Checkpoint inhibitors in triple‐negative breast cancer (TNBC): Where to go from here

Kwa, Maryann; Adams, Sylvia

doi:10.1002/cncr.31272

Cited by 157 publications

(134 citation statements)

References 77 publications

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“…Checkpoint inhibitors have demonstrated to prolong survival in melanoma, lung cancer and recently in PD-L1 positive metastatic TNBC [9,10]. Several programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors are currently investigated in early stage and metastatic BC [11]. Phase I studies showed an increased clinical response and suggested a correlation with PD-L1 expression [12].…”

Section: Introductionmentioning

confidence: 99%

A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study

et al. 2019

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This study is a joint study of the German Breast Group (GBG) and the Arbeitsgemeinschaft Gynäkologische Onkologie Breast (AGO-B). Background: Combining immune-checkpoint inhibitors with chemotherapy yielded an increased response rates in patients with metastatic triple-negative breast cancer (TNBC). Therefore, we evaluated the addition of durvalumab to standard neoadjuvant chemotherapy (NACT) in primary TNBC. Patients and methods: GeparNuevo is a randomised phase II double-blind placebo-controlled study randomising patients with TNBC to durvalumab or placebo given every 4 weeks in addition to nab-paclitaxel followed by standard EC. In the windowphase durvalumab/placebo alone was given 2 weeks before start of nab-paclitaxel. Randomisation was stratified by stromal tumour-infiltrating lymphocyte (sTILs). Patients with primary cT1b-cT4a-d disease, centrally confirmed TNBC and sTILs were included. Primary objective was pathological complete response (pCR) (ypT0 ypN0). Results: A total of 174 patients were randomised, 117 participated in the window-phase. Median age was 49.5 years (range 23-76); 47 patients (27%) were younger than 40 years; 113 (65%) had stage !IIA disease, 25 (14%) high sTILs, 138 of 158 (87%) were PD-L1-positive. pCR rate with durvalumab was 53.4% (95% CI 42.5% to 61.4%) versus placebo 44.2% (95% CI 33.5% to 55.3%; unadjusted continuity corrected v 2 P ¼ 0.287), corresponding to OR ¼ 1.45 (95% CI 0.80-2.63, unadjusted Wald P ¼ 0.224). Durvalumab effect was seen only in the window cohort (pCR 61.0% versus 41.4%, OR ¼ 2.22, 95% CI 1.06-4.64, P ¼ 0.035; interaction P ¼ 0.048). In both arms, significantly increased pCR (P < 0.01) were observed with higher sTILs. There was a trend for increased pCR rates in PD-L1-positive tumours, which was significant for PD-L1-tumour cell in durvalumab (P ¼ 0.045) and for PD-L1-immune cell in placebo arm (P ¼ 0.040). The most common immune-related adverse events were thyroid dysfunction any grade in 47%.

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Section: Introductionmentioning

confidence: 99%

A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study

et al. 2019

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“…Whether similar results may be achieved with chemotherapy plus immunotherapy in later lines is unknown at this time. Of note, increased ORR have been observed in patients with previously untreated metastatic TNBC with monotherapy PD-1/PD-L1 inhibitors, suggesting that these agents may be more active in less heavily pretreated metastatic disease (120).…”

Section: Immune Subtypes Of Tnbcmentioning

confidence: 99%

Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment

2019

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Triple-negative breast cancer (TNBC) remains the most challenging breast cancer subtype to treat. To date, therapies directed to specifi c molecular targets have rarely achieved clinically meaningful improvements in outcomes of patients with TNBC, and chemotherapy remains the standard of care. Here, we seek to review the most recent efforts to classify TNBC based on the comprehensive profi ling of tumors for cellular composition and molecular features. Technologic advances allow for tumor characterization at ever-increasing depth, generating data that, if integrated with clinical-pathologic features, may help improve risk stratifi cation of patients, guide treatment decisions and surveillance, and help identify new targets for drug development.Signifi cance: TNBC is characterized by higher rates of relapse, greater metastatic potential, and shorter overall survival compared with other major breast cancer subtypes. The identifi cation of biomarkers that can help guide treatment decisions in TNBC remains a clinically unmet need. Understanding the mechanisms that drive resistance is key to the design of novel therapeutic strategies to help prevent the development of metastatic disease and, ultimately, to improve survival in this patient population. TNBC AND INTRINSIC BREAST CANCER SUBTYPESEarly transcriptomic profi ling of breast cancer using microarrays classifi ed tumors into fi ve intrinsic subtypes: luminal-A, luminal-B, HER2-enriched, basal-like, and a normal breast-like group ( 5,6 ). Although all intrinsic subtypes can be found within immunohistochemically defi ned triplenegative disease, basal-like tumors exhibit the greatest overlap with TNBC. Between 50% and 75% of TNBC have basal phenotype, and approximately 80% of basal-like tumors are ER-negative/HER2-negative ( Fig. 2 ; refs. 7, 8 ). Characterization Research.on August 1, 2020.

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“…12,13 ). However, even among such potentially immunogenic cancers, immune checkpoint inhibitors benefit only a relatively small number of patients 7,12,14–18 .…”

Section: Introductionmentioning

confidence: 99%

TIM-3 expression in breast cancer

et al. 2018

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Tumor-infiltrating lymphocytes (TILs) are predominantly present in breast cancer patients with estrogen receptor negative tumors, among whom increasing levels correlate with favorable outcomes. Nevertheless, currently available immune checkpoint inhibitors appear to benefit only a small number of women with breast cancer. Upregulation of additional immune checkpoint markers is one mechanism of resistance to current inhibitors that might be amenable to targeting with newer agents. T-cell Immunoglobulin and Mucin domain-containing molecule 3 (TIM-3) is an immune checkpoint receptor that is an emerging target for cancer immunotherapy. We investigated TIM-3 immunohistochemical expression in 3,992 breast cancer specimens assembled into tissue microarrays, linked to detailed outcome, clinico-pathological parameters and biomarkers including CD8, PD-1, PD-L1 and LAG-3. We scored and reported absolute counts for TIM-3+ intra-epithelial and stromal TILs (iTILs and sTILs), and find that breast cancer patients with TIM-3+ iTILs (≥ 1) represent a minority of cases (11%), with a predilection for basal-like breast cancers (among which 28% had TIM-3+ iTILs). TIM-3+ sTILs (≥ 2) represented 20% of cases and included more non-basal cases. The presence of TIM-3+ iTILs highly correlates with hematoxylin and eosin-stained stromal TILs and with other immune checkpoint markers (PD-1+ iTILs, LAG-3+ iTILs and PD-L1+ tumors). In prognostic analyses, early breast cancer patients with TIM-3+ iTILs have significantly improved breast cancer-specific survival whereas TIM-3+ sTILs did not reach statistical significance. In multivariate analyses, the presence of TIM-3+ iTILs is an independent favorable prognostic factor in the whole cohort as well as among ER negative patients. Our study supports TIM-3 as a target for breast cancer immunotherapy.

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Checkpoint inhibitors in triple‐negative breast cancer (TNBC): Where to go from here

Cited by 157 publications

References 77 publications

A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study

A randomised phase II study investigating durvalumab in addition to an anthracycline taxane-based neoadjuvant therapy in early triple-negative breast cancer: clinical results and biomarker analysis of GeparNuevo study

Insights into Molecular Classifications of Triple-Negative Breast Cancer: Improving Patient Selection for Treatment

TIM-3 expression in breast cancer

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