Advanced Triple-negative Breast Cancer Research Articles

A New Kid on the Block: Sacituzumab Govitecan for the Treatment of Breast Cancer and Other Solid Tumors.

Human trophoblast cell-surface antigen-2 (Trop-2) is a membrane glycoprotein involved in cell proliferation and motility, frequently overexpressed in epithelial tumors. Thus, it represents an attractive target for anticancer therapies. Sacituzumab govitecan (SG) is a third-generation antibody-drug conjugate, consisting of an anti-Trop-2 monoclonal antibody (hRS7), a hydrolyzable linker, and a cytotoxin (SN38), which inhibits topoisomerase 1. Specific pharmacological features, such as the high antibody to payload ratio, the ultra-toxic nature of SN38, and the capacity to kill surrounding tumor cells (the bystander effect), make SG a very promising drug for cancer treatment. Indeed, unprecedented results have been observed with SG in patients with heavily pretreated advanced triple-negative breast cancer and urothelial carcinomas, and the drug has already received approval for these indications. These results are coupled with a manageable toxicity profile, with neutropenia and diarrhea as the most frequent adverse events, mainly of grades 1–2. While several trials are exploring SG activity in different tumor types and settings, potential biomarkers of response are under investigation. Among these, Trop-2 overexpression and the presence of BRCA1/2 mutations seem to be the most promising. We review the available literature concerning SG, with a focus on its toxicity spectrum and possible biomarkers of its response.

Single-cell analyses reveal key immune cell subsets associated with response to PD-L1 blockade in triple-negative breast cancer

In triple-negative breast cancer (TNBC), the benefit of combining chemotherapy with checkpoint inhibitors is still not very clear. We utilize single-cell RNA- and ATAC-sequencing to examine the immune cell dynamics in 22 patients with advanced TNBC treated with paclitaxel or its combination with the anti-PD-L1 atezolizumab. We demonstrate that high levels of baseline CXCL13+ Tcells are linked to the proinflammatory features of macrophages and can predict effective responses to the combination therapy. In responsive patients, lymphoid tissue inducer (LTi) cells, follicular B (Bfoc) cells, CXCL13+ Tcells, and conventional type 1 dendritic cells (cDC1) concertedly increase following the combination therapy, but instead decrease after paclitaxel monotherapy. Our data highlight the importance of CXCL13+ Tcells in effective responses to anti-PD-L1 therapies and suggest that their reduction by paclitaxel regimen may compromise the clinical outcomes of accompanying atezolizumab for TNBC treatment.

Immune checkpoint inhibitors plus neoadjuvant chemotherapy in early triple-negative breast cancer: a systematic review and meta-analysis

PurposeSome studies have shown that Immune checkpoint inhibitors (ICIs) have a favorable efficacy in advanced triple negative breast cancer (TNBC) patients, but the results are controversial in neoadjuvant chemotherapy (NACT) stage. The purpose of this study is to evaluate the efficacy and safety after NACT plus ICIs in early TNBC patients.MethodsAfter searching PubMed, EMBASE, the Cochrane library and several mainly oncology conferences up to 30 January 2021 systematically, and define randomized controlled trials (RCTs) exploring the efficacy and safety of programmed death protein-1/programmed cell death-Ligand 1(PD-1/PD-L1) inhibitors plus neoadjuvant chemotherapy in TNBC patients. The primary endpoint was the pathological complete response (pCR) in intention-to-treat populations (ITT), and the secondary endpoints were event-free survival (EFS) and safety analysis in the ITT populations.ResultsSix RCTs (N = 2142) were included in our meta-analysis; NACT plus ICIs increased pCR rates compared with NACT in intention-to-treat (ITT) populations (OR: 1.91; 95% CI: 1.32–2.78, P < 0.001). The pCR rate also increased in both PD-L1 positive (OR: 1.65; 95% CI: 1.26–2.16, P < 0.001) and PD-L1 negative patients (OR: 1.56; 95% CI: 1.04–2.33, P = 0.03), especially in PD-L1 positive patients. The benefit was also observed in nodal-positive populations (OR: 2.52; 95% CI: 1.69–3.77, P < 0.001) and Eastern Cooperative Oncology Group performance-status score (ECOG PS) 0 subgroup (OR: 1.90; 95% CI: 1.42–2.53, P < 0.001). Three RCTs (N = 1615) reported EFS and the results showed that adding PD-1/PD-L1 inhibitors increased EFS (HR 0.65, 95% CI 0.50–0.83, P = 0.0007) in ITT populations with a short follow-up time. In the safety analysis of 2205 patients with early TNBC from five eligible studies, NACT plus ICIs had a higher risk of grade 3–4 diarrhea (OR: 2.54; 95% CI: 1.21–5.32; P = 0.01), any grade of adverse effects(AEs)including vomiting (OR: 1.37; 95% CI: 1.00–1.86; P = 0.05), hyperthyroidism (OR: 6.04; 95% CI: 2.39–15.29; P < 0.001), and hypothyroidism (OR: 5.04; 95% CI: 3.02–8.39; P < 0.001).ConclusionsPD-1/PD-L1 inhibitors combined with chemotherapy can improve pCR rates and EFS, and with an increased incidence of some immune-related AEs compared with chemotherapy alone. NACT plus ICIs might be an option in patients with in PD-L1 positive and high-risk populations with positive nodal disease early TNBC.

Emerging combination immunotherapy strategies for breast cancer: dual immune checkpoint modulation, antibody–drug conjugates and bispecific antibodies

Breast cancer has historically been considered a non-immunogenic tumor. Multiple studies over the last 10-15years have demonstrated that a small subset of breast cancers is immune-activated, with PD-L1 expression and/or TILs in the tumor microenvironment. The PD-1 inhibitor pembrolizumab in combination with chemotherapy is now approved by the US FDA for the first-line treatment of metastatic PD-L1 + triple negative breast cancer, and the PD-L1 inhibitor atezolizumab has also demonstrated clinical activity. The median progression-free survival for pembrolizumab or atezolizumab combined with chemotherapy increased with the addition of immunotherapy by 4.1months and 2.5months, respectively. Despite this success, there is major room for improvement. Clinical benefit is modest. Only about 40% of triple negative breast cancers are PD-L1 + , not all PD-L1 + patients with advanced triple negative breast cancer respond, and immunotherapy is not yet approved for advanced PD-L1-negative triple negative breast cancer, HER2 + breast cancer, or ER + breast cancer. It is likely that redundant pathways of immune suppression are active in breast cancer, or that important pathways of immune activation are silent. In this review, we discuss emerging strategies for targeting multiple pathways of immunoregulation in advanced breast cancer with dual immune checkpoint inhibition, bispecific antibodies, and novel antibody drug conjugates. We also discuss the potential of nanotechnology to improve the delivery of immunotherapeutics to the breast tumor microenvironment to enhance their antitumor activity.

Emerging immunotherapeutic strategies for the treatment of breast cancer.

Immunotherapy has resulted in unprecedented gains in long-term outcomes for many cancer types and has revolutionized the treatment landscape of solid tumor oncology. Checkpoint inhibition in combination with chemotherapy has proven to be effective for the treatment of a subset of advanced triple-negative breast cancer in the first-line setting. This initial success is likely just the tip of the iceberg as there is much that remains unknown about how to best harness the immune system as a therapeutic strategy in all breast cancer subtypes. Therefore, numerous ongoing studies are currently underway to evaluate the safety and efficacy of immunotherapy in breast cancer. In this review, we will discuss emerging immunotherapeutic strategies for breast cancer treatment including the following: (1) Intratumoral therapies, (2) Anti-tumor vaccines, (3) B-specific T-cell engagers, and (4) Chimeric antigen receptor T-cell therapy, and (5) Emerging systemic immunotherapy strategies. For each topic, we will review the existing preclinical and clinical literature, discuss ongoing clinical trials, and highlight future directions in the field.

A Nomogram to Predict Disease-Free Survival Following Neoadjuvant Chemotherapy for Triple Negative Breast Cancer.

BackgroundNeoadjuvant chemotherapy (NACT) is considered a standard treatment strategy for locally advanced triple negative breast cancer (TNBC). TNBC patients who achieve a pathologic complete response (pCR) are predicted to have a better prognosis while unfavorable chemo-sensitivity is still associated with a higher risk of disease relapse. The objective of this study was to construct a nomogram to predict disease-free survival (DFS) for TNBC patients following NACT.MethodsA total of 165 TNBC patients who underwent standard NACT and surgery were retrospectively reviewed, and data on their clinicopathological factors before and after NACT were collected. Independent prognostic factors for DFS were identified by Cox regression based on lower Akaike information criteria (AIC) and Bayesian information criterion (BIC). A nomogram to predict the 2-year and 5-year DFS following NACT for TNBC was constructed based on training cohort (n = 132) and validated by a validation cohort (n = 33).ResultsEither limited or full pCR (breast-only pCR, node-only pCR, or both-pCR) indicated significantly improved DFS and overall survival (OS) (p < 0.001). Lager residual tumor size (hazard ratio [HR] 1.175, p = 0.011) and the presence of lymphatic vessel invasion (LVI) (HR 3.168, p = 0.001) were identified as independent predictors of disease relapse in the training cohort. Five variables, including age, primary tumor size, histological grade, residual tumor size, and LVI were used to establish the nomogram. The C-index of the nomogram was 0.815, and calibration curves showed an acceptable consistency between the actual and nomogram-predicted 2-year and 5-year DFS. The proposed nomogram demonstrated superior predictive performance compared with Residual Cancer Burden (RCB) classification and the 8th American Joint Committee on Cancer Post Neoadjuvant Therapy Classification (AJCC ypTNM) staging system (area under the curve [AUC] for 2-year DFS: 0.870 vs. 0.758 vs. 0.711, respectively; AUC for 5-year DFS: 0.794 vs. 0.731 vs. 0.702, respectively) in the validation cohort.ConclusionsThe nomogram proposed in our study enabled to quantify the risk of disease relapse and demonstrated superior predictive performance than a survival predict instrument. It was an easy-to-use tool for clinicians to guide individualized surveillance of TNBC patients following standard NACT.

Network Pharmacology-Based Identification of Key Mechanisms of Xihuang Pill in the Treatment of Triple-Negative Breast Cancer Stem Cells.

Xihuang pill, an approved Chinese medicine formula (state medical permit number. Z11020073), is a commonly used adjuvant drug for cancer patients in China. Xihuang pill has a satisfactory effect in treating breast cancer in clinics, especially triple-negative breast cancer (TNBC), which is the most aggressive type of breast cancer, and finite effective therapies. However, the mechanism of Xihuang pill in treating TNBC remains unclear. The present study aims to explore the pharmacological mechanism of Xihuang pill in treating advanced TNBC. We identified the main chemical components of Xihuang pill by using HPLC-Q-TOF-MS/MS. The 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) analysis shows that serum containing Xihuang pill (XS) had no obvious killing effect on any subtype of breast cancer cells, but it inhibited mammosphere colony formation of two TNBC cell lines (4T1 and HCC1806 cells) and could enhance the inhibitory effect of paclitaxel (PTX) on the proliferation of 4T1 and HCC1806 cells when combined with PTX. Seventy-six active compounds in Xihuang pill, their 300 protein targets, and 16667 TNBC stem cell–related genes were identified. The drug–herb–active compound–target gene–disease network and enrichment analyses were constructed with 190 overlapping candidate targets. Through text mining and molecular docking, the target gene NR3C2 and its active compound naringenin were selected for further validation. According to the TCGA database, we observed that a high expression of NR3C2 promoted a higher survival probability regarding overall survival (OS). In vitro experiments indicated that naringenin presented an identical effect to XS, possibly by regulating the NR3C2 expression. Overall, this study explored the effect of Xihuang pill in treating advanced TNBC cells and showed that naringenin, which is the key active compound of Xihuang pill, could lessen the stemness of TNBC cells to produce a synergistic effect on PTX by regulating the NR3C2 gene.

Efficacy, Safety, and Tumor Marker Inhibition of Apatinib Combined with Conventional Chemotherapy Regimens for Patients with Advanced Triple-Negative Breast Cancer.

Objective Triple-negative breast cancer (TNBC) is an aggressive disease with highly invasive nature and poor outcomes. Due to the absence of specific treatment strategies for this tumor subgroup, patients with TNBC are treated with conventional therapeutics, frequently leading to systemic relapse. In this study, we sought to investigate apatinib combined with conventional chemotherapy regimens in treating patients with advanced TNBC concerning the efficacy, safety, expressions of tumor markers, and patient survival. Methods This is a prospective study including 150 cases of advanced TNBC who were randomly arranged into a conventional group and combined group, with 75 cases per group. The patients in the conventional group were treated with conventional chemotherapy, and those in the combined group were treated with apatinib combined with conventional chemotherapy. The peripheral blood was collected from each patient, and carcinoembryonic antigen (CEA), carbohydrate antigen 153 (CA153), and carbohydrate antigen 125 (CA125) were determined. The expressions of nuclear proliferation antigen marker (Ki67), β-catenin, and E-cadherin were determined in the biopsy collected from each patient. Results The objective remission rate (ORR) and disease control rate (DCR) (41.33% and 81.33%) in the combined group were notably higher than those in the conventional group (29.33% and 68.00%) (P < 0.05). After treatment, the serum levels of CEA, CA153, and CA125 and the expressions of Ki67 and β-catenin were declined, but the expression of E-cadherin was increased in both groups; the combined group exhibited lower serum levels of CEA, CA153, and CA125, and the expressions of Ki67 and β-catenin were concurrent with a higher expression of E-cadherin than the conventional group (P < 0.05). No significant difference was noted between the two groups regarding the occurrence of adverse reactions (P > 0.05). Improved progression-free survival (PFS) was observed in the combined group compared to the conventional group (P < 0.05. Conclusion These findings suggest that apatinib combined with conventional chemotherapy regimens confers a prolonged PFS for treating patients with advanced TNBC.

Growth Inhibition of Triple-Negative Breast Cancer: The Role of Spatiotemporal Delivery of Neoadjuvant Doxorubicin and Cisplatin.

Combinations of platinum-based compounds with doxorubicin in free and/or in liposomal form for improved safety are currently being evaluated in the neoadjuvant setting on patients with advanced triple-negative breast cancer (TNBC). However, TNBC may likely be driven by chemotherapy-resistant cells. Additionally, established TNBC tumors may also exhibit diffusion-limited transport, resulting in heterogeneous intratumoral delivery of the administered therapeutics; this limits therapeutic efficacy in vivo. We studied TNBC cells with variable chemosensitivities, in the absence (on monolayers) and presence (in 3D multicellular spheroids) of transport barriers; we compared the combined killing effect of free doxorubicin and free cisplatin to the killing effect (1) of conventional liposomal forms of the two chemotherapeutics, and (2) of tumor-responsive lipid nanoparticles (NP), specifically engineered to result in more uniform spatiotemporal microdistributions of the agents within solid tumors. This was enabled by the NP properties of interstitial release, cell binding/internalization, and/or adhesion to the tumors’ extracellular matrix. The synergistic cell kill by combinations of the agents (in all forms), compared to the killing effect of each agent alone, was validated on monolayers of cells. Especially for spheroids formed by cells exhibiting resistance to doxorubicin combination treatments with both agents in free and/or in tumor-responsive NP-forms were comparably effective; we not only observed greater inhibition of outgrowth compared to the single agent(s) but also compared to the conventional liposome forms of the combined agents. We correlated this finding to more uniform spatiotemporal microdistributions of agents by the tumor-responsive NP. Our study shows that combinations of NP with properties specifically optimized to improve the spatiotemporal uniformity of the delivery of their corresponding therapeutic cargo can improve treatment efficacy while keeping favorable safety profiles.

Interobserver Agreement of PD-L1/SP142 Immunohistochemistry and Tumor-Infiltrating Lymphocytes (TILs) in Distant Metastases of Triple-Negative Breast Cancer: A Proof-of-Concept Study. A Report on Behalf of the International Immuno-Oncology Biomarker Working Group.

Simple SummaryTriple-negative breast cancer (TNBC) is an aggressive breast cancer subtype that lacks significant expression of estrogen receptor, progesterone receptor, and HER2. Patients with locally advanced or metastatic TNBC benefit from treatment with atezolizumab, a humanized monoclonal antibody that blocks the PD-L1 protein. Immunohistochemical analysis of the tumor microenvironment is essential to determine the amount of tumor-infiltrating PD-L1-positive immune cells. The PD-L1/SP142 clone is the companion diagnostic for atezolizumab. Here we investigate the degree of interobserver agreement among ten breast pathologists in the assessment of PD-L1/SP142 immunohistochemistry, as well as the assessment of tumor-infiltrating lymphocytes (TILs) in 49 metastatic TNBCs. This multicenter study shows that both PD-L1 assessment and TILs assessment are robust markers at the group level, but the observed interobserver variability likely affects treatment decisions for individual patients.Patients with advanced triple-negative breast cancer (TNBC) benefit from treatment with atezolizumab, provided that the tumor contains ≥1% of PD-L1/SP142-positive immune cells. Numbers of tumor-infiltrating lymphocytes (TILs) vary strongly according to the anatomic localization of TNBC metastases. We investigated inter-pathologist agreement in the assessment of PD-L1/SP142 immunohistochemistry and TILs. Ten pathologists evaluated PD-L1/SP142 expression in a proficiency test comprising 28 primary TNBCs, as well as PD-L1/SP142 expression and levels of TILs in 49 distant TNBC metastases with various localizations. Interobserver agreement for PD-L1 status (positive vs. negative) was high in the proficiency test: the corresponding scores as percentages showed good agreement with the consensus diagnosis. In TNBC metastases, there was substantial variability in PD-L1 status at the individual patient level. For one in five patients, the chance of treatment was essentially random, with half of the pathologists designating them as positive and half negative. Assessment of PD-L1/SP142 and TILs as percentages in TNBC metastases showed poor and moderate agreement, respectively. Additional training for metastatic TNBC is required to enhance interobserver agreement. Such training, focusing on metastatic specimens, seems worthwhile, since the same pathologists obtained high percentages of concordance (ranging from 93% to 100%) on the PD-L1 status of primary TNBCs.

Immunomodulating Therapies in Breast Cancer-From Prognosis to Clinical Practice.

Simple SummaryThe role of the immune system in breast cancer has been debated for decades. It is generally accepted that tumor-infiltrating lymphocytes are associated with positive prognostic and predictive effects, especially in triple negative breast cancer. This subset of breast cancer is characterized by the absence of hormone receptors and human epidermal growth factor receptor 2. Compared to other breast cancer subtypes, triple-negative breast cancer has more mutations and neoantigens, making it more immunogenic. Releasing the brakes on the immune system with the help of so-called immune checkpoint inhibitors leads to activation of the immune system and destruction of cancer cells. This, in turn, improves survival, especially in early and advanced triple-negative breast cancer. A new and promising strategy is the enhancement of the immune response using individualized mRNA vaccines against tumor-specific neoantigens.The role of the immune system in breast cancer has been debated for decades. The advent of technologies such as next generation sequencing (NGS) has elucidated the crucial interplay between somatic mutations in tumors leading to neoantigens and immune responses with increased tumor-infiltrating lymphocytes and improved prognosis of breast cancer patients. In particular, triple-negative breast cancer (TNBC) has a higher mutational burden compared to other breast cancer subtypes. In addition, higher levels of tumor-associated antigens suggest that immunotherapies are a promising treatment option, specifically for TNBC. Indeed, higher concentrations of tumor-infiltrating lymphocytes are associated with better prognosis and response to chemotherapy in TNBC. An important target within the cancer immune cell cycle is the “immune checkpoint”. Immune checkpoint inhibitors (ICPis) block the interaction of certain cell surface proteins that act as “brakes” on immune responses. Recent studies have shown that ICPis improve survival in both early and advanced TNBC. However, this comes at the price of increased toxicity, particularly immune-mediated toxicity. As an alternative approach, individualized mRNA vaccination strategies against tumor-associated neoantigens represent another promising approach leading to neoantigen-specific immune responses. These novel strategies should help to improve treatment outcomes, especially for patients with triple negative breast cancer.

Investigational immunomodulatory drugs for enhancement of triple negative breast cancer (TNBC) immunotherapy: early phase development

ABSTRACT Introduction Immunotherapy through the blockade of PD1-PDL1 axis has shown to improve outcomes in advanced and early triple negative breast cancer (TNBC). To further enhance immune-stimulation, and ultimately improve patient outcomes, a wide variety of next-generation immunotherapies (NGIO) is being developed for this disease. Areas covered In the present article, we discuss the immune landscape of TNBC and recapitulate the rationale and available clinical evidence of NGIO under early phase development for TNBC, highlighting challenges and opportunities in this emerging field of research. Expert opinion Multiple immunotherapeutic strategies beyond PD-(L)1 blockade have been tested for TNBC, including the targeting of further inhibitory checkpoints, the agonism of costimulatory molecules, the intratumoral administration of immunotherapies and cancer vaccines. Most of these strategies have demonstrated to be safe in early clinical trials, with some exhibiting early signs of antitumor activity. To optimally harness the potential of NGIO, a refined patient selection based on emerging immune biomarkers will be required, through an adaptation of immunotherapeutic strategies based on patient and tumor characteristics. More mature data from ongoing clinical trials, added to the progressively increasing knowledge on breast cancer immune landscape, will hopefully clarify the role of NGIO for the treatment of TNBC.

Clinicopathological characteristics of breast cancer patients from Northern Tanzania: common aspects of late stage presentation and triple negative breast cancer

PurposeBreast cancer (BC) is the second most common cancer among Tanzanian women. Oestrogen (ER), progesterone and human epidermal growth factor receptor 2 play major roles in prognosis and treatment but data for Tanzania are sparse. This study aimed to determine these patterns and histological types, tumour grading and staging of BC patients in northern Tanzania for a better understanding of BC in the Sub-Saharan African (SSA) setting.MethodsA cross-sectional study recorded newly diagnosed BC cases at Kilimanjaro Christian Medical Centre between October 2018 and March 2019. Receptor status, histological types and grade, clinical stage and socio-demographic were recorded and descriptive and bivariate analyses performed.Results116 patients were enrolled. Median age was 53 years, 71.6% were ≥45 years. The commonest molecular subtype was triple negative breast cancer (TNBC) (n = 33; 28.4%). One hundred and two (87.9%) patients had invasive ductal carcinoma (IDC), poorly differentiated tumours (60; 51.7%) and clinical stage III disease (62; 53.0%). ER negative tumours were associated with poorly differentiated histological grade (relative risk (RR): 1.34 (0.87–2.07)), tumour size > 5 cm (RR: 1.67 (0.33–8.35)) and IDC (RR: 3.35 (0.56–20.23)). Clinical stages III & IV (odds ratio (OR): 1.64 (0.63–4.24)) were associated with hormone receptor (HR) negative tumours and metastasis (OR: 1.60 (0.68–3.74)) with TNBC. 18% of the patients reported about first-degree relatives with BC.ConclusionsMost patients presented in advanced stages and TNBC in their menopause. HR negative tumours were associated with poor histological differentiation and IDC. The high percentage of positive family history of BC and the differences in receptor patterns compared to other parts of the world should urge further genetic research on BC in SSA.

Clinical impact of PD-L1 expression in triple-negative breast cancer patients with residual tumor burden after neoadjuvant chemotherapy

BackgroundStudies on PD-L1 expression in breast cancer have gained importance in recent years, especially in triple-negative breast cancer (TNBC). Our aim was to analyze the differential expression of PD-L1 to explore its correlation with response to neoadjuvant chemotherapy (NACT) and patient survival.MethodsPD-L1 expression was evaluated immunohistochemically (Ventana SP263 clone kit) by staining tumor specimen. PD-L1 positivity was defined as membranous staining > 1%, > 5%, > 10%, and > 20% on either tumor cell (TC) and /or immune cell (IC).ResultsFifty patients with locally advanced TNBC, who had a partial response to NACT, were included in the study. PD-L1 staining was observed in TCs in 25 patients (50%) and in ICs in 23 patients (46%) when PD-L1 > 1% was considered positive. Patients with PD-L1 positivity on ICs were more likely to respond to chemotherapy as measured by “MD Anderson Cancer Center Residual Cancer Burden Index” (14/22, 63.6% vs. 10/27, 37%, p = 0.064). The 5-year disease-free survival (DFS) and disease-specific survival (DSS) rates were 46.3% and 51.4%, respectively. A high (> 20%) tumoral PD-L1 positivity was associated with a better DFS and DSS.ConclusionsStudies in the literature mostly focused on PD-L1 expression in inflammatory cells. However, our results suggest that patients with a high PD-L1 expression on TCs were more likely to have a better outcome. Since patients with residual tumor burden who express PD-L1 on TILs were more likely to respond to NACT, an immune checkpoint inhibitor therapy in addition to NACT would be an important option for TNBC with locally advanced disease.

A narrative review of biomarkers in advanced triple negative breast cancer

: Triple negative breast cancer (TNBC) is a heterogeneous disease; while clinically diagnosed as a single entity disease, at the molecular level, TNBC includes characteristic subtypes with potential for subtype specific targeted therapies which are still underway. Chemotherapy remains the backbone of treatment of TNBC. Although new targeted therapies have been introduced in the metastatic setting, including immunotherapy, PARP inhibitors and antibody drug conjugates (ADC), identifying patients who would selectively benefit from these treatments is awaiting a more refined selection process driven by better understanding of the biology of TNBC subtypes. More importantly, there is a need for validated tools of genomic precision and biomarker driven targeted therapy that can readily identify TNBC subtypes in the clinic and translate complex molecular analysis into individualized treatment plans for patients. This review presents biomarkers in advanced TNBC with potential for targeted therapies and discusses ongoing strategies to managing the heterogeneity of TNBCs. We discuss biomarkers including TP53, androgen receptor, breast cancer susceptibility genes (BRCA), homologous recombination deficiency (HRD), PI3K/AKT/mTOR, immune biomarkers, and ADC. The review concludes with a summary of the landscape of biomarker driven targeted therapies in advanced TNBC that has been improving outcomes of this aggressive disease.

337TiP An open-label, phase Ib/II study to evaluate the safety and efficacy of fruquintinib in combination with tislelizumab in patients with advanced triple-negative breast cancer

Immune checkpoint inhibitors (ICIs) have improved clinical outcomes in triple-negative breast cancer (TNBC), but many patients (pts) do not respond to ICIs or will develop resistance. Combining VEGFR inhibition may potentiate ICI efficacy by normalizing vascular immune crosstalk and improving immune effector cell infiltration. Tislelizumab (T) is a humanized, IgG4-variant monoclonal antibody against PD-1. Fruquintinib (F) is a novel, highly selective, oral, tyrosine kinase inhibitor of VEGFR-1, 2, 3.

268P Anti-EGFR-immunoliposomes loaded with doxorubicin in patients with advanced triple-negative, EGFR positive breast cancer: A multicenter single arm phase II trial [SAKK 24/14

Advanced triple-negative breast cancer (TNBC) is an aggressive, but initially chemo-sensitive disease. The prognosis is poor and more than three quarters of patients experience a progression 12 months after the initiation of conventional first-line chemotherapy. Approximately 2/3 of TNBC express epidermal growth factor receptor 1 (EGFR) on malignant cells. We have developed an anti-EGFR targeted nanocontainer drug by inserting anti-EGFR antibody fragments into the membrane of pegylated liposomes (anti-EGFR-ILs-dox).

Monoclonal Antibodies: New Drugs, New Indications.

The newest indications for monoclonal antibodies are as treatment for homozygous familial hypercholesterolemia, advanced triple-negative breast cancer, advanced urothelial cancer, relapsed or refractory large B-cell lymphoma, and non-small cell lung cancer with epidermal growth factor receptor exon 20 insertion mutations.

275P A phase II study of LAG525 in combination with spartalizumab (PDR001), PDR001 and carboplatin (Carbo), or Carbo, as first- or second-line therapy in patients (Pts) with advanced (Adv) triple-negative breast cancer (tnbc)

In TNBC, despite high initial response to chemotherapy (CT), many pts relapse, and options for treating recurrence are limited. Combining immunotherapy and CT may synergise to enhance therapeutic efficacy. Here we evaluate LAG525, an anti-LAG-3 antibody (ab), with PDR001, an anti-PD-1 ab, and/or carbo in pts with adv TNBC.

620P MGC018, an anti-B7-H3 antibody-drug conjugate (ADC), in patients with advanced solid tumors: Preliminary results of phase I cohort expansion

MGC018 is an investigational ADC with a duocarmycin payload linked to an anti-B7-H3 monoclonal antibody. B7-H3 is expressed on multiple solid tumors with limited normal tissue expression. It is hypothesized that MGC018 may exert activity against B7-H3-expressing tumors with an acceptable safety profile. Phase I dose escalation was completed with two dose-limiting toxicities: one neutropenia grade 4 and one grade 3 fatigue of 72 hrs. There was 1 confirmed partial response in a melanoma patient, and 5/9 patients with 50% prostate-specific antigen (PSA) reduction in metastatic castration resistant prostate cancer (mCRPC). The cohort expansion characterizes safety and preliminary efficacy with the recommended phase II dose of 3 mg/kg IV every 3 weeks. Patients with advanced mCRPC, non-small cell lung cancer (NSCLC), triple-negative breast cancer (TNBC), squamous cell carcinoma of the head and neck (SCCHN), and melanoma are eligible for enrollment. Response is evaluated per RECIST v1.1 for all participants. mCRPC tumor response and PSA are evaluated using Prostate Cancer Working Group 2 criteria. The cohort expansion enrolled and dosed 49/80 patients as of May 3, 2021. mCRPC n=26/40, NSCLC, n=16/20, and TNBC n=7/20. At least 1 treatment emergent adverse event occurred in 43 patients (87.7%); the most common (≥10%) were neutropenia/neutrophil count decreased, fatigue, asthenia, palmar plantar erythrodysesthesia, and headache. Febrile neutropenia was not reported. Of 13 mCRPC patients with measurable disease, six were not yet evaluable, and seven had first 9-week imaging. Of the seven, four had reductions in target lesion sums of 13%, 21%, 27%, and 35% (unconfirmed partial response); 12 of the 13 remain on treatment. There are 11/22 evaluable patients with ≥50% PSA reduction. Results to date have demonstrated a manageable safety profile with evidence of clinical activity by PSA and tumor responses in mCRPC. Enrollment is ongoing in advanced mCRPC, NSCLC, TNBC, SCCHN, and melanoma. Updated data will be provided.