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Neoadjuvant immunotherapy in breast cancer: a paradigm shift?

ABSTRACT: Despite advances in clinical management, a proportion of patients with early-stage triple-negative breast cancer (TNBC) recur after local treatment. The concept of neoadjuvant systemic therapy has been widely adopted to improve clinical outcomes of patients with TNBC and other breast tumour types. Recently, promising data were reported from the first prospective phase III, randomised trial assessing neoadjuvant chemotherapy combined with the programmed cell death protein 1 (PD-1) inhibitor pembrolizumab versus placebo in patients with early-stage TNBC. The addition of pembrolizumab resulted in a significant increase in pathologic complete response (pCR) rates. Similarly, in the IMpassion031 trial, the use of atezolizumab in combination with neoadjuvant chemotherapy in patients with early-stage TNBC led to improved pCR rates compared to placebo, regardless of programmed death ligand 1 (PD-L1) expression. Ongoing trials are testing other PD-1/PD-L1 inhibitors in combination with neoadjuvant chemotherapy in TNBC and other tumour subtypes. However, not all patients benefit from the addition of immunotherapy, while a proportion of patients experiences serious adverse events. It is critical to identify predictive biomarkers of response, to accurately select patients who will benefit from immunotherapy, thus sparing the rest from ineffective treatments with unnecessary toxicity and treatment costs. In this review, we summarise the literature on reported and ongoing neoadjuvant clinical trials evaluating immunotherapy in breast cancer.

SUBMITTER: Fountzila E

PROVIDER: S-EPMC7864681 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Neoadjuvant immunotherapy in breast cancer: a paradigm shift?

Fountzila Elena E Ignatiadis Michail M

Ecancermedicalscience 20201203

Despite advances in clinical management, a proportion of patients with early-stage triple-negative breast cancer (TNBC) recur after local treatment. The concept of neoadjuvant systemic therapy has been widely adopted to improve clinical outcomes of patients with TNBC and other breast tumour types. Recently, promising data were reported from the first prospective phase III, randomised trial assessing neoadjuvant chemotherapy combined with the programmed cell death protein 1 (PD-1) inhibitor pembr ...[more]

PMID: 33574892

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Project description:Metastasis accounts for approximately 90% of breast cancer-related deaths. Therefore, novel approaches which prevent or control breast cancer metastases are of significant clinical interest. Interleukin-12 (IL-12)-based immunotherapies have shown promise in controlling metastatic disease, yet modest responses and severe toxicities due to systemic administration of IL-12 in early trials have hindered clinical application. We hypothesized that localized delivery of IL-12 co-formulated with chitosan (chitosan/IL-12) could elicit tumor-specific immunity and provide systemic protection against metastatic breast cancer while minimizing systemic toxicity. Chitosan is a biocompatible polysaccharide derived primarily from the exoskeletons of crustaceans. In a clinically relevant resection model, mice bearing spontaneously metastatic 4T1 mammary adenocarcinomas received intratumoral injections of chitosan/IL-12, or appropriate controls, prior to tumor resection. Neoadjuvant chitosan/IL-12 immunotherapy resulted in long-term tumor-free survival in 67% of mice compared to only 24% or 0% of mice treated with IL-12 alone or chitosan alone, respectively. Antitumor responses following chitosan/IL-12 treatment were durable and provided complete protection against rechallenge with 4T1, but not RENCA renal adenocarcinoma, cells. Lymphocytes from chitosan/IL-12-treated mice demonstrated robust tumor-specific lytic activity and interferon-γ production. Cell-mediated immune memory was confirmed in vivo via clinically relevant delayed-type hypersensitivity (DTH) assays. Comprehensive hematology and toxicology analyses revealed that chitosan/IL-12 induced transient, reversible leukopenia with no changes in critical organ function. Results of this study suggest that neoadjuvant chitosan/IL-12 immunotherapy prior to breast tumor resection is a promising translatable strategy capable of safely inducing to tumor-specific immunity and, in the long term, reducing breast cancer mortality due to progressive recurrences.

Project description:PurposeThis study aims to explore whether neoadjuvant chemotherapy with immunotherapy (NACI) leads to different tumor shrinkage patterns, based on magnetic resonance imaging (MRI), compared to neoadjuvant chemotherapy (NAC) alone in patients with triple-negative breast cancer (TNBC). Additionally, the study investigates the relationship between tumor shrinkage patterns and treatment efficacy was investigated.MethodsThis retrospective study included patients with TNBC patients receiving NAC or NACI from January 2019 until July 2021 at our center. Pre- and post-treatment MRI results were obtained for each patient, and tumor shrinkage patterns were classified into three categories as follows: 1) concentric shrinkage (CS); 2) diffuse decrease; and 3) no change. Tumor shrinkage patterns were compared between the NAC and NACI groups, and the relevance of the patterns to treatment efficacy was assessed.ResultsOf the 99 patients, 65 received NAC and 34 received NACI. The CS pattern was observed in 53% and 20% of patients in the NAC and NACI groups, respectively. Diffuse decrease pattern was observed in 36% and 68% of patients in the NAC and NACI groups. The association between the treatment regimens (NAC and NACI) and tumor shrinkage patterns was statistically significant (p = 0.004). The postoperative pathological complete response (pCR) rate was 45% and 82% in the NAC and NACI groups (p < 0.001), respectively. In the NACI group, 17% of patients with the CS pattern and 56% of those with the diffuse decrease pattern achieved pCR (p = 0.903). All tumor shrinkage patterns were associated with achieved a high pCR rate in the NACI group.ConclusionOur study demonstrates that the diffuse decrease pattern of tumor shrinkage is more common following NACI than that following NAC. Furthermore, our findings suggest that all tumor shrinkage patterns are associated with a high pCR rate in patients with TNBC treated with NACI.Trial registrationClinicalTrials.gov Identifier: NCT04909554.

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Neoadjuvant immunotherapy in breast cancer: a paradigm shift?

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Neoadjuvant immunotherapy in breast cancer: a paradigm shift?

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