Tumor Intrinsic Subtype Affects Relationship Between pCR and EFS in ERBB2+/HER2+ Early Breast Cancer


Tumor intrinsic subtype impacted the association between pCR and EFS after chemotherapy and ERBB2/HER2 blockade in ERBB2/HER2-positive early breast cancer.

ERBB2/HER2-positive early breast cancer

ERBB2/HER2-positive early breast cancer

Patients with ERBB2/HER2-positive early breast cancer experienced a varying association between pathologic complete response (pCR) and event-free survival (EFS) following neoadjuvant chemotherapy plus ERBB2/HER2 blockade depending on their tumor intrinsic subtype, according to findings from a pooled analysis published in JAMA Oncology. The analysis aggregated data from the phase 3 CALGB 40601 (NCT00770809), NeoALTTO (NCT00553358), and NSABP B-41 (NCT00486668) clinical trials.

Findings from the analysis of 758 pooled patients revealed that those with ERBB2-enriched (HR, 0.45; 95% CI, 0.29-0.70; P < .001) and basal-like (HR, 0.19; 95% CI, 0.04-0.86; P = .03) tumors experienced an association between pCR results and EFS. However, patients with luminal A or B tumors did not experience an association between pCR and EFS. Additionally, there was an independent EFS benefit of treatment with trastuzumab (Herceptin) plus lapatinib (Tykerb) compared with trastuzumab monotherapy observed only among patients with ERBB2-enriched disease (HR, 0.47; 95% CI, 0.27-0.83; P = .009). Overall, 44.5% and 1.5% of gene expression signatures (n = 618) were significantly associated with pCR and EFS, respectively.

“In patients with ERBB2/HER2-positive early breast cancer, the association between pCR and EFS differed by tumor intrinsic subtype, and the benefit of dual ERBB2/HER2 blockade was limited to ERBB2-enriched tumors. Immune-activated signatures were concordantly associated with higher pCR rates and better EFS, whereas luminal signatures were associated with lower pCR rates,” Aranzazu Fernandez-Martinez, MD, PhD, a research associate at Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, and coauthors wrote.

To conduct their analysis, investigators pooled data from a total of 1289 patients with ERBB2/HER2-positive early breast cancer who received chemotherapy plus either trastuzumab, lapatinib, or trastuzumab plus lapatinib in the CALGB 40601, NeoALTTO, and NSABP B-41 studies. The combined median follow-up was 5.5 years; gene expression profiling via RNA sequencing was gathered from 758 samples, and intrinsic subtypes and gene expression signatures were calculated.

The data analyses were conducted between June 1, 2020, to January 1, 2023. Study authors used logistic regression and Cox analyses to study the association of clinical variables and gene expression biomarkers with pCR and EFS.

Investigators noted that all 3 studies had pCR, correlative, and/or survival end points, and enrolled previously untreated patients with early ERBB2/HER2-positive breast cancer. All trials randomly assigned eligible patients to receive chemotherapy in combination with trastuzumab monotherapy, lapatinib monotherapy, or dual trastuzumab and lapatinib.

Study authors also highlighted that differences between the 3 trials included a 6-week lead-in phase of the randomized anti-ERBB2/HER2 agent(s) in NeoALTTO, all chemotherapy was given as neoadjuvant therapy in NSABP B-41, neoadjuvant treatment durations ranged from 16 weeks in CALGP 40601 to 28 weeks in NSABP B-41, and that the adjuvant anti-ERBB2/HER2 therapy in NeoALTTO was as randomly assigned but was trastuzumab monotherapy in CALGP 40601and NSABP B-41. A pCR was uniformly defined as the absence of invasive tumor cells in the breast and EFS was defined as the time from randomization to the event. Although a slight difference in event definition existed between the 3 trials (progressions during the neoadjuvant phase were regarded as events in CALGB 40601 and NeoALTTO but not in NSABP B-41), only 3 patients from NeoALTTO and 5 from NSABP B-41 progressed during the neoadjuvant phase.

The median age of patients in the pooled analysis was 49 years. Most patients were White (75%); 12% of patients were Asian and 6% were Black. The baseline clinicopathologic features across the 3 clinical trials were generally similar. The data cutoff dates for NeoALTTO, CALGB 40601, and NSABP B-41 were May 26, 2016; June 10, 2021; and December 31, 2016, respectively. Gene expression profiles were obtained from NeoALTTO (n = 249), CALGB 40601 (n = 264), and NSABP B-41 (n = 245). In the overall cohort, patients had ERBB2-enriched (57.9%), luminal B (15.0%), luminal A (9.9%), basal-like (8.8%), and normal-like (8.3%) tumors.

Additional findings from the analysis revealed the estimated 5-year EFS rates with trastuzumab plus lapatinib (83%) vs trastuzumab monotherapy (79%) vs lapatinib monotherapy (73%) were not significantly different according to a multivariable Cox analysis (adjusted HR, 0.74; 95% CI, 0.54-1.01; P = .056). Moreover, patients who received trastuzumab plus lapatinib achieved significantly higher pCR rates compared with those treated with trastuzumab monotherapy (adjusted OR, 1.80; 95% CI, 1.36-2.39; P < .001), according to a multivariable analysis for pCR prediction.

Finally, patients with residual disease (n = 409) experienced a significantly better prognosis if the tumors were baseline hormone receptor-positive (adjusted HR, 0.50; 95% CI, 0.34-0.74; P < .001); those with luminal expression subtypes also had a better prognosis compared with patients with HER2-enriched disease (adjusted HR, 0.55; 95% CI, 0.35-0.86; P = .01).

“This pooled analysis of 3 phase 3 clinical trials with similar designs illustrates how the association between pCR and survival in ERBB2/HER2-positive early breast cancer varies by genomic intrinsic subtype and is only significant in patients with ERBB2/HER2-positive/ERBB2-enriched and ERBB2/HER2-positive/basal-like tumors,” study authors wrote in conclusion. “These results support our previous findings, suggesting that the combination of tumor and immune-related biomarkers provide essential prognostic information to stratify patients with ERBB2/HER2-positive early breast cancer in different groups that could benefit from different treatment strategies; some newer commercially available predictors already integrate these elements into a single assay.”


Fernandez-Martinez A, Rediti M, Tang G, et al. Tumor intrinsic subtypes and gene expression signatures in early-stage ERBB2/HER2-positive breast cancer: a pooled analysis of CALGB 40601, NeoALTTO, and NSABP B-41 trials. JAMA Oncol. Published online March 28, 2024. doi:10.1001/jamaoncol.2023.7304

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