Telli, Melinda L

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.

The NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget’s disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The panel convenes annually to update recommendations based on a review of recently published clinical trials. This selection from the NCCN Guidelines for Breast Cancer focuses on the recommendations for the management of recurrent or stage IV (M1) metastatic breast cancer. It summarizes the treatment strategies stratified by tumor biology, including hormone receptor status and HER2 expression, as well as clinical factors such as prior therapy and disease-free interval. Throughout all treatment lines, supportive care, quality of life preservation, toxicity minimization, and clinical trial participation are emphasized as integral components of patient care.

The treatment landscape of invasive early-stage and metastatic breast cancer is evolving constantly. These NCCN Guidelines Insights focus on recent updates included in the most recent version (version 5.2025) of the NCCN Guidelines for Breast Cancer specific to workup, locoregional therapy, surveillance, and systemic neoadjuvant/adjuvant therapy recommendations for invasive, nonmetastatic breast cancer.

Breast cancer is treated with a multidisciplinary approach involving surgical oncology, radiation oncology, and medical oncology. The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget’s disease, Phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of systemic therapy (preoperative and adjuvant) options for nonmetastatic breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org .

The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for Breast Cancer address all aspects of management for breast cancer. The treatment landscape of metastatic breast cancer is evolving constantly. The therapeutic strategy takes into consideration tumor biology, biomarkers, and other clinical factors. Due to the growing number of treatment options, if one option fails, there is usually another line of therapy available, providing meaningful improvements in survival. This NCCN Guidelines Insights report focuses on recent updates specific to systemic therapy recommendations for patients with stage IV (M1) disease.

The therapeutic options for patients with noninvasive or invasive breast cancer are complex and varied. These NCCN Clinical Practice Guidelines for Breast Cancer include recommendations for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, and management of breast cancer during pregnancy. The content featured in this issue focuses on the recommendations for overall management of ductal carcinoma in situ and the workup and locoregional management of early stage invasive breast cancer. For the full version of the NCCN Guidelines for Breast Cancer, visit NCCN.org .

The NCCN Guidelines for Breast Cancer include up-to-date guidelines for clinical management of patients with carcinoma in situ, invasive breast cancer, Paget disease, phyllodes tumor, inflammatory breast cancer, male breast cancer, and breast cancer during pregnancy. These guidelines are developed by a multidisciplinary panel of representatives from NCCN Member Institutions with breast cancer–focused expertise in the fields of medical oncology, surgical oncology, radiation oncology, pathology, reconstructive surgery, and patient advocacy. These NCCN Guidelines Insights focus on the most recent updates to recommendations for adjuvant systemic therapy in patients with nonmetastatic, early-stage, hormone receptor–positive, HER2-negative breast cancer.

Several new systemic therapy options have become available for patients with metastatic breast cancer, which have led to improvements in survival. In addition to patient and clinical factors, the treatment selection primarily depends on the tumor biology (hormone-receptor status and HER2-status). The NCCN Guidelines specific to the workup and treatment of patients with recurrent/stage IV breast cancer are discussed in this article.

Abstract Background: PARP inhibitor (PARPi) monotherapy has previously demonstrated clinical activity only in patients with a germline BRCA mutation (BRCAmut), while single-agent anti-programmed cell death protein 1 (PD-1) therapy has achieved response rates of only 5–20% in advanced triple negative breast cancer (TNBC). In preclinical studies, PARP inhibition enhanced anti-tumor immunity, increased infiltration of proliferating CD8+ T cells, and synergized with anti-PD-1 agents in BRCA wildtype (wt) tumors. TOPACIO is a fully enrolled, phase I/II trial of niraparib + pembrolizumab (pembro) in advanced TNBC. This combination achieved 28% objective response rate (ORR) and 50% disease control rate (DCR) in evaluable patients. Although activity was highest in patients with BRCAmut (ORR=60%; DCR=80%), durable clinical benefit was also observed in patients without BRCA mutations. In this study, we conducted exploratory biomarker analyses to evaluate their potential correlation with durable clinical benefit (any complete response [CR] or partial response [PR] regardless of duration or stable disease [SD] for ≥16 weeks) beyond BRCA mutations. Method: ORR was assessed by RECIST v1.1. Duration of disease control (DDC) was defined as time from first dose of study treatment to radiologic disease progression or death. Tumor mutational status of homologous recombination repair (HRR) and other DNA damage repair (DDR) pathway genes was determined using an NGS panel. Immunoprofiling was conducted using NanoString IO360 panel complimented with 30 DNA repair spike-ins. Tumor immune micro-environment was characterized using multiplex immuno-fluorescence (CycIF). PD-L1 status was determined using the Agilent/DAKO 22C3 IHC clinical trial assay. Results: Of 46 evaluable patients, 20 achieved durable clinical benefit (any CR/PR or SD≥16 weeks) with niraparib + pembro combination, of which 8 were tumor BRCA wild type (wt), and 1 was BRCA unknown. Of the 9 BRCAwt/unknown patients, 5 had deleterious mutations in HRR/DDR pathway genes, whereas the remaining 4 had no mutations (HRR/DDR wt). Mutations that were associated with response include CHEK1 (CR; DDC=10.3 mos), ATR (CR; DDC=6.4 mos), PALB2 (PR; DDC=3.5 mos), BLM (SD; DDC=8.1 mos), and NBN/RAD51C (SD; DDC=3.7 mos). Of 4 patients that had no identified mutations (HRR/DDR wt), 1 patient had CR; DDC=10.3 mos, and the remaining 3 patients had SD with DDC ranging from ∼4-8 mos. Of note, all 4 HRR/DDR wt patients were also PD-L1-negative. Table:Durable clinical benefit in BRCAwt/unknown patientsHRR/DRR MutationsPD-L1 StatusBest ResponseDDC (Months)CHEK1+CR10.3†ATR+CR6.4PALB2*UnknownPR3.5BLM-SD8.1NBN/RAD51C+SD3.7None-CR10.3†None-SD8.2None-SD4.2None-SD3.9*BRCA status unknown; †Treatment is ongoing. Conclusion: Patients with mutations beyond BRCA achieved durable clinical benefit with niraparib + pembro treatment; five of these patients had DDC >6 mos. Mutations in genes that are associated with the HRR/DDR pathway appear to confer sensitivity to niraparib + anti-PD1. Additional translational analyses, including immunoprofiling and CycIF, will be presented. Funding: TESARO, Inc., Waltham, MA, USA sponsored the study. Citation Format: Vinayak S, Tolaney SM, Schwartzberg L, Mita M, McCann G, Tan AR, Wahner Hendrickson A, Forero A, Anders C, Wulf G, Dillon P, Lynce F, Zarwan C, Erban J, Färkkilä A, Zhou Y, Buerstatte N, Graham JR, Arora S, Dezube B, Telli ML. Durability of clinical benefit with niraparib + pembrolizumab in patients with advanced triple-negative breast cancer beyond BRCA: (TOPACIO/Keynote-162) [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr PD5-02.