥ 2), hematologic toxicity (grade ≥ 4), febrile neutropenia, and any serious adverse event or event that requires dose delay or treatment discontinuation.

Results

Participants were enrolled between May 2013 and December 2016, with 383 patients administered T-DM1 and 114 patients received TH.

Nearly half of the patients had tumors that were larger than 1 cm, about 75% had HR-positive disease, 4% had micrometastatic nodal involvement, and the remaining patients had node-negative disease.

Follow-up was an average of 5.8 years with 11 invasive disease-free survival events found in the T-DM1 arm. This data was consistent with a 5 year invasive disease-free survival of 97%. After 5 years, the recurrence-free interval (RFI) was 98.3%, with a 5-year overall survival of 97.8% and a 5-year breast cancer–specific survival of 99.4%.

Of the 11 invasive disease-free survival events found with T-DM1, there were 3 distant recurrences, 2 ipsilateral recurrences, 3 new contralateral primary breast cancers, and 3 non–breast cancer–related deaths.

The TH arm had 9 invasive disease-free survival events that were consistent with the 5-year invasive disease-free survival rate of 91.1%. After the 5-year period, the RFI was 93.2%, the overall survival was 97.9%, and the breast cancer–specific survival was 99%. There were only 2 distant recurrences found in the TH arm among the 9 invasive disease-free survival events.

Despite tumor size and hazard ratio status, survival outcomes were examined for T-DM1. For patients with tumors smaller than 1 cm, the 5-year invasive disease-free survival rate was 98.7%; this dropped slightly to 95.6% for tumors 1 cm or larger. Patients with HR-positive tumors had a 96.8% five-year invasive disease-free survival rate, and patients with HR-negative tumors, 97.6%.

The patients who received T-DM1 for less than 6 months had a 5-year invasive disease-free survival rate of 96.8% and a RFI of 100%. Similarly, patients who received 6 or more months of T-DM1 treatment had a 5-year invasive disease-free survival of 97% and an RFI of 98.1%.

HER2DX Analysis

About 37.6% of patients enrolled in the ATEMPT trial underwent standardized HER2DX genomic testing.

The HER2DX genomic test was developed in 2022 and can provide patients with HER2-positive early breast cancer a single 27-gene expression and clinical feature–based classifier able to produce 2 independent scores to predict long-term prognosis and likelihood of pathological complete response.³

Patients with available HER2DX testing were 95.4% of the 5-year invasive disease-free survival group and 97% of the 5-year RFI cohort.¹ There were 93.6% of patients with HER2DX low-risk disease and 6.4% with high-risk disease. Individuals with lower risk had more favorable RFI and invasive disease-free survival vs patients who had HER2DX high-risk disease.

There were 6.8% of patients who had both HER2DX information and single-cell fluorescent in situ hybridization (FISH) results available to evaluate the HER2 heterogeneity.

HER2 Heterogeneity Analysis

A higher proportion of tumor cells expressed weak to moderate and incomplete membrane staining associated with HR-positive tumors. HR-negative tumors were linked to a higher proportion of tumor cells with intense and complete circumferential staining for HER2. There were no associations between the HER2 stain intensity proportion features and risk of recurrence among patients.

Observations did not find higher entropy in HER2 staining distribution in ER-positive vs ER-negative cases or PR-positive vs PR-negative cases, but neither were significant. The study did not display differences in entropy distribution between patients who experienced recurrence or did not experience recurrence either in the study cohort or when evaluating each arm separately.

FISH Analysis of HER2 Heterogeneity

FISH analysis is conducted on patients with HER2 breast cancer to determine the primary tumor and to determine if samples are negative, equivocal, or positive to identify patients for anti-HER2 therapy.⁴

There were no relevant associations between HER2 genetic heterogeneity and recurrence.¹ Among the patients who were receiving T-DM1, 16.7% of patients who experienced recurrence had HER2 genetic heterogeneity vs the 5.6% who did not have recurrence.

Tumors with HER2 genetic heterogeneity had higher entropy of the immunohistochemistry HER2 stain intensity distribution than tumors without genetic heterogeneity.

Spatial Proteomic Analysis

A spatial proteomic analysis was conducted on tumor samples for 13 patients who experienced invasive disease-free survival events in the trial and 21 matched controls. There were 3 cases of up-regulated primary tumors and 5 cases of down-regulated proteins.

Thrombocytopenia Analysis

There were 54 single nucleotide polymorphisms (SNPs) found with the occurrence of thrombocytopenia bleeding and 103 SNPs with occurrence of thrombocytopenia. However, none of the variants had a P value that reached the threshold for genome-wide significance.

Conclusion

Although the study design limited our ability to identify genetic factors associated with T-DM1 adverse effects, the treatment showed promising results for stage 1 HER2-positive breast cancer with low recurrence rates. Additionally, the HER2DX score emerged as a potential indicator for recurrence risk.

References

1. Tarantino P, Tayob N, Villacampa G, et al. Adjuvant trastuzumab emtansine verseus paclitaxel plus trastuzumab for stage I HER2-positive breast cancer: 5-year results and correlative analyses from ATEMPT. J Clin Oncol. 2024;1-32.

2. Stenger M. Adjuvant paclitaxel and trastuzumab in node-negative, HER2-positive breast cancer: long-term follow-up. The ASCO Post. March 7, 2023. Accessed June 27, 2024. https://ascopost.com/news/march-2023/adjuvant-paclitaxel-and-trastuzumab-in-node-negative-her2-positive-breast-cancer-long-term-follow-up/

3. Guarneri V, Brasó-Maristany F, Dieci MV, et al. HER2DX genomic test in HER2-positive/hormone receptor-positive breast cancer treated with neoadjuvant trastuzumab and pertuzumab: a correlative analysis from the PerELISA trial. eBioMedicine. 2022;85:104320. doi:10.1016/j.ebiom.2022.104320

4. Grüntkemeier L, Khurana A, Bischoff FZ, et al. Single HER2-positive tumor cells are detected in initially HER2-negative breast carcinomas using the DEPArray-HER2-FISH workflow. Breast Cancer. 2022;29(3):487-497. doi:10.1007/s12282-022-01330-8