Search

Background Within HR+/HER2- disease, patients with non-luminal subtypes of breast cancer (HER2-enriched [HER2-E] and Basal-like) have poorer prognosis than those with luminal subtypes, may be more sensitive to chemotherapy, and have higher expression of immune-related genes and tumor infiltrating lymphocytes (TILs). Here, we report the interim efficacy and safety data of the TATEN trial (NCT04251169), the first study designed to evaluate pembrolizumab and paclitaxel in HR+/HER2-negative, PAM50 non-luminal, metastatic breast cancer (MBC). Methods TATEN is a single-arm, multicenter phase II study evaluating pembrolizumab in combination with paclitaxel in patients with HR+/HER2-, PAM50 non-luminal, MBC. Key inclusion criteria include progression to prior CDK4/6 inhibitors, presence of measurable disease by RECIST V1.1, no prior chemotherapy for MBC, and ECOG 0-1. Patients receive pembrolizumab at 200 mg every 3 weeks (on D1 of each 21-day cycle, beginning at cycle 1) in combination with weekly paclitaxel at 80 mg/m2, beginning at cycle 2. The primary endpoint is to evaluate overall response rate (ORR), defined as the rate of complete (CR) and partial response (PR) according to RECIST V1.1. Secondary endpoints include clinical benefit rate (CBR; CR + PR + stable disease >24 weeks), progression free survival, overall survival, safety, and predictive biomarkers. Tumor samples collected during advanced/metastatic disease are mandatory to assess PAM50 and other translational endpoints. This study had a planned interim analysis after 15 patients were evaluable for ORR based on a Simon’s two stage design with 80% power and a type I error rate of 0.05. Stage I of the trial would be considered successful if at least 6 patients achieved a PR and/or CR. In that case, the trial would recruit up to 46 evaluable patients for a target ORR ≥ 41. Here we report results from the patients who received at least one dose of combination treatment and had a first, post-baseline, tumor assessment according to RECIST v1.1 (evaluable population). Results From July 2020 to December 2021, 119 patients were screened, and 25 PAM50 non-luminal tumors were identified (21%). From these, 17 (68%) patients were recruited, and 15 were evaluable for primary endpoint. Two patients discontinued the trial before the first dose of pembrolizumab and paclitaxel, because of clinical progressive disease (PD). Baseline patient characteristics were as follows: median age 53 years (range: 40-77), ECOG 0 52.9%, de novo MBC at diagnosis 29.4%, and visceral disease 64.7% (including 53.3% with liver metastasis). Ten patients had received paclitaxel treatment in the adjuvant setting. Regarding PAM50 intrinsic subtype, two patients had basal-like and 13 HER2-E tumors. At the time of data cut-off (May 17,2022), 8 patients (53.3%) had stopped their treatment because of PD and 2 (13.3%) due to toxicity. Five patients (33.3%) were still on treatment. The ORR was 53.3 % (8 of 15, 95% CI 26.6-78.7), meeting the pre-specified ORR for the first stage of the trial. The CBR was 86.6% (13 of 15, 95%CI 59.5-98.34), and median PFS was 7.5 months (95% CI: 5.6 – 10.2). Overall, all patients experienced treatment-related adverse events (TRAEs) of any grade, while 53.3% of patients experienced grade 3 TRAEs. No grade 4 or 5 TRAEs were reported in the evaluable population. Correlative analysis including gene expression analysis and centralized TILs scoring and PD-L1 IHC will be presented. Conclusions The first stage of TATEN combining pembrolizumab with paclitaxel after progression to CDK4/6 inhibitors in patients with HR+/HER2-negative, PAM50 non-luminal MBC met its pre-specified endpoint. Completion of the stage II part of the trial with the inclusion of up to 46 patients is warranted to assess the activity of this combination in this group of patients. Correlative studies to find predictive biomarkers of response to this regimen are ongoing and will be presented at the meeting. This study was funded by MSD. Citation Format: Aleix Prat, Tomás Pascual, Montserrat Muñoz, Cristina Hernando, Silvia Vazquez, Salvador Blanch, Manuel Alva, Mafalda Oliveira, Esther Sanfeliu, Lorea Villanueva, Fara Brasó-Maristany, Nuria Chic, Eva Ciruelos. TATEN TRIAL (SOLTI-1716) Targeting non-Luminal disease by PAM50 with pembrolizumab + paclitaxel in Hormone Receptor-positive/HER2-negative (HR+/HER2-) metastatic breast cancer (MBC): interim analysis [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 P3-06-02.

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.

Supplementary Data

Introduction: Tumor-Infiltrating Lymphocytes (TILS) is a well-known predictor of response to primary chemotherapy1,2 and a prognostic factor for improved survival in different breast cancer subtypes3. We present data on the association of the level of TILs and morphologic characteristics of such infiltrate with pCR. Material and methods: A series of 477 breast cancer patients (479 tumors) treated with primary chemotherapy at Catalan Institut of Oncolgy - H.U. Bellvitge between January 2009 and December 2016. Chemotherapy consisted on anthracyclines and taxanes (plus trastuzumab if Her-2 positive disease). Levels of percentage of TILs using hematoxylin-eosin-stained sections of diagnostic core-needle biopsy were evaluated according to international guidelines in a prospectively defined retrospective analysis. Characterization of TILS consisted on identification of plasma cells, intraepithelial infiltrate vs stromal infiltrate and homogeneous vs heterogeneous infiltrate. A sub-classification using levels of TILS and heterogeneity was done for statistical purposes. Levels of TILS and their morphological characteristics were examined for their associations with pCR adjusted for predictive clinic-pathological factors, by univariate and multivariate logistic regression, statistical significance set at 0.05. A ROC curve was performed to look for a cut-point of TILs to predict PCR. Results: The mean value of TILs was 23.79% (SD, 24%). TILs were significantly higher in ductal carcinomas (39.1% vs 0%, p=0.007), grade 3 (55.2 vs 17.7%p30 (48.8% vs 24.5%, p 20% (15.2% vs 41.5%, OR: 3.96 [95%CI, 2.57-6.10]; P < 0.001); plasma cells (OR 6.61 [95%CI, 1.51-28.8]; P=0.01), intraepithelial TILS (OR: 10.34 [95%CI, 2.22-48.01]; P =0.003), homogeneous high infiltrate (OR: 13.6 [95%CI, 3.04-60.77]; P =0.001). In luminal tumors, TILs over 20% predicted pCR (OR 12.3 [95%CI, 4.0-37.7]; P < 0.001) as well as in TNBC (OR 4.32 [95%CI, 1.77-10.53]; P=0 .001) but not in those cases with HER2 positive tumors (luminalB HER2 + HER2) (OR 1.65 [95%CI, 0.88-3.07]; P=0.118). In the multivariate analyses, levels of TILs > 20% were associated with higher pCR rates (adjusted odds ratio, 2.44 [95%CI, 1.48-4.01]; P < .001). Conclusions: The presence of TILs over 20% at diagnosis is an independent, positive, predictive marker of pCR in early breast cancer treated with neoadjuvant chemotherapy. Interestingly, the predictive information added by TILs >20% was higher in luminal and triple negative tumors compared to HER2 positive cases. Careful morphological characterization of TILS may add valuable predictive information and can be done in current pathologic laboratories with a well-trained breast cancer pathologist. References: 1.J Clin Oncol 2009; 28:105-113. doi: 10.1200/JCO.2009.23.73702.JAMA Oncol. 2015;1(4):448-454. doi:10.1001/jamaoncol.2015.08303.Lancet Oncol 2018: 19: 40-50 http://dx.doi.org/10.1016/S1470-2045(17)30904-X. N%Age years (mean, sd)Grade*I326.7II19540.7III15152.6Ki 67≤3020442.6>3027557.4Molecular subtype*Luminal A469.6Luminal B HER2 -14329.9Luminal B HER2+9219.2HER+ enriched7615.9Triple negative12225.5Pathologic responseNon-pCR35874.7pCR12125.3 Citation Format: Catalina Falo, Juan Azcarate, Ana Petit, Andrea Vethencourt, Sergi Fernandez Gonzalez, Amparo Garcia-Tejedor, Silvia Vazquez, Hector Perez, Maria Laplana, Charo Taco, Esther Guerra, Anna Guma, Raul Ortega, Agostina Stradella, Sabela Recalde, Adela Fernandez-Ortega, Rafael Villanueva, F Javier Perez, M Jesus Pla, Miriam Campos, Diana Perez, Eulalia Fernandez-Montoliu, Veronica Obadia, Monica Cejuela, Miguel Gil-Gil, Sonia Pernas, Mar Varela, Teresa Soler-Monzo. Morphologic characterization of tumor-infiltrating lymphocytes and its relation with pathological response in a series of breast cancer patients treated with primary chemotherapy [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 P1-08-26.

Background: Most breast cancers (BC) exhibit low immune infiltration and are unresponsive to immunotherapy. Inhibitors of the Receptor Activator of NFkB (RANK) pathway, such as denosumab, used for the treatment of bone metastasis, have been shown to prevent BC, reducing tumor cell proliferation and survival. Our recent data supports that RANK pathway inhibition in BC cells enhances anti-tumor immune response. However, the population of BC patients who may benefit from denosumab remains to be identified. The aim of the study is to evaluate the antiproliferative, proapoptotic and/or immunomodulatory activity of denosumab in early BC and to identify biomarkers of response. Methods: Patients with early stage HER2-negative BC, candidates to tumor excision as first therapeutic approach were included. Patients were randomized 2: 1 to denosumab (two doses of 120mg/Kg subcutaneous denosumab, days 1 and 8 plus oral calcium 1000 mg daily for a month) and control arm (no treatment). Blood and tumor samples were collected at baseline and at surgery (2-4 weeks later). Putative changes in tumor cell proliferation by Ki67 immunohistochemistry (IHC), survival by Cleaved caspase-3 IHC and tumor infiltrating lymphocytes (TILs) quantified in H&E were evaluated between initial biopsy and surgery. RANK and RANKL expression will be analysed by IHC and the infiltrating immune populations will be characterized by specific antibodies (CD3, CD4, CD8, CD20, FoxP3, CD68, PDL1, PD1). We will analyse denosumab driven gene expression changes in tumor samples and tools such as CIBERSORT will be used to characterize the immune infiltrate. To assess the increase in TILs and the variation in Ki 67 and Cleaved caspase-3, the T-test for paired samples was used. A value of p less than 0.05 was defined as statistically significant. Result: We present results from the initial 45 patients enrolled out of 60, 31 cases in the experimental arm and 13 in the control arm. Mean age was 55,97 (range 37-88) years. 38 women with luminal breast cancer were analysed and 7 cases of triple negative BC (5 in experimental arm and 2 in control arm). Clinical and tumor characteristics were well balanced between both groups. No relevant toxicities were reported. There was no reduction of Ki67 in either of the two arms and no changes in Cleaved caspase-3 were observed. Interestingly, a statistically significant increase in TILs was observed in the denosumab treated group (p=0.0092, Paired t test) but not in the control group (p=0.68). 29.03% of patients treated with denosumab showed a ≥10% increase in TILs vs 7.14% in the control group (p=0.13). Denosumab was associated with an effective systemic inhibition of RANKL. No relationship was found between serum RANKL levels at baseline and response to denosumab. RNAseq analysis and immunophenotyping is still in progress. Conclusion: Short term neoadjuvant denosumab induces an immunomodulatory effect with an increase in stromal TILs in early BC. ClinicalTrials.gov Identifier: NCT03691311 Table 1.ResultsBiopsySurgeryKi 67 (mean frequency) Control24.5729.57Ki 67 (mean frequency) Experimental22.3927.90Cleaved caspase 3 (mean area) Control0.260.58Cleaved caspase 3 (mean area) Experimental0.350.42TILs (mean percentage) Control9.3410.29TILs (mean percentage) Experimental8.2913.54TILs incrementControl p=0.68 vs. Experimental p=0.009 Citation Format: Andrea Vethencourt, Eva M Trinidad, Anna Petit, María T Soler-Monsó, Clara Gómez Aleza, Ander Urruticochea, Amparo García-Tejedor, Anna Gumà Martinez, Veronica Obadia, Silvia Vazquez, Rafael Villanueva, Adela Fernánez, Monica Cejuela, Sabela Recalde Penabad, Agostina Stradella, Miguel Gil-Gil, Sonia Pernas, Eva Gonzalez-Suarez, Catalina Falo. First results of the randomized window of opportunity clinical trial D-Biomark: Immunomodulatory effect of denosumab in early breast cancer [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 P2-08-10.

Introduction and objectives. Metaplastic breast cancer is an heterogenous and infrequent disease (0.5-2%). Histologically, it is defined by differentiation of neoplastic epithelium into squamous or mesenchymal-like elements. Although they are mainly triple negative tumors, they present a more aggressive course with less response to chemotherapy and worse prognosis. The aim of our study was to characterize the molecular profile and tumor evolution in matched (primary-relapse) samples of patients (pts) with metaplastic breast cancer. Material and Methods. Genomic profiling of tumor biopsies from different time points in patients with early-stage metaplastic breast cancer who had disease recurrence/progression, and were treated at our institution between 2010 and 2020. Tumor samples were analyzed by DNA- Next Generation Sequencing (NGS; Illumina 2x75bp) using the ActionOncoKitDX panel (Imegen-Health in Code group). It allowed the study of point mutations in 50 genes, CNVs, fusion genes among 8 genes and pharmacogenetic SNPs associated with treatment efficacy or toxicity. It also determined MSI through 110 markers. The results were classified following the recommendations of the ACMG (American College of Medical Genetics). Only pathogenic and likely pathogenic variants were considered for analysis and afterwards we categorized them following the ComPerMed (The Personalized Medicine Commission) criteria. Results. We have analyzed 21 matched diagnosis-relapse tumor samples (8 primary tumor samples, and 13 loco-regional or metastatic disease) from 8 patients. In 4 patients, genomic characterization was performed at 3 different time points of their tumor evolution. Pathogenic alterations identified were mutations in TP53 (in 100% of the samples), TERT promoter (29%), and MYC amplifications (24% of samples, of which 75% were relapse/progression samples). We didn’t find any mutation in PI3KCA, but PTEN was found to have variations in 38% samples (10% mutations and 38% deletions). Amplification of FGFR1 was identified in 13% of the pts (only in the primary tumor). No ERBB2 or EGFR gene amplifications were detected, neither high grade MSI. We did not find a significant increase in point mutations between primary and relapse/progression samples, although gene amplifications were found more frequently in the former ones. Sixty three percent of the cases were Tier I and II category alterations, which could have future implications in the management of this neoplasia. Conclusion. In our series of metaplastic carcinoma, the most frequent pathogenic alterations occurred in cycle regulation’s genes, including TP53 and TERT promoter mutations, and MYC amplifications. Relapse/progression samples were enriched in MYC amplification and inTP53 allelic frequency. Larger studies are required to better characterize these tumors, and identify new strategies to improve the prognosis of these patients. Citation Format: Mónica Cejuela, Agostina Stradella, Anna Petit, Pablo Gargallo, Jan Bosch, Paula Carbonell, Sabela Recalde, Andrea Vethencourt, Adela Fernández, Catalina Falo, Miguel Gil-Gil, Silvia Vazquez, Rafael Villanueva, Teresa Soler, Inés Calabria, Sonia Pernas. Genomic characterization and tumor evolution in matched(primary-relapse)samplesof patients with METAPLASTIC breast cancer [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 P5-07-06.