Faculty Bibliography

PURPOSE/OBJECTIVE:Immunotherapy has recently been shown to improve outcomes for advanced PD-L1-positive triple-negative breast cancer (TNBC) in the Impassion130 trial, leading to FDA approval of the first immune checkpoint inhibitor in combination with taxane chemotherapy. To further develop predictive biomarkers and improve therapeutic efficacy of the combination, interrogation of the tumor immune microenvironment before therapy as well as during each component of treatment is crucial. Here we use single-cell RNA sequencing (scRNA-seq) on tumor biopsies to assess immune cell changes from two patients with advanced TNBC treated in a prospective trial at predefined serial time points, before treatment, on taxane chemotherapy and on chemo-immunotherapy. METHODS:Both patients (one responder and one progressor) received the trial therapy, in cycle 1 nab-paclitaxel given as single agent, in cycle 2 nab-paclitaxel in combination with pembrolizumab. Tumor core biopsies were obtained at baseline, 3 weeks (after cycle 1, chemotherapy alone) and 6 weeks (after cycle 2, chemo-immunotherapy). Single-cell RNA sequencing (scRNA-seq) of both cancer cells and infiltrating immune cells isolated were performed from fresh tumor core biopsy specimens by 10 × chromium sequencing. RESULTS:). In contrast, tumors from the patient with rapid disease progression showed a prevalent and persistent myeloid compartment. CONCLUSIONS:Our study provides a deep cellular analysis of on-treatment changes during chemo-immunotherapy for advanced TNBC, demonstrating not only feasibility of single-cell analyses on serial tumor biopsies but also the heterogeneity of TNBC and differences in on-treatment changes in responder versus progressor.

Background: PD-1/PD-L1 checkpoint blockade in combination with chemotherapy has improved outcomes in triple-negative breast cancer, but its role in hormone receptor-positive (HR+) metastatic breast cancer (MBC) is less clear. We report the results of the HR+ cohort of a HER2-negative MBC trial.
Method(s): Prospective phase 2 trial where 20 HR+/HER2- MBC patients (pts) received nab-paclitaxel (A) (100mg/m2 IV d1/8, q 3 wks) and pembrolizumab (P) (200mg IV d1, q 3 wks, starting with cycle 2). Eligibility: ER/PR >=1%, HER2 negative, maximum of 2 lines of cytotoxic therapy for MBC, pts could have received prior endocrine and/or targeted therapy. Primary endpoint: best overall response rate (BORR) by RECIST v1.1; secondary endpoints: safety, PFS, clinical benefit rate (CBR), duration of response (DOR), and overall survival (OS). Biomarker analyses are ongoing.
Result(s): In this 20-patient cohort, the median age was 56 (34-75), median lines of cytotoxic chemotherapy was 1 (0-2), 70% (14/20) were ER>10%, 80% (16/20) received prior hormone therapy, and 60% (12/20) received prior CDK 4/6 inhibitors. BORR was partial response (PR) in 5/20, stable disease (SD) in 7/20, and progressive disease (PD) in 7/20. CBR was 35% (7/20). Median PFS was 5.6 mos (95%CI 2.07-8.18), median OS 15.7 mos (95%CI 3.88-27.70) and median DOR was 3.9 mos (95%CI 2.07-not yet reached). Out of 5 pts who achieved PR, 4 (80%) received prior CDK 4/6 inhibitors. The most common related adverse events (AE) were anemia (50%), diarrhea, nausea and ALT abnormalities (40% each). 14 pts experienced grade 3 AEs, the most common being neutropenia, 1 pt had grade 4 AEs (pneumonitis, blood/lymphatics, hyponatremia), and no grade 5 AEs. [Formula presented]
Conclusion(s): P plus A was efficacious with PR in 5/20 and SD in 7/20 pts with a manageable toxicity profile. Importantly, responses were observed in patients previously treated with CDK 4/6 inhibitors. Further investigation of this regimen in HR+/HER2- MBC is warranted. Clinical trial identification: NCT02752685. Legal entity responsible for the study: NYU Langone Health.
Funding(s): Merck (drug-pembrolizumab and financial funding); Celgene (drug-nab-paclitaxel). Disclosure: F. Muggia: Advisory/Consultancy, Member of data safety monitoring committee of Pembrolizumab trials run by Merck: Merck. S. Adams: Advisory/Consultancy, Research grant/Funding (institution), consultant (uncompensated): Merck; Research grant/Funding (institution): Celgene. All other authors have declared no conflicts of interest.
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BACKGROUND:Of women diagnosed with metastatic breast cancer (MBC), 20% to 30% survive ≥5 years. We evaluated data from a large breast cancer program to identify features associated with MBC survival. PATIENTS AND METHODS:, and Fisher exact tests. Odds ratios (ORs) were calculated using multivariate logistic regression models. RESULTS:Long-term survivors were significantly (P < .05) younger, premenopausal, partnered, had estrogen receptor (ER)-positive, progesterone receptor-positive, and HER2-positive disease, lower Charlson Comorbidity Index, lower rates of visceral metastases, and higher household income. After adjustment for potential confounders, de novo MBC, premenopausal status, ER-positive status, and HER2-positive status remained significantly positively associated with long-term survival (respectively: OR, 2.68 [95% confidence interval (CI), 1.48-4.88]; OR, 1.96 [95% CI, 1.02-3.79]; OR, 3.74 [95% CI, 1.72-8.14]; OR, 2.88 [95% CI, 1.61-5.14]). Triple-negative status, visceral with bone metastases, and brain metastases remained negatively associated with long-term survival (respectively: OR, 0.12 [95% CI, 0.05-0.29]; OR, 0.18 [95% CI, 0.07-0.47]; OR, 0.16 [95% CI, 0.04-0.60]). Partner status and household income were significant in univariate but not multivariate analyses. CONCLUSION:Diagnosis of de novo MBC, premenopausal status, ER-positive status, and HER2-positive status were positively associated whereas triple-negative status, brain metastases, and visceral with bone metastases were inversely associated with long-term survival. These findings can be applied to better prognosticate survival for MBC patients.