Faculty Bibliography

BACKGROUND:Unresectable locally advanced or metastatic triple-negative (hormone-receptor-negative and human epidermal growth factor receptor 2 [HER2]-negative) breast cancer is an aggressive disease with poor outcomes. Nanoparticle albumin-bound (nab)-paclitaxel may enhance the anticancer activity of atezolizumab. METHODS:In this phase 3 trial, we randomly assigned (in a 1:1 ratio) patients with untreated metastatic triple-negative breast cancer to receive atezolizumab plus nab-paclitaxel or placebo plus nab-paclitaxel; patients continued the intervention until disease progression or an unacceptable level of toxic effects occurred. Stratification factors were the receipt or nonreceipt of neoadjuvant or adjuvant taxane therapy, the presence or absence of liver metastases at baseline, and programmed death ligand 1 (PD-L1) expression at baseline (positive vs. negative). The two primary end points were progression-free survival (in the intention-to-treat population and PD-L1-positive subgroup) and overall survival (tested in the intention-to-treat population; if the finding was significant, then it would be tested in the PD-L1-positive subgroup). RESULTS:Each group included 451 patients (median follow-up, 12.9 months). In the intention-to-treat analysis, the median progression-free survival was 7.2 months with atezolizumab plus nab-paclitaxel, as compared with 5.5 months with placebo plus nab-paclitaxel (hazard ratio for progression or death, 0.80; 95% confidence interval [CI], 0.69 to 0.92; P=0.002); among patients with PD-L1-positive tumors, the median progression-free survival was 7.5 months and 5.0 months, respectively (hazard ratio, 0.62; 95% CI, 0.49 to 0.78; P<0.001). In the intention-to-treat analysis, the median overall survival was 21.3 months with atezolizumab plus nab-paclitaxel and 17.6 months with placebo plus nab-paclitaxel (hazard ratio for death, 0.84; 95% CI, 0.69 to 1.02; P=0.08); among patients with PD-L1-positive tumors, the median overall survival was 25.0 months and 15.5 months, respectively (hazard ratio, 0.62; 95% CI, 0.45 to 0.86). No new adverse effects were identified. Adverse events that led to the discontinuation of any agent occurred in 15.9% of the patients who received atezolizumab plus nab-paclitaxel and in 8.2% of those who received placebo plus nab-paclitaxel. CONCLUSIONS:Atezolizumab plus nab-paclitaxel prolonged progression-free survival among patients with metastatic triple-negative breast cancer in both the intention-to-treat population and the PD-L1-positive subgroup. Adverse events were consistent with the known safety profiles of each agent. (Funded by F. Hoffmann-La Roche/Genentech; IMpassion130 ClinicalTrials.gov number, NCT02425891 .).

Morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer is gaining momentum as evidence strengthens the clinical relevance of this immunological biomarker. TILs in the post-neoadjuvant residual disease setting are acquiring increasing importance as a stratifying marker in clinical trials, considering the raising interest on immunotherapeutic strategies after neoadjuvant chemotherapy. TILs in ductal carcinoma in situ, with or without invasive carcinoma, represent an emerging area of clinical breast cancer research. The aim of this report is to update pathologists, clinicians and researchers on TIL assessment in both the post-neoadjuvant residual disease and the ductal carcinoma in situ settings. The International Immuno-Oncology Working Group proposes a method for assessing TILs in these settings, based on the previously published International Guidelines on TIL Assessment in Breast Cancer. In this regard, these recommendations represent a consensus guidance for pathologists, aimed to achieve the highest possible consistency among future studies.

The extent of tumor-infiltrating lymphocytes (TILs), along with immunomodulatory ligands, tumor-mutational burden and other biomarkers, has been demonstrated to be a marker of response to immune-checkpoint therapy in several cancers. Pathologists have therefore started to devise standardized visual approaches to quantify TILs for therapy prediction. However, despite successful standardization efforts visual TIL estimation is slow, with limited precision and lacks the ability to evaluate more complex properties such as TIL distribution patterns. Therefore, computational image analysis approaches are needed to provide standardized and efficient TIL quantification. Here, we discuss different automated TIL scoring approaches ranging from classical image segmentation, where cell boundaries are identified and the resulting objects classified according to shape properties, to machine learning-based approaches that directly classify cells without segmentation but rely on large amounts of training data. In contrast to conventional machine learning (ML) approaches that are often criticized for their "black-box" characteristics, we also discuss explainable machine learning. Such approaches render ML results interpretable and explain the computational decision-making process through high-resolution heatmaps that highlight TILs and cancer cells and therefore allow for quantification and plausibility checks in biomedical research and diagnostics.

Triple negative breast cancer (TNBC) is a heterogeneous disease that comprises 15-20% of all breast cancers and is more frequently seen in younger women, African-Americans, and BRCA1 expression. Advanced TNBC carries aggressive features and is associated with overall poor outcomes. Unfortunately, there are no targeted therapies available for non-BRCA associated TNBC, which remains a high unmet therapeutic need. One emerging treatment modality includes antibody-drug conjugates which are highly selective monoclonal antibodies conjugated to cytotoxic agents, designed to deliver cytotoxic drugs to antigen-expressing tumor cells. This review will highlight three antibody-drug conjugates currently being evaluated in TNBC (CDX-011, SGN-LIV1a, IMMU-132), including one that has been given Breakthrough Therapy designation from the US FDA.

The immune system encompasses a broad array of defense mechanisms against foreign threats, including invading pathogens and transformed neoplastic cells. Toll-like receptors (TLRs) are critically involved in innate immunity, serving as pattern recognition receptors whose stimulation leads to additional innate and adaptive immune responses. Malignant cells exploit the natural immunomodulatory functions of TLRs, expressed mainly by infiltrating immune cells but also aberrantly by tumor cells, to foster their survival, invasion, and evasion of anti-tumor immune responses. An extensive body of research has demonstrated context-specific roles for TLR activation in different malignancies, promoting disease progression in certain instances while limiting cancer growth in others. Despite these conflicting roles, TLR agonists have established therapeutic benefits as anti-cancer agents that activate immune cells in the tumor microenvironment and facilitate the expression of cytokines that allow for infiltration of anti-tumor lymphocytes and the suppression of oncogenic signaling pathways. This review focuses on the clinical application of TLR agonists for cancer treatment. We also highlight agents that are undergoing development in clinical trials, including investigations of TLR agonists in combination with other immunotherapies.

Immune-checkpoint blockade (ICB), in particular PD-1 inhibition, has rapidly changed the treatment landscape and altered therapeutic paradigms across many tumor types, with unprecedented rates of durable clinical responses in a number of cancers. Despite this success, only a subset of patients responds to ICB and, as a result, predictive biomarkers would be useful to guide the selection of patients for these therapies. This article highlights currently used biomarkers, as well as several promising novel candidates, and also discusses the challenges involved in establishing their analytic validity and clinical utility. Progress is being evaluated in melanoma and non-small cell lung cancer, for which PD-1 ± CTLA-4 inhibitors have become standard therapy, to other malignancies for which PD-L1 inhibitors remain investigational. Although single biomarkers have substantial limitations, a combination of biomarkers that reflect the interaction of host and tumor will likely be needed to provide a reproducible surrogate for the benefit of checkpoint modulation. Cancer Immunol Res; 6(10); 1122-8. ©2018 AACR.

BACKGROUND:Recent data support the use of post-mastectomy radiation therapy (PMRT) in women with one to three positive lymph nodes; however, the benefit of PMRT in patients with micrometastatic nodal disease (N1mi) is unknown. We evaluated the survival impact of PMRT in patients with N1mi within the National Cancer Database. METHODS:The pattern of care and survival benefit of PMRT was examined in women with pT1-2N1mi breast cancer who underwent mastectomy without neoadjuvant chemotherapy. Univariable and multivariable Cox proportional hazard models were employed for survival analysis, and subanalyses of high-risk patients and a propensity score-matched (PSM) cohort were completed. RESULTS:From 2004 to 2014, we identified 14,019 patients who fitted the study criteria. PMRT was delivered in 18.5% of patients and its use increased over the study period. Patients treated with PMRT were younger, had better performance status and larger primaries, were estrogen receptor (ER)-negative, had higher grade, lymphovascular invasion and positive surgical margins, and more often received systemic therapy. PMRT was significantly associated with overall survival (OS) in univariable analysis (hazard ratio [HR] 0.75 [0.64-0.89]), but was not significant in multivariable analysis (adjusted HR 1.01 [0.84-1.20]). There was no survival benefit to PMRT in ER-negative, high-grade, and/or young patients. There were 2 (0.9%) death events in the sentinel lymph node biopsy (SLNB) + PMRT group versus 21 (2.9%) in the SLNB-alone group (log-rank p = 0.053), and 8 (3.9%) death events in the axillary lymph node biopsy (ALNB) + PMRT group versus 27 (3.6%) in the axillary lymph node dissection-alone group (p = 0.82). There was no significant association between PMRT and OS within the PSM subgroup. CONCLUSION/CONCLUSIONS:In this largest reported retrospective study, no OS differences were associated with PMRT, which suggests that PMRT may not benefit every patient with microscopic nodal disease.

PURPOSE/OBJECTIVE:This study examined the feasibility, efficacy (abscopal effect) and immune effects of TGFβ blockade during radiotherapy in metastatic breast cancer patients. EXPERIMENTAL DESIGN/METHODS:Prospective randomized trial comparing two doses of TGFβ blocking antibody fresolimumab. Metastatic breast cancer patients with at least three distinct metastatic sites whose tumor had progressed after at least one line of therapy were randomized to receive 1 or 10 mg/kg of fresolimumab, every 3 weeks for 5 cycles, with focal radiotherapy to a metastatic site at week 1, (3 doses of 7.5 Gy), that could be repeated to a second lesion at week 7. Research bloods were drawn at baseline, week 2, 5 and 15 to isolate PBMCs, plasma and serum. RESULTS:Twenty-three patients were randomized, median age 57 (range 35 to 77). Seven grade 3/4 adverse events occurred in 5/11 patients in the 1mg/kg arm and in 2/12 patients in the 10mg/kg arm, respectively. Response was limited to 3 stable disease. At a median follow up of 12 months, 20/23 patients are deceased. Patients receiving the 10mg/kg had a significantly higher median overall survival than those receiving 1mg/kg fresolimumab dose (hazard ratio: 2.73 with 95% CI: 1.02, 7.30; p=0.039). The higher dose correlated with improved peripheral blood mononuclear cell counts and a striking boost in the CD8 central memory pool. CONCLUSIONS:TGFβ blockade during radiotherapy was feasible and well tolerated. Patients receiving the higher fresolimumab dose had a favorable systemic immune response and experienced longer median overall survival than the lower dose group.

The matrix metalloproteinases (MMP) are a family of proteolytic enzymes that degrade multiple components of the extracellular matrix. A large body of experimental and clinical evidence has implicated MMPs in tumor invasion, neoangiogenesis, and metastasis, and therefore they represent ideal pharmacologic targets for cancer therapy. From the 1990s to early 2000s, synthetic inhibitors of MMPs (MMPI) were studied in various cancer types. Unexpectedly, despite strongly promising preclinical data, all trials were unsuccessful in reducing tumor burden or improving overall survival; in addition, MMPIs had unforeseen, severe side effects. Two main reasons can explain the failure of MMPIs in clinical trials. It has now become apparent that some MMPs have antitumor effects; therefore, the broad-spectrum MMPIs used in the initial trials might block these MMPs and result in tumor progression. In addition, although MMPs are involved in the early stages of tumor progression, MMPIs were tested in patients with advanced disease, beyond the stage when these compounds could be effective. As more specific MMPIs are now available, MMP targeting could be reconsidered for cancer therapy; however, new trials should be designed to test their antimetastatic properties in early-stage tumors, and endpoints should focus on parameters other than decreasing metastatic tumor burden. Mol Cancer Ther; 1-9. ©2018 AACR.

Advances in cancer immunotherapy and a growing body of research have focused on the role of the antitumor response in breast cancer. Triple-negative breast cancer (TNBC) is the most immunogenic breast cancer subtype, and there is strong evidence that tumor-infiltrating lymphocytes in TNBC have prognostic value and are associated with clinical outcome and improved survival. Evading antitumor immunity is a hallmark for the development and progression of cancer. Immunotherapy studies have focused on the role of the programmed cell death-1 (PD-1) receptor/programmed death-ligand 1 (PD-L1) pathway in maintaining immunosuppression in the tumor microenvironment. Blockade of the PD-1/PD-L1 axis has emerged as a promising therapeutic option to enhance antitumor immunity and is actively being investigated in TNBC, with encouraging results. In this article, the authors review the current literature on checkpoint inhibitors in TNBC with a focus on PD-1/PD-L1 antibodies and discuss combination strategies and novel approaches for improving antitumor immunity and clinical outcome. Cancer 2018. © 2018 American Cancer Society.