Débora Martínez

<b>Summary</b> This metadata record provides details of the data supporting the claims of the related manuscript: "Circulating tumor DNA dynamics using a standardized multi-gene panel in advanced breast cancer treated with CDK4/6 inhibition and endocrine therapy". The related study aimed to answer critical questions regarding circulating tumor DNA (ctDNA) levels as predictors of response to anticancer drugs such as which assay or statistical method to use. Specifically, it investigated the hypothesis that a standardised plasma-based sequencing assay that analyses multiple genes simultaneously at baseline and after 4 weeks (cycle 2 day 1 [C2D1]) of CDK4/6i plus ET can identify patients with HR+/HER2-negative advanced disease with different treatment outcomes. Type of data: circulating tumour DNA (ctDNA) Subject of data: <i>Homo sapiens</i> Sample size: 45 Population characteristics: Eligible patients were ≥18 years of age with histologically confirmed HR+/HER2- negative inoperable or metastatic breast cancer treated with a CDK4/6 inhibitor and ET. Recruitment: This is a prospective, single-center study in 45 consecutive patients that fulfilled the inclusion criteria. Date of data collection: May/2016 to June/2019 <b>Data access</b> The ctDNA and clinical data are available in two separate tabs in the Excel spreadsheet "ctDNA and clinical dataset.xlsx". This spreadsheet is openly available and shared as part of this metadata record. The CDK serie - ctDNA and clinicopathological dataset is not publicly available in order to protect patient privacy. Requests for access to this dataset can be made to the corresponding author. <b>Corresponding author(s) for this study</b> Aleix Prat, MD, PhD, Hospital Clinic of Barcelona,Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, Villarroel 170, 08035, Barcelona, Spain. Email: alprat@clinic.cat, Telephone number: (+34) 93 227 54 00. <br> <b>Study approval </b> The study was performed in accordance with Good Clinical Practice guidelines and the World Medical [...]

<b>Summary</b> This metadata record provides details of the data supporting the claims of the related manuscript: "Circulating tumor DNA dynamics using a standardized multi-gene panel in advanced breast cancer treated with CDK4/6 inhibition and endocrine therapy". The related study aimed to answer critical questions regarding circulating tumor DNA (ctDNA) levels as predictors of response to anticancer drugs such as which assay or statistical method to use. Specifically, it investigated the hypothesis that a standardised plasma-based sequencing assay that analyses multiple genes simultaneously at baseline and after 4 weeks (cycle 2 day 1 [C2D1]) of CDK4/6i plus ET can identify patients with HR+/HER2-negative advanced disease with different treatment outcomes. Type of data: circulating tumour DNA (ctDNA) Subject of data: <i>Homo sapiens</i> Sample size: 45 Population characteristics: Eligible patients were ≥18 years of age with histologically confirmed HR+/HER2- negative inoperable or metastatic breast cancer treated with a CDK4/6 inhibitor and ET. Recruitment: This is a prospective, single-center study in 45 consecutive patients that fulfilled the inclusion criteria. Date of data collection: May/2016 to June/2019 <b>Data access</b> The ctDNA and clinical data are available in two separate tabs in the Excel spreadsheet "ctDNA and clinical dataset.xlsx". This spreadsheet is openly available and shared as part of this metadata record. The CDK serie - ctDNA and clinicopathological dataset is not publicly available in order to protect patient privacy. Requests for access to this dataset can be made to the corresponding author. <b>Corresponding author(s) for this study</b> Aleix Prat, MD, PhD, Hospital Clinic of Barcelona,Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, Villarroel 170, 08035, Barcelona, Spain. Email: alprat@clinic.cat, Telephone number: (+34) 93 227 54 00. <br> <b>Study approval </b> The study was performed in accordance with Good Clinical Practice guidelines and the World Medical [...]

Background: There is an increasing need in the clinic to biopsy metastatic disease in patients with advanced breast cancer (ABC). However, the microenvironment and tumor cell biology of breast cancer metastasis is largely unknown. Here, we report a molecular characterization of ABC according to the site of metastasis. Methods: RNA from 184 FFPE metastatic samples were evaluated using the nCounter BC 360 Panel, which includes the expression of 689 BC-related genes and 82 immune-related genes. PAM50 subtypes (Basal-like, HER2-enriched [HER2-E], Luminal A, Luminal B and Normal-like) were also determined. HER2 protein expression was assessed by immunohistochemistry (IHC) in 115 tumor samples, and HER2-low tumors (i.e. 1+ or 2+ and ISH-negative) were identified. Descriptive statistics, significance analysis of microarrays (using False Discovery Rate [FDR]) and logistic regressions were used to identify organ-specific gene expression profiles. Finally, we derived an organ-specific predict...

<b>Summary</b> This metadata record provides details of the data supporting the claims of the related manuscript: "Circulating tumor DNA dynamics using a standardized multi-gene panel in advanced breast cancer treated with CDK4/6 inhibition and endocrine therapy". The related study aimed to answer critical questions regarding circulating tumor DNA (ctDNA) levels as predictors of response to anticancer drugs such as which assay or statistical method to use. Specifically, it investigated the hypothesis that a standardised plasma-based sequencing assay that analyses multiple genes simultaneously at baseline and after 4 weeks (cycle 2 day 1 [C2D1]) of CDK4/6i plus ET can identify patients with HR+/HER2-negative advanced disease with different treatment outcomes. Type of data: circulating tumour DNA (ctDNA) Subject of data: <i>Homo sapiens</i> Sample size: 45 Population characteristics: Eligible patients were ≥18 years of age with histologically confirmed HR+/HER2- negative inoperable or metastatic breast cancer treated with a CDK4/6 inhibitor and ET. Recruitment: This is a prospective, single-center study in 45 consecutive patients that fulfilled the inclusion criteria. Date of data collection: May/2016 to June/2019 <b>Data access</b> The ctDNA and clinical data are available in two separate tabs in the Excel spreadsheet "ctDNA and clinical dataset.xlsx". This spreadsheet is openly available and shared as part of this metadata record. The CDK serie - ctDNA and clinicopathological dataset is not publicly available in order to protect patient privacy. Requests for access to this dataset can be made to the corresponding author. <b>Corresponding author(s) for this study</b> Aleix Prat, MD, PhD, Hospital Clinic of Barcelona,Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, Villarroel 170, 08035, Barcelona, Spain. Email: alprat@clinic.cat, Telephone number: (+34) 93 227 54 00. <br> <b>Study approval </b> The study was performed in accordance with Good Clinical Practice guidelines and the World Medical [...]

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 (>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, Begona Bermejo, Juan Miguel Cejalvo, Yann Izarzugaza, Blanca Cantos, Salvador Blanch, Mireia Margeli, Jose Luis Alonso, Alejandro Martinez, Rafael Villanueva, Juan Antonio Guerra, Raquel Andres, Pilar Zamora, Esteban Nogales, Manel Juan, Blanca Gonzalez, Rita Laeufle, Gerard Nuovo, Grey Wilkinson, Matt Coffey, Azucena Gonzalez, Debora Martinez, Laia Pare, Fernando Salvador, Xavier Gonzalez, Aleix Prat, Joaquin Gavila. 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 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS12-08.

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 st...

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, an...

<b>Summary</b> This metadata record provides details of the data supporting the claims of the related manuscript: "Circulating tumor DNA dynamics using a standardized multi-gene panel in advanced breast cancer treated with CDK4/6 inhibition and endocrine therapy". The related study aimed to answer critical questions regarding circulating tumor DNA (ctDNA) levels as predictors of response to anticancer drugs such as which assay or statistical method to use. Specifically, it investigated the hypothesis that a standardised plasma-based sequencing assay that analyses multiple genes simultaneously at baseline and after 4 weeks (cycle 2 day 1 [C2D1]) of CDK4/6i plus ET can identify patients with HR+/HER2-negative advanced disease with different treatment outcomes. Type of data: circulating tumour DNA (ctDNA) Subject of data: <i>Homo sapiens</i> Sample size: 45 Population characteristics: Eligible patients were ≥18 years of age with histologically confirmed HR+/HER2- negative inoperable or metastatic breast cancer treated with a CDK4/6 inhibitor and ET. Recruitment: This is a prospective, single-center study in 45 consecutive patients that fulfilled the inclusion criteria. Date of data collection: May/2016 to June/2019 <b>Data access</b> The ctDNA and clinical data are available in two separate tabs in the Excel spreadsheet "ctDNA and clinical dataset.xlsx". This spreadsheet is openly available and shared as part of this metadata record. The CDK serie - ctDNA and clinicopathological dataset is not publicly available in order to protect patient privacy. Requests for access to this dataset can be made to the corresponding author. <b>Corresponding author(s) for this study</b> Aleix Prat, MD, PhD, Hospital Clinic of Barcelona,Translational Genomics and Targeted Therapies in Solid Tumors, IDIBAPS, Villarroel 170, 08035, Barcelona, Spain. Email: alprat@clinic.cat, Telephone number: (+34) 93 227 54 00. <br> <b>Study approval </b> The study was performed in accordance with Good Clinical Practice guidelines and the World Medical [...]

Background: There is an increasing need in the clinic to biopsy metastatic disease in patients with advanced breast cancer (ABC). However, the microenvironment and tumor cell biology of breast cancer metastasis is largely unknown. Here, we report a molecular characterization of ABC according to the site of metastasis. Methods: RNA from 184 FFPE metastatic samples were evaluated using the nCounter BC 360 Panel, which includes the expression of 689 BC-related genes and 82 immune-related genes. PAM50 subtypes (Basal-like, HER2-enriched [HER2-E], Luminal A, Luminal B and Normal-like) were also determined. HER2 protein expression was assessed by immunohistochemistry (IHC) in 115 tumor samples, and HER2-low tumors (i.e. 1+ or 2+ and ISH-negative) were identified. Descriptive statistics, significance analysis of microarrays (using False Discovery Rate [FDR]) and logistic regressions were used to identify organ-specific gene expression profiles. Finally, we derived an organ-specific predict...

Circulating tumor DNA (ctDNA) levels may predict response to anticancer drugs, including CDK4/6 inhibitors and endocrine therapy combinations (CDK4/6i+ET); however, critical questions remain unanswered such as which assay or statistical method to use. Here, we obtained paired plasma samples at baseline and week 4 in 45 consecutive patients with advanced breast cancer treated with CDK4/6i+ET. ctDNA was detected in 96% of cases using the 74-gene Guardant360 assay. A variant allele fraction ratio (VAFR) was calculated for each of the 79 detected mutations between both timepoints. Mean of all VAFRs (mVAFR) was computed for each patient. In our dataset, mVAFR was significantly associated with progression-free survival (PFS). Baseline VAF, on-treatment VAF or absolute changes in VAF were not associated with PFS, nor were CA-15.3 levels at baseline, week 4 or the CA-15.3 ratio. These findings demonstrate that ctDNA dynamics using a standardized multi-gene panel and a unique methodological ...

Background: There is an increasing need in the clinic to biopsy metastatic disease in patients with advanced breast cancer (ABC). However, the microenvironment and tumor cell biology of breast cancer metastasis is largely unknown. Here, we report a molecular characterization of ABC according to the site of metastasis. Methods: RNA from 184 FFPE metastatic samples were evaluated using the nCounter BC 360 Panel, which includes the expression of 689 BC-related genes and 82 immune-related genes. PAM50 subtypes (Basal-like, HER2-enriched [HER2-E], Luminal A, Luminal B and Normal-like) were also determined. HER2 protein expression was assessed by immunohistochemistry (IHC) in 115 tumor samples, and HER2-low tumors (i.e. 1+ or 2+ and ISH-negative) were identified. Descriptive statistics, significance analysis of microarrays (using False Discovery Rate [FDR]) and logistic regressions were used to identify organ-specific gene expression profiles. Finally, we derived an organ-specific predict...

Circulating tumor DNA (ctDNA) levels may predict response to anticancer drugs, including CDK4/6 inhibitors and endocrine therapy combinations (CDK4/6i+ET); however, critical questions remain unanswered such as which assay or statistical method to use. Here, we obtained paired plasma samples at baseline and week 4 in 45 consecutive patients with advanced breast cancer treated with CDK4/6i+ET. ctDNA was detected in 96% of cases using the 74-gene Guardant360 assay. A variant allele fraction ratio (VAFR) was calculated for each of the 79 detected mutations between both timepoints. Mean of all VAFRs (mVAFR) was computed for each patient. In our dataset, mVAFR was significantly associated with progression-free survival (PFS). Baseline VAF, on-treatment VAF or absolute changes in VAF were not associated with PFS, nor were CA-15.3 levels at baseline, week 4 or the CA-15.3 ratio. These findings demonstrate that ctDNA dynamics using a standardized multi-gene panel and a unique methodological ...

Purpose: To assess palbociclib in combination with trastuzumab with or without endocrine therapy in patients with HER2-positive advanced breast cancer. Patients and Methods: PATRICIA is a prospective, open-label, multicenter phase II trial. Patients had received 2–4 prior lines of anti-HER2–based regimens. Treatment consisted of palbociclib 200 mg daily for 2 weeks and 1 week off plus trastuzumab. The study was based on a Simon two-stage design comprising three cohorts: estrogen receptor (ER)-negative (cohort A), ER-positive (cohort B1), and ER-positive with letrozole (cohort B2). ER-positive patients were randomized to cohorts B1 or B2. Primary endpoint was progression-free survival rate at 6 months (PFS6). Secondary objectives included safety and evaluation of the PAM50 intrinsic subtypes. Results: Seventy-one patients were recruited (n = 15 in cohort A and 28 in each cohort B). The PFS6 rate in cohorts A, B1, and B2 was 33.3% (5/15), 42.8% (12/28), and 46.4% (13/28), respectively. Regarding safety, grade 1–2 and 3–4 toxicities occurred in 97.7% and 84.4% of patients, respectively. The most common grade 3–4 toxicities were neutropenia (66.4%) and thrombocytopenia (11.3%). Regarding PAM50, 59 (83.1%) tumors were profiled. Luminal disease defined by PAM50 was found independently associated with longer PFS compared with non-luminal disease (10.6 vs. 4.2 months median PFS; adjusted hazard ratio = 0.40; P = 0.003). Conclusions: Palbociclib in combination with trastuzumab is safe and exhibits promising survival outcomes in trastuzumab pretreated ER-positive/HER2-positive advanced breast cancer with a PAM50 Luminal A or B subtype. The enrollment was stopped prematurely, and a new randomized cohort was opened in this population.

Circulating tumor DNA (ctDNA) levels may predict response to anticancer drugs, including CDK4/6 inhibitors and endocrine therapy combinations (CDK4/6i+ET); however, critical questions remain unanswered such as which assay or statistical method to use. Here, we obtained paired plasma samples at baseline and week 4 in 45 consecutive patients with advanced breast cancer treated with CDK4/6i+ET. ctDNA was detected in 96% of cases using the 74-gene Guardant360 assay. A variant allele fraction ratio (VAFR) was calculated for each of the 79 detected mutations between both timepoints. Mean of all VAFRs (mVAFR) was computed for each patient. In our dataset, mVAFR was significantly associated with progression-free survival (PFS). Baseline VAF, on-treatment VAF or absolute changes in VAF were not associated with PFS, nor were CA-15.3 levels at baseline, week 4 or the CA-15.3 ratio. These findings demonstrate that ctDNA dynamics using a standardized multi-gene panel and a unique methodological ...

Purpose: To assess palbociclib in combination with trastuzumab with or without endocrine therapy in patients with HER2-positive advanced breast cancer. Patients and Methods: PATRICIA is a prospective, open-label, multicenter phase II trial. Patients had received 2–4 prior lines of anti-HER2–based regimens. Treatment consisted of palbociclib 200 mg daily for 2 weeks and 1 week off plus trastuzumab. The study was based on a Simon two-stage design comprising three cohorts: estrogen receptor (ER)-negative (cohort A), ER-positive (cohort B1), and ER-positive with letrozole (cohort B2). ER-positive patients were randomized to cohorts B1 or B2. Primary endpoint was progression-free survival rate at 6 months (PFS6). Secondary objectives included safety and evaluation of the PAM50 intrinsic subtypes. Results: Seventy-one patients were recruited (n = 15 in cohort A and 28 in each cohort B). The PFS6 rate in cohorts A, B1, and B2 was 33.3% (5/15), 42.8% (12/28), and 46.4% (13/28), respectively. Regarding safety, grade 1–2 and 3–4 toxicities occurred in 97.7% and 84.4% of patients, respectively. The most common grade 3–4 toxicities were neutropenia (66.4%) and thrombocytopenia (11.3%). Regarding PAM50, 59 (83.1%) tumors were profiled. Luminal disease defined by PAM50 was found independently associated with longer PFS compared with non-luminal disease (10.6 vs. 4.2 months median PFS; adjusted hazard ratio = 0.40; P = 0.003). Conclusions: Palbociclib in combination with trastuzumab is safe and exhibits promising survival outcomes in trastuzumab pretreated ER-positive/HER2-positive advanced breast cancer with a PAM50 Luminal A or B subtype. The enrollment was stopped prematurely, and a new randomized cohort was opened in this population.

Purpose: To assess palbociclib in combination with trastuzumab with or without endocrine therapy in patients with HER2-positive advanced breast cancer. Patients and Methods: PATRICIA is a prospective, open-label, multicenter phase II trial. Patients had received 2–4 prior lines of anti-HER2–based regimens. Treatment consisted of palbociclib 200 mg daily for 2 weeks and 1 week off plus trastuzumab. The study was based on a Simon two-stage design comprising three cohorts: estrogen receptor (ER)-negative (cohort A), ER-positive (cohort B1), and ER-positive with letrozole (cohort B2). ER-positive patients were randomized to cohorts B1 or B2. Primary endpoint was progression-free survival rate at 6 months (PFS6). Secondary objectives included safety and evaluation of the PAM50 intrinsic subtypes. Results: Seventy-one patients were recruited (n = 15 in cohort A and 28 in each cohort B). The PFS6 rate in cohorts A, B1, and B2 was 33.3% (5/15), 42.8% (12/28), and 46.4% (13/28), respectively. Regarding safety, grade 1–2 and 3–4 toxicities occurred in 97.7% and 84.4% of patients, respectively. The most common grade 3–4 toxicities were neutropenia (66.4%) and thrombocytopenia (11.3%). Regarding PAM50, 59 (83.1%) tumors were profiled. Luminal disease defined by PAM50 was found independently associated with longer PFS compared with non-luminal disease (10.6 vs. 4.2 months median PFS; adjusted hazard ratio = 0.40; P = 0.003). Conclusions: Palbociclib in combination with trastuzumab is safe and exhibits promising survival outcomes in trastuzumab pretreated ER-positive/HER2-positive advanced breast cancer with a PAM50 Luminal A or B subtype. The enrollment was stopped prematurely, and a new randomized cohort was opened in this population.

The immune checkpoint inhibitor atezolizumab is approved for PD-L1-positive triple-negative breast cancer (TNBC). However, no activity of atezolizumab in PD-L1-negative TNBC has been reported to date. Here, we present the case study of a woman with TNBC with low tumor infiltrating lymphocytes and PD-L1-negative disease, which achieved a significant response to atezolizumab monotherapy and durable response after the combination of atezolizumab and nab-paclitaxel. The comprehensive genomic analysis that we performed in her tumor and plasma samples revealed high tumor mutational burden (TMB), presence of the APOBEC genetic signatures, high expression of the tumor inflammation signature, and a HER2-enriched subtype by the PAM50 assay. Some of these biomarkers have been shown to independently predict response to immunotherapy in other tumors and may explain the durable response in our patient. Our work warrants further translational studies to identify biomarkers of response to immune ch...

The immune checkpoint inhibitor atezolizumab is approved for PD-L1-positive triple-negative breast cancer (TNBC). However, no activity of atezolizumab in PD-L1-negative TNBC has been reported to date. Here, we present the case study of a woman with TNBC with low tumor infiltrating lymphocytes and PD-L1-negative disease, which achieved a significant response to atezolizumab monotherapy and durable response after the combination of atezolizumab and nab-paclitaxel. The comprehensive genomic analysis that we performed in her tumor and plasma samples revealed high tumor mutational burden (TMB), presence of the APOBEC genetic signatures, high expression of the tumor inflammation signature, and a HER2-enriched subtype by the PAM50 assay. Some of these biomarkers have been shown to independently predict response to immunotherapy in other tumors and may explain the durable response in our patient. Our work warrants further translational studies to identify biomarkers of response to immune ch...

Trastuzumab emtansine (T-DM1) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (BC) and for residual disease after neoadjuvant therapy; however, not all patients benefit. Here, we hypothesized that the heterogeneity in the response seen in patients is partly explained by the levels of human epidermal growth factor receptor 2 gene (ERBB2) mRNA. We analyzed ERBB2 expression using a clinically applicable assay in formalin-fixed paraffin-embedded (FFPE) tumors (primary or metastatic) from a retrospective series of 77 patients with advanced HER2+ BC treated with T-DM1. The association of ERBB2 levels and response was further validated in 161 baseline tumors from the West German Study (WGS) Group ADAPT phase II trial exploring neoadjuvant T-DM1 and 9 in vitro BC cell lines. Finally, ERBB2 expression was explored in 392 BCs from an in-house dataset, 368 primary BCs from The Cancer Genome Atlas (TCGA) dataset and 10,0...

Trastuzumab emtansine (T-DM1) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-positive (HER2+) metastatic breast cancer (BC) and for residual disease after neoadjuvant therapy; however, not all patients benefit. Here, we hypothesized that the heterogeneity in the response seen in patients is partly explained by the levels of human epidermal growth factor receptor 2 gene (ERBB2) mRNA. We analyzed ERBB2 expression using a clinically applicable assay in formalin-fixed paraffin-embedded (FFPE) tumors (primary or metastatic) from a retrospective series of 77 patients with advanced HER2+ BC treated with T-DM1. The association of ERBB2 levels and response was further validated in 161 baseline tumors from the West German Study (WGS) Group ADAPT phase II trial exploring neoadjuvant T-DM1 and 9 in vitro BC cell lines. Finally, ERBB2 expression was explored in 392 BCs from an in-house dataset, 368 primary BCs from The Cancer Genome Atlas (TCGA) dataset and 10,0...

BackgroundA previous phase 2 study in metastatic breast cancer demonstrated a statistically significant improvement in overall survival (OS) in patients treated with pelareorep (pela) in combination with paclitaxel (PTX) versus PTX alone.1 Given that pela is an intravenously delivered immuno-oncolytic reovirus, 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, we are conducting together with the SOLTI group the AWARE-1 study (a window-of-opportunity study of pela in early breast cancer), which is currently enrolling and for which initial translational research results are presented.MethodsAWARE-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, while atezolizumab is admin...

Purpose The therascreen PIK3CA mutation assay and the alpha-specific PI3K inhibitor alpelisib are FDA-approved for identifying and treating patients with advanced PIK3CA-mutated (PIK3CAmut) breast cancer (BC). However, it is currently unknown to what extend this assay detects most PIK3CA mutations in BC. This information is critical as patients and clinicians are using this and other genomic assays to indicate alpelisib. Methods Data from 6338 patients with BC was explored across 10 publicly available studies. The primary objective was to evaluate the proportion and distribution of PIK3CA mutations in BC. Secondary objectives were (1) to evaluate in silico the spectrum of PIK3CA mutations in BC that would be captured by the therascreen panel; (2) to evaluate the proportion and distribution of PIK3CA mutations in hormone receptor-positive/HER2-negative (HR+/HER2−), HER2+, and triple-negative BC (TNBC); and (3) to explore the identification of PIK3CA mutations in a cohort of 48 HR+/HE...

The BOLERO-2 study previously demonstrated that adding everolimus (EVE) to exemestane (EXE) significantly improved progression-free survival (PFS) by more than twofold in patients with hormone-receptor-positive (HR(+)), HER2-negative advanced breast cancer that recurred or progressed during/after treatment with nonsteroidal aromatase inhibitors (NSAIs). The overall survival (OS) analysis is presented here. BOLERO-2 is a phase III, double-blind, randomized international trial comparing EVE 10 mg/day plus EXE 25 mg/day versus placebo (PBO) + EXE 25 mg/day in postmenopausal women with HR(+) advanced breast cancer with prior exposure to NSAIs. The primary end point was PFS by local investigator assessment; OS was a key secondary end point. At the time of data cutoff (3 October 2013), 410 deaths had occurred and 13 patients remained on treatment. Median OS in patients receiving EVE + EXE was 31.0 months [95% confidence interval (CI) 28.0-34.6 months] compared with 26.6 months (95% CI 22....

Background PgR expression is a biomarker of ER functionality, cellular progression to malignancy, and response to endocrine therapy (ET) in HR+ BC. Onapristone (ONA), a type 1 antiprogestin, was shown to have a single agent anti-tumor activity in patients with metastatic breast cancer (Robertson et al., 1999; Jonat et al., 2002). However, this once daily immediate-release formulation was associated with liver function test abnormalities in one-third of patients. A new, extended-release formulation (ONA XR) was developed and was evaluated in a BID schedule that reduced peak serum concentrations while sustaining the minimum plasma concentrations previously associated with the higher dose. Safety results of two phase I-II studies confirmed this hypothesis (Cottu et al., 2018; Jayaram et al., 2017; Lewis et al, 2020). Considering BC heterogeneity and that PgR analysis by standard immunohistochemistry (IHC) does not perfectly correlate with PgR target gene expression, the identification ...