Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial

Pusztai, Lajos; Yau, Christina; Wolf, Denise M.; Han, Hyo S.; Du, Lili; Wallace, Anne M.; String-Reasor, Erica; Boughey, Judy C.; Chien, Amy Jo; Elias, Anthony; Beckwith, Heather; Nanda, Rita; Albain, Kathy S.; Clark, Amy S.; Kemmer, Kathleen; Kalinsky, Kevin; Isaacs, Claudine; Thomas, Alexandra; Shatsky, Rebecca; Helsten, T; Forero‐Torres, Andres; Liu, Minetta C.; Brown-Swigart, Lamorna; Petricoin, Emanuel F.; Wulfkuhle, Julia; Asare, Smita; Wilson, Amy; Singhrao, Ruby; Sit, Laura; Hirst, Gillian L.; Berry, Scott M.; Sanil, Ashish; Asare, Adam; Matthews, Jeffrey B.; Perlmutter, Jane; Melisko, Michelle; Rugo, Hope S.; Schwab, Richard B.; Symmans, W. Fraser; Yee, D; Veer, Laura J. van’t; Hylton, Nola M.; DeMichele, Angela; Berry, Donald A.; Esserman, Laura J.

doi:10.1016/j.ccell.2021.05.009

Cited by 184 publications

(165 citation statements)

References 32 publications

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“…To solve this conundrum, scientists have attempted to combine immunotherapy with other adjuvant treatment therapies, such as chemotherapy, radiotherapy, and targeted therapy, and have observed clinical benefits in various malignancies [ 198 – 202 ]. However, although olaparib accompanied with durvalumab could improve pathological completed rates of HER2-negative breast cancer patients in I-SPY 2 trial and radiotherapy was found to increase responses combined with immunotherapy in metastatic NSCLC, chemotherapy was still the major partner of immunotherapy [ 203 – 205 ].…”

Section: Introductionmentioning

confidence: 99%

Targeting nucleotide metabolism: a promising approach to enhance cancer immunotherapy

Gong

et al. 2022

J Hematol Oncol

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Targeting nucleotide metabolism can not only inhibit tumor initiation and progression but also exert serious side effects. With in-depth studies of nucleotide metabolism, our understanding of nucleotide metabolism in tumors has revealed their non-proliferative effects on immune escape, indicating the potential effectiveness of nucleotide antimetabolites for enhancing immunotherapy. A growing body of evidence now supports the concept that targeting nucleotide metabolism can increase the antitumor immune response by (1) activating host immune systems via maintaining the concentrations of several important metabolites, such as adenosine and ATP, (2) promoting immunogenicity caused by increased mutability and genomic instability by disrupting the purine and pyrimidine pool, and (3) releasing nucleoside analogs via microbes to regulate immunity. Therapeutic approaches targeting nucleotide metabolism combined with immunotherapy have achieved exciting success in preclinical animal models. Here, we review how dysregulated nucleotide metabolism can promote tumor growth and interact with the host immune system, and we provide future insights into targeting nucleotide metabolism for immunotherapeutic treatment of various malignancies.

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Section: Introductionmentioning

confidence: 99%

Targeting nucleotide metabolism: a promising approach to enhance cancer immunotherapy

Gong

et al. 2022

J Hematol Oncol

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“…We additionally used an unpublished dataset that was obtained as part of a collaboration with Massachusetts General Hospital (MGH). Overall, we identified and set aside 21 datasets 20,24,[42][43][44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60] the evaluation setsas unseen data for evaluation. See Table S1 and Supplementary Note 1 for full details.…”

Section: Tuning and Evaluation Datasetsmentioning

confidence: 99%

Clinically oriented prediction of patient response to targeted and immunotherapies from the tumor transcriptome

Dinstag

Shulman

Elis

et al. 2022

Preprint

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Precision oncology is gradually advancing into mainstream clinical practice, demonstrating significant survival benefits. However, eligibility and response rates remain limited in many cases, calling for better predictive biomarkers. Here we present ENLIGHT, a transcriptomics-based computational approach that identifies clinically relevant genomic interactions and uses them to predict patients' response to a variety of therapies in multiple cancer types without training on previous response data. We study ENLIGHT in two translationally oriented scenarios, Personalized Medicine (PM), aimed at prioritizing treatments for a single patient, and Clinical Trial Design (CTD), selecting the most likely responders in a patient cohort. Evaluating ENLIGHT's PM performance on 21 blinded clinical trial datasets, we show that it can effectively predict treatment response across multiple therapies and cancer types (obtaining an odds ratio of 2.59), substantially improving upon SELECT, a previously published transcriptomics-based approach, and performing as well as supervised predictors developed for specific indications and drugs, but on a much broader array of therapies and indications. In the CTD scenario, ENLIGHT can markedly enhance the success of clinical trials by excluding non-responders while achieving more than 90% of the response rate attainable under an optimal exclusion strategy. In sum, ENLIGHT is one of the first approaches to demonstrably predict therapeutic response across multiple cancer types by leveraging the transcriptome.

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“…In germline BRCA1/2-mutated metastatic breast cancer, the durvalumab/olaparib combination shows promising antitumour activity and safety [ 82 ]. In addition, the triple combination of durvalumab, olaparib and paclitaxel shows superior efficacy compared to standard neoadjuvant chemotherapy in human epidermal growth factor receptor 2 (HER2)-negative breast cancer [ 83 ]. Similar results have been found for other combinations.…”

Section: Ddr-targeted Agents Modulate Pathways In Tumour Cells That Impact Their Relationships With Immune Cellsmentioning

confidence: 99%

Impact of DNA Damage Response—Targeted Therapies on the Immune Response to Tumours

Lutfi

Galindo-Campos

Yélamos

2021

Cancers

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The DNA damage response (DDR) maintains the stability of a genome faced with genotoxic insults (exogenous or endogenous), and aberrations of the DDR are a hallmark of cancer cells. These cancer-specific DDR defects present new therapeutic opportunities, and different compounds that inhibit key components of DDR have been approved for clinical use or are in various stages of clinical trials. Although the therapeutic rationale of these DDR-targeted agents initially focused on their action against tumour cells themselves, these agents might also impact the crosstalk between tumour cells and the immune system, which can facilitate or impede tumour progression. In this review, we summarise recent data on how DDR-targeted agents can affect the interactions between tumour cells and the components of the immune system, both by acting directly on the immune cells themselves and by altering the expression of different molecules and pathways in tumour cells that are critical for their relationship with the immune system. Obtaining an in-depth understanding of the mechanisms behind how DDR-targeted therapies affect the immune system, and their crosstalk with tumour cells, may provide invaluable clues for the rational development of new therapeutic strategies in cancer.

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Durvalumab with olaparib and paclitaxel for high-risk HER2-negative stage II/III breast cancer: Results from the adaptively randomized I-SPY2 trial

Cited by 184 publications

References 32 publications

Targeting nucleotide metabolism: a promising approach to enhance cancer immunotherapy

Targeting nucleotide metabolism: a promising approach to enhance cancer immunotherapy

Clinically oriented prediction of patient response to targeted and immunotherapies from the tumor transcriptome

Impact of DNA Damage Response—Targeted Therapies on the Immune Response to Tumours

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