Virginia F. Borges

PURPOSE: EA1181 (ClinicalTrials.gov identifier: NCT04266249 ) is a single-arm trial evaluating neoadjuvant taxane, trastuzumab, and pertuzumab (THP) in patients with clinical stage II/IIIa human epidermal growth factor receptor 2 (HER2)–positive breast cancer. This report focuses on the secondary end points of pathologic complete response (pCR) rates and associated factors. The primary end point—3-year recurrence-free survival among patients achieving a pCR (ypT0/Tis, ypN0)—will be reported when data mature. Methods: Patients received four cycles of trastuzumab and pertuzumab (HP) with either once per week paclitaxel (12 weeks) or docetaxel (every 3 weeks for four cycles), followed by surgery. Clinicopathologic characteristics were assessed in all patients. The HER2DX pCR score was determined using diagnostic biopsy samples in a representative subset. Logistic regression models identified factors associated with pCR. RESULTS: A total of 2,175 patients were enrolled (781 HER2+/estrogen receptor‑negative [ER–]; 1,394 HER2+/ER+). Of 2,141 patients who initiated THP, the overall pCR rate was 43.8%: 63.7% in HER2+/ER– and 32.4% in HER2+/ER+ tumors. Higher pCR rates were observed in tumors that were ER-negative or low ER expressing, progesterone receptor-negative or low expressing, HER2 immunohistochemistry (IHC) 3+, and in patients treated with once per week paclitaxel. T3 disease was associated with a lower pCR rate in HER2+/ER– tumors; otherwise, tumor (T) and nodal (N) stage did not significantly affect pCR. Among 569 patients assessed for HER2DX pCR scores, a high score was independently associated with higher pCR rates, after adjustment for clinicopathologic variables. CONCLUSION: Neoadjuvant THP achieved pCR in nearly two-thirds of patients with HER2+/ER– and one third with HER2+/ER+ breast cancer. Low hormone receptor expression, HER2 IHC 3+ status, once per week paclitaxel use, and a high HER2DX pCR score were independent predictors of pCR. These findings should help optimize risk stratification and treatment personalization for patients with HER2-positive breast cancer.

PURPOSE: Metastasis-directed therapy is increasingly used for oligometastatic breast cancer, despite its uncertain benefit during first-line systemic therapy. We evaluated whether metastasis-directed ablation improves progression-free survival (PFS) compared with first-line systemic therapy alone in patients with oligometastatic breast cancer. METHODS: NRG-BR002 is a randomized phase II/III trial across US/Canadian institutions. Participants had ≤4 metastases, controlled primary disease, ≤12 months of first-line systemic therapy without progression with all visible metastases amenable to stereotactic body radiation therapy (SBRT) or surgical resection and were randomly assigned 1:1 to systemic therapy alone (no ablation) or with metastasis-directed ablation (ablation). The primary end point was PFS, defined as time to progression or death. Secondary end points included overall survival (OS) and toxicity. Circulating tumor cells (CTCs) were evaluated as exploratory biomarkers. RESULTS: From December 2014 to September 2019, 129 patients were enrolled; 125 were eligible for analysis. Median age was 54 years; 79% had hormone receptor–positive, human epidermal growth factor receptor 2‑negative disease, 60% solitary metastasis, 50% bone involvement, and 37% bone only. Ablation was delivered via SBRT for 93%. With 72 PFS events and a median follow-up of 29.9 months, median PFS was 23.0 months (no ablation) versus 19.5 months (ablation; hazard ratio [HR], 0.92 [70% CI, 0.71 to 1.17; 95% CI, 0.57 to 1.47]; one-sided P = .36; stratified P = .42). Thus, the trial did not proceed to phase III. OS did not differ significantly between arms (HR, 1.07 [95% CI, 0.60 to 1.89]; one-sided P = .41; stratified P = .52). No grade 5 toxicities occurred. Exploratory analysis suggested improved PFS with ablation in patients with low or absent pretreatment CTCs. CONCLUSION: The addition of metastasis-directed ablation added to first-line systemic therapy did not improve PFS or OS in patients with oligometastatic breast cancer. Ablation should not be routinely used outside of clinical trials, except for palliation.

Representative multiplex immunofluorescence image with nuclei (blue), CD8 (aqua), PDL1 (green), FOXP3 (yellow), PD1 (orange), CD3 (red), and cytokeratin (white) stains depicted.

Multiplex immunofluorescence staining conditions.

Representative multiplex immunofluorescence images with nuclei (blue), CD8 (aqua), FOXP3 (yellow), CD3 (red), and cytokeratin (white) stains depicted.

Tumor-infiltrating lymphocytes assessment workflow.

Multivariate survival analysis by moderate or marked versus absent or mild stromal lymphocytic infiltration, with adjustment for tumor grade, stage, and chemotherapy receipt.

Purpose:The role of tumor-infiltrating lymphocytes (TIL) remains unclear in hormone receptor (HR)–positive/HER2-negative breast cancer, particularly in young patients, whose immune microenvironment could be altered by age-related host and tumor differences.Experimental Design:Patients with stage I to III HR-positive/HER2-negative tumors were identified from a prospective cohort study of patients with breast cancer diagnosed at age ≤40 years. Multiplexed immunofluorescence and semiautomated quantitative software measured cytotoxic T, non–CD8 T, T regulatory, exhausted T, and PDL1+ cells in stroma and tumor. Univariate analyses assessed differences in clinicopathologic characteristics by high versus low immune infiltration, divided based on median. TIL subtypes were evaluated as a continuous variable per 10% increase in Cox regression analyses for invasive breast cancer–free survival, distant disease–free survival (DDFS), and overall survival, adjusted for clinicopathologic parameters.Results:Among 390 patients, high immune infiltration was associated with increasing age, Black race, grade 3 tumors, and metaplastic or micropapillary histologic subtypes. Over a median follow-up of 8 years, higher stromal and intratumoral non–CD8 T-cell infiltration, T regulatory–cell infiltration, and PDL1 expression were associated with improved invasive breast cancer–free survival. Higher intratumoral non–CD8 T-cell infiltration, T regulatory–cell infiltration, and PDL1 expression were associated with improved DDFS; higher stromal PDL1 expression was also associated with improved DDFS. Higher intratumoral cytotoxic T-cell infiltration and PDL1 expression were associated with improved overall survival.Conclusions:Characterization of immune subpopulations could help refine the prognostic value of TILs in young patients with HR-positive breast cancer, who may benefit from risk stratification for treatment individualization.See related commentary by Salgado and Kok, p. 2133

Pearson’s correlation coefficients between tumor-infiltrating lymphocyte subtypes within stroma, with p-values in parentheses.

Representativeness of Study Participants