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  • 1
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    Author Correction: Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer
    Springer Science and Business Media LLC ; 2023
    In:  npj Breast Cancer Vol. 9, No. 1 ( 2023-04-29)
    Details
    In: npj Breast Cancer, Springer Science and Business Media LLC, Vol. 9, No. 1 ( 2023-04-29)
    Type of Medium: Online Resource
    ISSN: 2374-4677
    URL: Article
    DOI: 10.1038/s41523-023-00538-x
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2023
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  • 2
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    Oestrogen receptor activity in hormone-dependent breast cancer during chemotherapy
    Elsevier BV ; 2021
    In:  eBioMedicine Vol. 69 ( 2021-07), p. 103451-
    Details
    In: eBioMedicine, Elsevier BV, Vol. 69 ( 2021-07), p. 103451-
    Type of Medium: Online Resource
    ISSN: 2352-3964
    URL: Article
    DOI: 10.1016/j.ebiom.2021.103451
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2021
    detail.hit.zdb_id: 2799017-5
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  • 3
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    Abstract PD17-07: Cell-Cycle Inhibition and Immune Microenvironment in HR+/HER2- Breast Cancer During and After preoperative ribociclib and letrozole vesus chemotherapy: A correlative analysis of the 1402-SOLTI/CORALLEEN phase 2 trial
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. PD17-07-PD17-07
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. PD17-07-PD17-07
    Abstract: Background Hormone receptor–positive/HER2-negative (HR+/HER2-) breast cancer (BC) is associated with low % of stromal tumor-infiltrating lymphocytes (sTIL) and immune gene expression and poor response to immune checkpoint inhibitors. Evaluating the effect of letrozole and ribociclib (L+R) on the immune microenvironment may suggest new opportunities for immunotherapy-based approaches for HR+/HER2- BCs. Here, we present an exploratory correlative analysis from CORALLEEN, a trial that evaluated the efficacy of L+R (vs. chemotherapy [CHT]) in patients with high-risk PAM50 Luminal B BC (Prat et al. Lancet Oncology. 2022). Methods CORALLEEN is a randomized exploratory study in postmenopausal women with operable stage I-III breast cancer, HR+/HER2- and Luminal B by Prosigna®. Patients were randomized 1:1 to receive either 6 cycles of ribociclib (600mg; 3-weeks-on/1-week-off) plus daily letrozole or CHT: 4 cycles of AC followed by 12 doses of weekly paclitaxel. The primary endpoint was the rate of PAM50 Risk of Relapse (ROR)-low score at surgery in each arm. Samples were prospectively collected at baseline, day 15, and surgery. sTILs score, ki67 IHC and gene expression analysis were determined in all available samples. Complete cell cycle arrest (CCCA) was defined as Ki67≤2.7%. Gene expression profiling by mRNA sequencing (RNAseq) was evaluated. We applied a collection of 194 immune- gene expression signatures (iGES), representing multiple biological pathways and cell types, including. Results 106 patients were randomly assigned to receive neoadjuvant L+R (n=52) or CTH (n=54). Overall, Ki67, sTILs and RNA-seq was available in 95.4%, 96.7% and 83.1% of the samples across the 3 time-points. In terms of cell-cycle inhibition, L+R achieved a significant decrease in Ki67 protein expression and led to higher rates of CCCA at 2 weeks (89.6% vs. 43.2%, p & lt; 0.001) and surgery (45.9% vs 25.5%, P=0.054) compared with CHT. Interestingly, the 11-gene PAM50 proliferative score was significantly lower in tumors with CCAA than in those with non-CCCA (p & lt; 0.001) after L+R, but not after CTH (p = 0.682). In contrast, tumors with CCCA after CHT had a significantly lower rate of tumor cellularity compared to tumors with non-CCAA (p = 0.002). This was not observed in the L+R arm (p=0.141). Compared to baseline, no clear and significant patterns in % of sTILs were observed at week 2 and surgery. However, % of TILs at surgery in tumors with CCCA after CHT was higher than in tumors with non-CCCA (median 15% versus 1%, p=0.017). This was not observed in the L+R arm (median 1% and 5%, p=0.584). Interestingly, this inverse relationship between immune infiltration and CCAA was further confirmed by RNA- CHT compared to tumors with non-CCCA, whereas 174 (89.7%) of iGES were upregulated (FDR & lt; 5%) in tumors with non-CCCA after L+R compared to tumors with CCCA. Finally, L+R and CTH treatment at week 2 and surgery showed an increase in adaptive immune signatures indicative of activated T-cell and B-cell phenotypes; however, CTH was uniquely associated with increased cytokine signaling, enhanced antigen presentation, dendritic, granulocyte, macrophage and NK cells and decrease in Th17, Th2 and Treg cells. Conclusion In early-stage Luminal B breast cancer, L+R induce a potent anti-proliferative effect compared to CHT. Both treatments generally increased T- and B-cell immune infiltration; however, an inverse relationship between immune infiltration and anti-proliferative response at surgery exists according to treatment, where immune infiltration is increased in residual tumors with non-CCAA when treated with L+R, but the opposite is observed with CHT. The prognostic value of immune and anti-proliferative effects of L+R in residual tumors is currently being evaluated in the prospective RIBOLARIS phase II clinical trial (NCT05296746). Citation Format: Tomás Pascual, Nuria Chic, Aranzazu Fernandez-Martinez, Blanca González-Farré, Laia Paré, Cristina Saura, Cristina Hernando, Montserrat Muñoz, Míriam Arumí, Patricia Galván, Xavier Gonzalez-Farré, Mafalda Oliveira, Miguel Gil Gil, Eva Ciruelos, Patricia Villagrasa, Joaquin Gavila Gregori, Aleix Prat, Charles M. Perou. Cell-Cycle Inhibition and Immune Microenvironment in HR+/HER2- Breast Cancer During and After preoperative ribociclib and letrozole vesus chemotherapy: A correlative analysis of the 1402-SOLTI/CORALLEEN phase 2 trial [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr PD17-07.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-PD17-07
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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  • 4
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    Abstract OT1-12-01: Solti-1804 HER2-PREDICT: Translational study of tumor samples from breast cancer patients treated with trastuzumab deruxtecan in the metastatic setting
    American Association for Cancer Research (AACR) ; 2022
    In:  Cancer Research Vol. 82, No. 4_Supplement ( 2022-02-15), p. OT1-12-01-OT1-12-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 82, No. 4_Supplement ( 2022-02-15), p. OT1-12-01-OT1-12-01
    Abstract: Background: Overexpression of human epidermal growth factor receptor 2 (HER2) occurs in 15-20% of breast cancers (BC). At the same time, HER2-low tumors (immunohistochemistry 1+ or 2+ with no gene amplification) comprise ~50% of all BC. Trastuzumab Deruxtecan (T-DXd) is an anti-HER2 antibody drug conjugate that has shown impressive and durable response rates not only in HER2+ and HER2low BC, but also in other cancer subtypes expressing the HER2 receptor. However, not all patients respond or benefit to the same extent. Thus, there is a need to identify predictive biomarkers. Here, we hypothesize that by performing several molecular studies in both tissue and plasma samples of those patients participating in the DESTINY studies receiving T-DXd, we will shed more light on the molecular features of HER2 expressing BC and will better characterize the patient population that benefits benefit from this promising new anti-HER2 agent. Methods: HER2-PREDICT is a multi-center, observational study within the biomarker program of SOLTI group, which will include patients who received T-DXd-only while participating in DESTINY trials. Both HER2-positive and HER2-low unresectable and/or metastatic breast cancer may be included in SOLTI-1804 HER2-PREDICT study (NCT04257162). All patients need to consent to obtain a fresh tumor biopsy or donate an archival metastatic biopsy. Primary tumors may be allowed under SOLTI acceptance. Additionally, for patients included before initiating T-DXd treatment blood samples for biomarker analyses on Cycle 1 Day 1 (C1D1), C2D1 and end of treatment will be obtained. Collection of tumor biopsies is an essential part of this study. Pathological analyses will include hematoxylin and eosin (H & E) staining of formalin-fixed paraffin-embedded (FFPE) tissue, identification of areas with the greater amount of tumor cells and determination of their tumor cell percentage. RNA will be isolated and analyzed using the nCounter platform (Nanostring Technologies). Molecular intrinsic subtypes will be identified by a research-based version of PAM50. Furthermore, we aim to evaluate 771 additional genes (+5 housekeeping genes) that encompass genomic signatures and individual genes of importance in breast cancer by means of the nCounter®Breast Cancer 360 Panel. Somatic mutations in PIK3CA, TP53, and additional genes (e.g., GATA3 and ERBB2) will be identified using next-generation sequencing (NGS) in FFPE tumor blocks and plasma samples. Objectives: The primary objectives are (1) to identify an optimal ERBB2 mRNA cut-off point predictive of T-DXd response and (2) to evaluate the correlation of baseline ERBB2 mRNA levels (as a continuous variable) with overall response rate (ORR). Secondary objectives include: to evaluate the association of ERBB2 mRNA levels, PAM50 intrinsic subtypes and immune-related genes with ORR, progression-free survival (PFS) and overall survival (OS); to design a new gene expression signature predictive of clinical benefit; to evaluate the correlation in early changes in circulating tumor DNA (ctDNA) with ORR, PFS and OS; and to identify acquired somatic mutations of resistance upon progression in plasma samples. The study is active in 13 sites in Spain, and 39 patients have been included in the trial since December 2019 until June 2021. Acknowledgments: We thank Daiichi Sankyo Inc. for their financial support for the study. Citation Format: Aleix Prat, Cristina Saura, Josefina Cruz, Esteban Nogales Fernández, Javier Salvador Bofill, Joaquin Gavilá, Maria José Bermejo-Perez, Vanesa Quiroga, Serafin Morales, Sonia Servitja, Ruben de Toro, Pilar Zamora, Patricia Galván, Nuria Chic, Débora Martínez, Fara Brasó-Maristany, Jordi Canes, Laia Paré, Juan M Ferrero-Cafiero, Tomás Pascual, Sonia Pernas. Solti-1804 HER2-PREDICT: Translational study of tumor samples from breast cancer patients treated with trastuzumab deruxtecan in the metastatic setting [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr OT1-12-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS21-OT1-12-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2022
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  • 5
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    Clinical, pathological, and PAM50 gene expression features of HER2-low breast cancer
    Springer Science and Business Media LLC ; 2021
    In:  npj Breast Cancer Vol. 7, No. 1 ( 2021-01-04)
    Details
    In: npj Breast Cancer, Springer Science and Business Media LLC, Vol. 7, No. 1 ( 2021-01-04)
    Abstract: Novel antibody-drug conjugates against HER2 are showing high activity in HER2-negative breast cancer (BC) with low HER2 expression (i.e., 1+ or 2+ and lack of ERBB2 amplification). However, the clinical and molecular features of HER2-low BC are yet to be elucidated. Here, we collected retrospective clinicopathological and PAM50 data from 3,689 patients with HER2-negative disease and made the following observations. First, the proportion of HER2-low was higher in HR-positive disease (65.4%) than triple-negative BC (TNBC, 36.6%). Second, within HR-positive disease, ERBB2 and luminal-related genes were more expressed in HER2-low than HER2 0. In contrast, no gene was found differentially expressed in TNBC according to HER2 expression. Third, within HER2-low, ERBB2 levels were higher in HR-positive disease than TNBC. Fourth, HER2-low was not associated with overall survival in HR-positive disease and TNBC. Finally, the reproducibility of HER2-low among pathologists was suboptimal. This study emphasizes the large biological heterogeneity of HER2-low BC, and the need to implement reproducible and sensitive assays to measure low HER2 expression.
    Type of Medium: Online Resource
    ISSN: 2374-4677
    URL: Article
    DOI: 10.1038/s41523-020-00208-2
    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 6
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    Abstract PS12-08: A window-of-opportunity study with atezolizumab and the oncolytic virus pelareorep in early breast cancer (REO-027, AWARE-1)
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 4_Supplement ( 2021-02-15), p. PS12-08-PS12-08
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 4_Supplement ( 2021-02-15), p. PS12-08-PS12-08
    Abstract: Background: A previous phase 2 study in metastatic breast cancer compared treatment with intravenously delivered oncolytic reovirus, pelareorep (pela), in combination with paclitaxel (PTX) versus PTX alone. This study demonstrated a statistically significant improvement in overall survival (OS), without differences in objective response or progression-free survival. We hypothesized that the OS benefit from pela + PTX may be attributed to an adaptive immune response triggered by pela. To test this hypothesis, and examine if pela can mediate the priming of an anti-tumor immune response, we designed a study called AWARE-1 (A window-of-opportunity study of pela in Early Breast Cancer), which is currently enrolling and for which initial translational research results are presented. Methods: AWARE-1 is evaluating the safety and effect of pela ± atezolizumab on the tumor microenvironment (TME) in 38 women with early breast cancer. Patients are treated with pela on days 1, 2, 8, and 9, while atezolizumab is administered on day 3. Tumor biopsies are collected at diagnosis, day 3, and day ~21. Five cohorts will be examined: Cohort 1: Hormone Receptor-positive/HER2-negative (HR+/HER2-neg) (10 patients), pelareorep + letrozole. Cohort 2: HR+/HER2-neg (10 patients), pelareorep + letrozole + atezolizumab. Cohort 3: Triple Negative Breast Cancer (TNBC) (6 patients), pelareorep + atezolizumab. Cohort 4: Hormone Receptor-positive/HER2-positive (HR+/HER2+) (6 patients), pelareorep + trastuzumab + atezolizumab. Cohort 5: Hormone Receptor-negative/HER2-positive (HR-/HER2+) (6 patients), pelareorep + trastuzumab + atezolizumab. The primary endpoint of the study is CelTIL score, a metric for quantifying the changes in tumor cellularity and infiltration of TILs, where an increase in CelTIL is associated with a favorable response to treatment. Tumor tissue was examined for pela replication, and changes to the TME were assessed by imaging mass cytometry (IMC), immunohistochemistry, and T cell receptor sequencing (TCR-seq). Peripheral blood was also examined by TCR-seq. Results: Detailed translational research results will be presented from patients in cohort 1, who received just pelareorep and letrozole. CelTIL score increased in 5/10 patients at day 3 biopsies and 6/10 patients at day 21 biopsies. Preliminary results show high levels of viral replication ( & gt;50% of tumor cells) while immunohistochemistry and IMC analysis revealed changes to the TME, with increases in CD8+ T cells and upregulation of PD-L1 at both day 3 and day 21 biopsies. Overall, preliminary data from cohort 1 of AWARE-1 demonstrate pela-mediated priming of an adaptive immune response. (NCT04102618) Citation Format: Luis Manso, Patricia Villagrasa, Nuria Chic, Begoña Bermejo, Juan Miguel Cejalvo, Yann Izarzugaza, Blanca Cantos, Salvador Blanch, Mireia Margeli, Jose Luis Alonso, Alejandro Martínez, Rafael Villanueva, Juan Antonio Guerra, Raquel Andrés, Pilar Zamora, Esteban Nogales, Manel Juan, Blanca González, Rita Laeufle, Gerard Nuovo, Grey Wilkinson, Matt Coffey, Azucena González, Débora Martínez, Laia Paré, Fernando Salvador, Xavier Gonzalez, Aleix Prat, Joaquín Gavilá. A window-of-opportunity study with atezolizumab and the oncolytic virus pelareorep in early breast cancer (REO-027, AWARE-1) [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-1 1; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-08.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS20-PS12-08
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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  • 7
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    Abstract P2-11-01: Immune response following neoadjuvant ribociclib plus letrozole versus chemotherapy in PAM50 Luminal B early breast cancer: A correlative analysis of the SOLTI-1402 CORALLEEN phase 2 randomized trial
    American Association for Cancer Research (AACR) ; 2020
    In:  Cancer Research Vol. 80, No. 4_Supplement ( 2020-02-15), p. P2-11-01-P2-11-01
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 80, No. 4_Supplement ( 2020-02-15), p. P2-11-01-P2-11-01
    Abstract: Background: CDK4/6 inhibitors increase tumor immunogenicity in preclinical models of breast cancer and several trials combining CDK4/6 inhibitors and anti-PD1/PDL1 therapies are underway. However, immune response data in tumor samples from patients (pts) treated with CDK4/6 inhibitors are scarce. Here, we present exploratory results of the CORALLEEN trial, which evaluated the efficacy of ribociclib and endocrine therapy in patients with high-risk Luminal B disease (Gavilá et al. submitted to SABCS 2019). Methods: CORALLEEN is a randomized exploratory study in postmenopausal women with operable stage I-III breast cancer, hormone receptor positive (HR+)/HER2-negative and Luminal B by Prosigna®. Pts were randomized 1:1 to receive either 6 cycles of ribociclib (600mg; 3-weeks-on/1-week-off) plus daily letrozole (R+L) or chemotherapy (CHT): 4 cycles of AC followed by 12 doses of weekly paclitaxel. The primary endpoint is the rate of PAM50 Risk of Relapse (ROR)-low disease at surgery in each arm. Baseline and surgical specimens were also collected for stromal tumor infiltrating lymphocyte (TIL) determination and gene expression analysis. Expression of 770 genes and 31 biological signatures were determined using the Breast360TM panel (nCounter). In order to identify genes whose expression correlated with TIL, a significance of microarrays (SAM) quantitative analysis was used with a false discovery rate (FDR) & lt;5%. Finally, interaction tests between each variable and tumor ROR response (i.e. relative decrease in ROR score) according to type of therapy were explored in logistic regression models. Results: From July-2017 to Nov-2018, 198 pts were screened and 106 (54%) pts with Luminal B disease were recruited. baseline characteristics were: mean age 64, mean tumor size 3.8 cm, N+ (39%), mean Ki67 33.2%; 86.8% of pts were ROR-high. A total of 95 pts (90%) were included in this analysis (46 pts in the CHT arm and 49 in the R+L arm). At baseline, 21.7% and 32.7% of pts in the CHT and R+L arms had ≥10% of TILs, respectively. Compared to baseline, no significant change patterns in TILs expression were observed. In the CHT arm, 32.6%, 28.3 % and 39.1% of tumors increased, decreased or did not show any change in TILs. In the R+L arm, 30.6%, 44.9% and 24.5% of tumors increased, decreased or did not show any change in TILs. At surgery, 15.2% of pts in the CHT arm and 26.5% of pts in the R+L arm had ≥10% of TILs. Moreover, 5 of the 13 pts (38.5%) with ≥10% of TILs at surgery following R+L had TILs & lt; 10% at baseline. In both arms, high expression of immune-related genes and signatures tracking CD8 T-cells (i.e. CD8A, PD1, LAG3 and CD8T-cell signature) were found associated with high TILs (FDR & lt;5%). when immune response was evaluated based on tumor ROR response (as a continuous variable), high TILs at surgery were associated with better response to CHT but not to R+L (interaction P=0.03). In the CHT arm, mean % of TILs at surgery in low and high ROR responders (defined as & lt;50% or ≥50% relative decrease in ROR score) were 4.2% and 11.2%, respectively. In the R+L arm, mean % of TILs at surgery in low and high ROR responders were 16.2% and 6.1%, respectively. Similar results were found with genes/signatures such as CD8A mRNA (interaction P=0.03), CD8 T-cell signature (interaction P=0.04), Tumor Inflammation Signature (interaction P=0.04) and GZMA mRNA (Granzyme A, interaction P=0.02). Conclusions: An increase in TILs following 24-weeks of R+L occurs in ~30% of pts with high-risk Luminal B tumors, regardless of tumor ROR response. These findings suggest that immune checkpoint blockade might be an interesting strategy to explore in patients with a low ROR response after R+L. Citation Format: Nuria Chic, Blanca González Farré, Laia Paré, Tomás Pascual, Cristina Saura, Cristina Hernando, Montserrat Muñoz, Pedro Fernandez, Patricia Galván, Xavier González Farré, Mafalda Oliveira, Miguel Gil Gil, Pamela Céliz, Eva Ciruelos, Patricia Villagrasa, Joaquín Gavilá, Aleix Prat. Immune response following neoadjuvant ribociclib plus letrozole versus chemotherapy in PAM50 Luminal B early breast cancer: A correlative analysis of the SOLTI-1402 CORALLEEN phase 2 randomized trial [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P2-11-01.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS19-P2-11-01
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2020
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    Abstract CT191: A window-of-opportunity study with atezolizumab and the oncolytic virus pelareorep in early breast cancer (AWARE-1)
    American Association for Cancer Research (AACR) ; 2021
    In:  Cancer Research Vol. 81, No. 13_Supplement ( 2021-07-01), p. CT191-CT191
    Details
    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 81, No. 13_Supplement ( 2021-07-01), p. CT191-CT191
    Abstract: Background: A previous phase 2 study in metastatic breast cancer demonstrated a statistically significant improvement in overall survival (OS) in patients treated with pelareorep (pela), an intravenously delivered immuno-oncolytic reovirus, given in combination with paclitaxel (PTX) versus PTX alone [1]. We hypothesized that the OS benefit from pela + PTX may be attributed to an adaptive T cell response triggered by pela. To examine if pela can mediate the priming of an anti-tumor immune response, and the impact of checkpoint blockade therapy on this response, we and SOLTI research group are conducting the AWARE-1 study (NCT04102618) in patients with early breast cancer. The initial translational research results from this study are presented here. Methods: AWARE-1 is a window-of-opportunity study to evaluate the safety and effect of pela ± atezolizumab on the tumor microenvironment (TME) in 38 women with early breast cancer. Patients are treated with pela on days 1, 2, 8, and 9, and atezolizumab is administered on day 3. Tumor biopsies are collected at diagnosis, day 3, and day ~21. Five patient cohorts are being examined: Cohort 1: HR+/HER2-neg (10 patients) receiving pelareorep + letrozole (without atezolizumab); Cohort 2: HR+/HER2-neg (10 patients) receiving pelareorep + letrozole + atezolizumab; Cohort 3: TNBC (6 patients) receiving pelareorep + atezolizumab; Cohort 4: HR+/HER2+ (6 patients) receiving pelareorep + trastuzumab + atezolizumab; Cohort 5: HR-neg/HER+ (6 patients) receiving pelareorep + trastuzumab + atezolizumab. The primary endpoint is CelTIL score [2], a metric for quantifying changes in tumor cellularity and the number of tumor infiltrating lymphocytes (TILs), where an increase in CelTIL score has been associated with a favorable response to treatment. Tumor tissue is being examined for pela replication, changes to the TME by immunohistochemistry (IHC), PD-L1 expression by the Ventana SP142 assay used as the atezolizumab companion diagnostic, and T cell clonality by T cell receptor sequencing (TCR-seq). Peripheral blood is also being examined by TCR-seq. Results: Changes in the TME by IHC demonstrate that treatment with pela in the presence of atezolizumab increases the CD8/Treg ratio, a predictor of greater therapeutic efficacy, similar to preclinical breast cancer mouse models [3, 4] . Detailed TCR-seq, Ventana PD-L1 assay results, and IHC analysis will be presented, focusing on differences between patients receiving pela in the absence or presence of atezolizumab (Cohorts 1 and 2, respectively), and between CelTIL scores of responders and non-responders. Overall, these data demonstrate that pela can promote an inflamed tumor phenotype that allows for synergy with checkpoint blockade therapy in breast cancer. References: [1] Bernstein, V., et al. Breast Cancer Res Treat, 2018. 167(2): p. 485-493. [2] Nuciforo, P., et al. Ann Oncol, 2018. 29(1): p. 170-177. [3] Mostafa, A.A., et al. Cancers (Basel), 2018. 10(6). [4] Lee, J., et al. Cancer Research, 2020. 80(16 Supplement): p. 2206-2206. Citation Format: Luis Manso, Fernando Salvador, Patricia Villagrasa, Nuria Chic, Begoña Bermejo, Juan M. Cejalvo, Yann Izarzugaza, Blanca Cantos, Salvador Blanch, Mireia Margeli, Jose L. Alonso, Alejandro Martínez, Rafael Villanueva, Juan A. Guerra, Raquel Andrés, Pilar Zamora, Esteban Nogales, Manel Juan, Blanca Gonzalez-Farre, Grey A. Wilkinson, Thomas C. Heineman, Gerard Nuovo, Houra Loghmani, Matt Coffey, Azucena Gonzalez, Débora Martínez, Laia Paré, Tomás Pascual, Xavier Gonzalez, Aleix Prat, Joaquín Gavilá. A window-of-opportunity study with atezolizumab and the oncolytic virus pelareorep in early breast cancer (AWARE-1) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr CT191.
    Type of Medium: Online Resource
    ISSN: 0008-5472 , 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.AM2021-CT191
    RVK:
    XA 36000
    RVK:
    XA 10000
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2021
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    Abstract P1-13-16: Dissecting the biological activity of different CDK4/6 inhibitors (CDK4/6i) in hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC)
    American Association for Cancer Research (AACR) ; 2023
    In:  Cancer Research Vol. 83, No. 5_Supplement ( 2023-03-01), p. P1-13-16-P1-13-16
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    In: Cancer Research, American Association for Cancer Research (AACR), Vol. 83, No. 5_Supplement ( 2023-03-01), p. P1-13-16-P1-13-16
    Abstract: Background: Palbociclib might be less effective than ribociclib in HR+/HER2- and HER2-enriched BC. This hypothesis is currently being tested in the HARMONIA prospective phase III clinical trial (NCT05207709). Here, we evaluated the downstream biological effects of both drugs using cell lines and patient tumor samples. Methods: Three HR+ BC cell lines (i.e., MCF7, T47D and BT474) were treated at 2 different dose levels of palbociclib or ribociclib (i.e., 100 nM and 500 nM) +/- fulvestrant (1 nM) for 72 hours (h). PAM50 gene signatures were determined on the nCounter, as well as phosphorylation of RB (p-RB) by Western Blot and senescence-associated β-galactosidase activity by FACS. In vitro experiments were performed in triplicates. PAM50 gene signatures were obtained from 49 paired baseline versus week-2 samples and 49 paired baseline versus surgery samples of the CORALLEEN phase II study (Prat, Lancet Oncol. 2020), which treated 49 women with PAM50 Luminal B HR+/HER2- early BC with neoadjuvant ribociclib (600 mg daily) plus endocrine therapy (ET). PAM50 signature scores were also evaluated in publicly available data from 23 paired baseline versus week-2 samples and 16 paired baseline versus surgery samples of the NEOPALANA phase II trial (Ma, Clin Cancer Res. 2017) which treated 50 patients with HR+/HER2- early BC with palbociclib (125 mg daily) plus anastrozole. Changes in PAM50 signatures upon CDK4/6i were determined by paired t-tests and significant analysis of microarray (SAM). Results: Across all cell lines, both palbociclib and ribociclib statistically significantly reduced p-RB at 72h with both doses (i.e., 100 and 500 nM) compared to non-treated cells (p & lt; 0.001). Senescence was also observed at 72h with both doses. Both drugs +/- ET significantly increased the Luminal A signature and decreased Luminal B and proliferation signatures with both doses. However, the HER2-enriched signature was only significantly reduced when both CDK4/6 inhibitors were given at 500 nM. In tumor samples from the CORALLEEN and NEOPALANA phase II studies, a similar change in PAM50 biology was observed with both drugs, namely an increase in Luminal A signature and a decrease in Luminal B and proliferation signatures after 2 weeks of treatment and at surgery. At 2 weeks of treatment, the HER2-enriched signature was significantly decreased in both studies with ribociclib (p & lt; 0.001) and palbociclib (p & lt; 0.001). However, the decrease in the HER2-enriched signature was only observed in surgical samples of patients treated with ribociclib (p & lt; 0.001), but not palbociclib (p=0.194). A difference in sample size could explain this result. Nevertheless, in CORALLEEN, the median number of days between the last dose of ribociclib and surgery was 13.1 days (range: 1-78). In NEOPALANA, the median number of days between the last dose of palbociclib and surgery was 29 days (range: 8-49), except for 8 patients who received additional 10-12 days of palbociclib immediately before surgery (Ma, Clin Cancer Res. 2017). In patients who underwent surgery at 8 days or before, the HER2-enriched signature was significantly decreased for both ribociclib (p & lt; 0.001) and palbociclib (p=0.013). Interestingly, in patients that underwent surgery after & gt;8 days from the last dose, a significant reduction of the HER2-enriched signature was only observed with ribociclib (p & lt; 0.001), but not with palbociclib (p=0.500). Conclusions: Both palbociclib and ribociclib have similar effects on PAM50 biology when given at the same dose. However, in clinical practice, palbociclib is given at a lower dose than ribociclib, and although HER2-enriched signature is significantly decreased in tumors after 2 weeks of CDK4/6i+ET, this effect is only maintained at later time points with ribociclib, indicating a dose-dependent efficacy of CDK4/6i in this biologically aggressive subtype. Citation Format: Natàlia Lorman-Carbó, Olga Martínez-Sáez, Aranzazu Fernandez-Martinez, Patricia Galván, Nuria Chic, Barbara Adamo, Maria Vidal, Montserrat Muñoz, Charles M. Perou, Joaquín Gavilá, Tomás Pascual, Aleix Prat, Fara Brasó-Maristany. Dissecting the biological activity of different CDK4/6 inhibitors (CDK4/6i) in hormone receptor-positive/HER2-negative (HR+/HER2-) breast cancer (BC) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-16.
    Type of Medium: Online Resource
    ISSN: 1538-7445
    URL: Article
    DOI: 10.1158/1538-7445.SABCS22-P1-13-16
    Language: English
    Publisher: American Association for Cancer Research (AACR)
    Publication Date: 2023
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