Triple negative breast cancer (TNBC) is a heterogeneous disease with distinct molecular subtypes that differentially respond to chemotherapy and targeted agents. The purpose of this study is to explore the clinical relevance of Lehmann TNBC subtypes by identifying any differences in response to neoadjuvant chemotherapy among them. We determined Lehmann subtypes by gene expression profiling in paraffined pre-treatment tumor biopsies from 125 TNBC patients treated with neoadjuvant anthracyclines and/or taxanes +/- carboplatin. We explored the clinicopathological characteristics of Lehmann subtypes and their association with the pathologic complete response (pCR) to different treatments. The global pCR rate was 37%, and it was unevenly distributed within Lehmann’s subtypes. Basal-like 1 (BL1) tumors exhibited the highest pCR to carboplatin containing regimens (80% vs 23%, p=0.027) and were the most proliferative (Ki-67>50% of 88.2% vs. 63.7%, p=0.02). Luminal-androgen receptor (LAR) patients achieved the lowest pCR to all treatments (14.3% vs 42.7%, p=0.045 when excluding mesenchymal stem-like (MSL) samples) and were the group with the lowest proliferation (Ki-67≤50% of 71% vs 27%, p=0.002). In our cohort, only tumors with LAR phenotype presented non-basal-like intrinsic subtypes (HER2-enriched and luminal A). TNBC patients present tumors with a high genetic diversity ranging from highly proliferative tumors, likely responsive to platinum-based therapies, to a subset of chemoresistant tumors with low proliferation and luminal characteristics.
Neoadjuvant Chemotherapy (NAC) in Breast Cancer (BC) has proved useful for the reduction in tumor burden prior to surgery, allowing for a more extensive breast preservation and the eradication of subjacent micrometastases. However, the impact on prognosis is highly dependent on the establishment of Pathological Complete Response (pCR), in particular for Triple Negative (TN) and Hormonal Receptor negative/Human Epidermal growth factor Receptor 2 positive (HR−/HER2+) subtypes. Several pCR predictors, such as PAM50, Integrative Cluster (IntClust), mutations in PI3KCA, or the Trastuzumab Risk model (TRAR), are useful molecular tools for estimating response to treatment and are prognostic. Major evolution events during BC NAC that feature the Residual Disease (RD) are the loss of HR and HER2, which are prognostic of bad outcome, and stemness and immune depletion-related gene expression aberrations. This dynamic nature of the determinants of response to BC NAC, together with the extensive heterogeneity of BC, raises the need to discern the individual and subtype-specific determinants of resistance. Moreover, refining the current approaches for a comprehensive monitoring of tumor evolution during treatment, RD, and eventual recurrences is essential for identifying new actionable alterations and the integral best management of the disease.
Introduction: While pCR has been amply associated with improved treatment outcome in patients treated with NAC and surgery, there are only few studies that explore the molecular determinants of pCR. Given the discrete percentage of patients who achieve pCR after NAC, it is of upmost need to identify biomarkers that can discern between responder and non-responder patients before NAC and therefore determine the best therapeutic approach in advance. Our aim is to find the best combination of variables to predict pCR in our cohort. Patients: To evaluate if there is a gene expression profile that could predict pathological complete response (pCR) to NAC, we selected a cohort of 69 patients treated with neoadjuvant chemotherapy consisting of anthracyclines + taxanes; HER2+ patients were further treated with trastuzumab. The median age was 48 years, and 71% of patients were premenopausal. The median of mammographic tumor size was 3,7. Most patients (89%) had invasive ductal carcinoma, and the histological grade was mainly 2 (55,7% Grade 1+2; 44,3% Grade 3). ER and PR positivity were seen in 63% and 53% of cases respectively. HER2 overexpression was seen in 20% of tumors. Methods: Gene expression was evaluated in 770 genes involved in 13 canonical cancer pathways as screened with the nCounter® PanCancer Pathways panel in FFPE pre-treatment tumor biopsies and analyzed with the nSolverTM software. The collected clinical and pathologic variables were age, mammographic tumor size, nodal status, tumor grade, HR status, HER2-overexpression, Ki67 percentage, IHQ subtype and PAM50 subtype. Finally, LASSO regression was used to predict pCR based on normalized gene expression levels and clinical and pathological data. Results: Out of the 69 enrolled patients, 27 achieved pCR (39%) and 42 did not (determined by Miller and Payne criteria). High-quality RNA was isolated from each patient for doing Nanostring nCounter experiment. Based on the gene expression levels of the PanCancer Pathways panel, Lasso regression identified a subset of genes as predictive of pCR. Therefore, the combination of expression levels of DTX3, CACNA1G, IL11, ETV4 and TSPAN7 genes, predicted pCR with an average 70% of Area Under the Curve ROC (AUC) on the test set in a cross-validation scheme. DTX3 is a member of Notch pathway, IL11 from JAK-STAT pathway, CACNA1G from MAPK pathway, ETV4 and TSPAN7 from Transcriptional misregulation pathway. DTX3, CACNA1G and TSPAN7 are down-regulated and IL11 and ETV4 are up-regulated in patients who achieved pCR. Regarding the clinical and pathological data, the best model for predict pCR obtained an 60% of AUC and the selected variables were age, mammographic tumor size, nodal status, tumor grade and Ki67 percentage. Conclusions: In our cohort, the combination of gene expression levels of DTX3, CACNA1G, IL11, ETV4 and TSPAN7 can predict tumor response to NAC even better than any clinical or pathological variable. Although validation in a separate cohort is necessary, our results indicate that this combination could constitute a predictive gene signature to discriminate resistant patients to NAC before the treatment in breast cancer tumors. Citation Format: Maria Rosario Chica-Parrado, Julio Montes-Torres, Cynthia Robles-Podadera, Martina Alvarez, Jose Jerez, Luis Vicioso, Lidia Pérez-Villa, Begoña Jimenez, Nuria Ribelles, Ana Godoy, Isabel Barragán-Mallofret, Emilio Alba. Gene expression levels of DTX3, CACNA1G, IL11, ETV4 and TSPAN7 selected by LASSO penalty regression could predict pCR after neoadjuvant chemotherapy in breast cancer tumors [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 P1-10-26.
Melanoma comprises a variety of malignant cell types from the skin, the mucous membranes, and the pigmented cells of the eye. Its incidence and mortality rates continue to rise worldwide, mainly driven by increased ultraviolet light exposure. Although screening improvements have led to a better diagnosis in the early stages, the outcome for patients with Metastatic Melanoma (MM) remains poor and the survival rate is considerably low. Recently, Immune Checkpoint Inhibitors (ICB) have revolutionized the treatment of MM, although only 30% of patients enjoy clinical benefit and a plethora of different molecular mechanisms is postulated to cause resistance. Several biomarkers are currently on the spotlight as putative predictors of response; however, they are not sufficiently informative and robust. Circular RNAs (circRNAs) are a class of single-stranded stable RNAs produced by 5′-to-3′ transcription of coding gene exons or long non-coding RNAs that act as translation templates, RNA-binding protein regulators, or miRNA-binding sponges. Here, we present an exploratory study to evaluate the potential use of circRNA as ICB response predictors. We recruited 23 MM patients treated with Nivolumab and categorized them as good responders (10 patients) and bad responders (11 patients). All RNA-seq with ribosomal depletion was performed on RNA isolated from pre-treatment FFPE tumor biopsies. Two bioinformatic tools that use de novo assembly for the identification of circRNAs (Starchip and Ciri) were employed independently to characterize the MM circRNAs profile and to identify a specific pattern for responders. Overall, a total of 731 circRNAs were detected. Interestingly, the number of circRNAs were comparatively higher in bad responders (11.917 reads, 321 circRNAs) versus good responders (7368 reads, 176 circRNAs), with 234 common circRNAs. Additionally, we also explored the biological function of the identified circRNAs in MM, by interrogating KEGG, GO and Reactome databases to delineate the gene regulatory networks specifically associated with the response-related phenotypes. The circRNAs exclusively expressed in patients presenting resistance to Nivolumab were associated with Transcriptional Misregulation in Cancer and Viral Infections processes. In contrast, circRNAs expressed uniquely in good responders were enriched in Generic Transcription pathways. Importantly, amongst the identified circRNAs, CDR1-AS was differentially downregulated in good responders (536 vs 1580 reads, p-value 0.002). Remarkably, CDR1-AS acts as miRNA-binding sponge of miRNA-7 in the context of invasion and migration in melanoma. In conclusion, our exploratory study paves the way to the utilization of novel biomarkers associated to immunotherapy failure in MM patients. Moreover, our results suggest that CDR1-AS is a novel putative predictor of ICB response. Citation Format: Juan Luis Onieva, Javier Oliver, Aurora Laborda-Illanes, Maria Rosario Chica-Parrado, Alicia Garrido-Aranda, Cynthia Robles-Podadera, Daniel Prieto, Elena Gallego, Alfonso Sanchez, Iñaki Comino, Vanessa De Luque, Martina Alvarez, Maria Jose Lozano, Pedro Jimenez, Miguel Angel Berciano-Guerrero, Emilio Alba, Manuel Cobo, Isabel Barragan. Evaluation of circular RNA profiling in metastatic melanoma patients treated with immune checkpoint blockade [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 281.
Background: Urachal carcinoma (UrC) represents < 1 % of bladder carcinomas and is developed from an embryonic remnant connecting to the umbilicus. Because of its rarity, the standard of care is not well defined. Methods:We identified patients (pts) treated for UrC by the GETUG-AFU group. Data were collected retrospectively and analyzed for pts characteristics and outcomes.Background: Seventy percent of testicular non-seminomatous germ cell tumors (NSGCT) are cured with only orchiectomy, so the adjuvant treatment is an overtreatment in most patients. The objective of the study was to find a gene expression model that would help us select the patients with the highest risk of relapse.Methods: Retrospective study of 54 patients with stage I NSGCT without adjuvant treatment (48% with relapse and 52% without relapse). Gene expression differences were analyzed using the PanCancer panel. Bioinformatics tools were used to find a gene expression signature, based on the selection of embedded type characteristics, using nine classification models (Lasso, Ridge, Gradient Boosting, Random Forest, ExtraTrees, LogisticRegression, SGDC, Passive Aggressive Classifier and SVR).Results: A nine gene model (MPL, Col24a1, NR4A1, FOSL1, CREB5, FANCB, LAMB4, ZBTB16, CALML3) was obtained with the ability to predict the risk of relapse in patients with NSGCT stage I without adjuvant treatment, AUC 0.8. Of these genes, four are related to the PI3K signaling pathway (Col24a1, NR4A1, CREB5, LAMB4). From the nine gene model highlights FOSL1, with a correlation with relapse of 0.43, and NR4A1 abstracts Annals of Oncology Volume 31 -Issue S4 -2020 S601and ZBTB16, with a differential expression close to statistical significance (0.075 in both cases). Conclusions:In stage I NSGCT treated with only orchiectomy a differential gene expression signature of nine genes has been identified (MPL, Col24a1, NR4A1, FOSL1, CREB5, FANCB, LAMB4, ZBTB16, CALML3) that allows selecting those patients with a high risk of relapse, although these data need validation in a larger population of patients.
We investigated the tumor microenvironment (TME) in estrogen receptor positive (ER+) primary breast cancers from stage I-III patients treated with estrogen deprivation (ED, induced with letrozole) for 10-21 days. We used primary breast cancer biopsies, collected from 198 patients, to assess tumor-infiltrating lymphocytes (TILs), transcriptomic profiles, and TME composition. Diagnostic biopsy and surgical on-treatment tumor specimens were collected; Ki67, ERα, PR, and HER2 expression were measured using automated quantitative analysis (AQUA). Tumors were categorized as estrogen deprivation-sensitive (ED-S) or -resistant (ED-R) based on the natural log (ln) of the Ki67 score (ln ≤1.0 or ≤2.7% Ki67+ cells vs. ln ≥2.0 or ≥7.4%, respectively) in the on-treatment (surgical) biopsy. Scoring of stromal (s)TILs, using hematoxylin and eosin staining of on-treatment specimens, revealed that sTILs were elevated in ED-R compared to ED-S tumors (p<0.0001). We next constructed tissue microarrays (TMAs) of on-treatment tumor sections and performed cyclic immunofluorescence (CyCIF) with 38 antibodies, including markers of hormone receptors, immune cells, signaling pathways, proliferation, DAPI (nuclei), and others. We then segmented single cells from each tumor core and designated them as immune, cancer, or stromal cells based on expression of a set of markers. Briefly, cells that stained strongly for CD45 (leukocyte marker), and/or CD4 (T lymphocyte marker), or CD68 (macrophage marker) were considered immune cells. CD45/CD4/CD68-negative cells were categorized as tumor, if E-cadherin and/or cytokeratin-positive, or stromal cells, if -negative. To investigate the TME composition, we next assessed cell specific spatial enrichment by quantifying the expression of immune markers in the area immediately adjacent to each tumor cell. Relative to ED-S, ED-R samples exhibited higher CD45+ cells (p<0.0001) and higher CD8+ T cells (p=0.0329), while CD4+ T cells showed no difference. Conversely, immune-suppressive T-reg (CD4+FOXP3+) cells were enriched in the ED-S samples (p=0.0004). In addition, PD1, a marker for T cell exhaustion, was higher in the ED-S group (p=0.0004), as were CD68+ cells (p<0.0001). To confirm and expand upon these findings, RNA-sequencing was performed on the on-treatment tumor sections. Gene set enrichment analysis of hallmark gene signatures revealed that immune-related gene sets, such as “IFNα response”, “IFNɣ response”, “allograft rejection”, and “inflammatory response” were enriched in ED-R vs. ED-S tumors. In summary, our study shows that activated anti-tumor immune cells are enriched in the TME of ER+ breast tumors resistant to estrogen deprivation, whereas ED-sensitive tumors show a more immunosuppressed or immune cold milieu. These data suggest a potential causal link between antiestrogen treatment and modulation of antitumor immunity in ER+ breast cancers. Citation Format: Fabiana Napolitano, Dhivya R. Sudhan, Yunguan Wang, Paula I. González-Ericsson, Luigi Formisano, Kyung-Min Lee, Chang-Ching Lin, María Rosario Chica-Parrado, Hongli Ma, Nathaniel Evans, Alberto Servetto, Saurabh Mendiratta, Spencer Barnes, Yisheng V. Fang, Justin M. Balko, Gordon B. Mills, Marilyne Labrie, Ariella B. Hanker, Carlos L. Arteaga. Immune cells infiltration and activation are higher in breast cancers resistant to antiestrogen therapy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3445.
Background CDK4/6 inhibitors (CDK4/6i), like palbociclib, ribociclib, and abemaciclib, along with antiestrogens, have revolutionized treatment for ER+/HER2- metastatic breast cancer (MBC). Although most patients initially respond, almost all eventually progress, and ER+ HER2- MBC remains incurable. There is an urgent need to understand the molecular processes that drive resistance in order to improve survival. The landscape of acquired somatic alterations causal to CDK4/6i resistance remains unknown. Here we report differences in mutational landscapes between ER+ HER2- MBC patients treated with and without CDK4/6i. Methods Deidentified data from 780 and 1073 ER+ HER2- MBC patients (solid tumor or ctDNA liquid biopsy sequencing respectively) with at least 6 months between diagnosis of Stage 4 disease and biopsy were analyzed. Patients were divided into either treated or untreated with CDK4/6i prior to biopsy. Sequencing was performed using the Tempus xT tumor assay (DNA sequencing of 595-648 genes at 500x coverage) and Tempus xF liquid biopsy (ctDNA sequencing of 105-523 genes). Gene alterations (consisting of pathogenic/likely pathogenic short variants and copy number alterations) were compared between groups by Chi-squared/Fisher’s Exact tests and p-values adjusted for false-discovery. Results We first analyzed sequencing data of both solid tumor and liquid ctDNA from ER+/HER2- MBC patients. ESR1 mutations were significantly more frequent in those that received CDK4/6i than those that did not (Solid tumor 33% vs 16%, p < 0.001, q = 0.001; Liquid biopsy 32% vs 16%, p < 0.001 and q < 0.001). We also saw more frequent mutations/amplifications in the following genes in the CDK4/6i treated cohort vs. those that were not. These results trended towards significance in our solid tumor, but not in our liquid biopsy cohort: CCND1 (18% vs 11% p = 0.028 q =0 .3); FGF3 (17% vs 9.5% p = 0.010 q = 0.2); FGF4 (17% vs 11% p = 0.035 q = 0.3), GATA3 (17% vs 8.9% p = 0.008 q = 0.2), PTEN (12% vs 6.1% p = 0.030 q = 0.3) and FGF19 (8.2% vs 1.7% p = 0.002 q = 0.12). Interestingly, 96-98% of CCND1, FGF3, FGF4 and FGF19 alterations were copy number amplifications. Conversely, we saw a trend towards significance for more mutations in TP53 (37% vs 27% p=0.008 and q=0.2) in those that had not received a CDK4/6i than those that did. Conclusions Here we present the landscape of somatic alterations in ER+/HER2- MBC patients with and without prior CDK4/6i therapy from our large real world de-identified data set. Patients with prior CDK4/6i therapy harbored significantly more ESR1 somatic alterations, demonstrated in both solid tissue and liquid biopsies. In solid tissue biopsies, patients with prior CDK4/6i therapy harbored more CCND1, FGF3, FGF4, and GATA3 alterations and less TP53 alterations. These trends were not significant after adjustment for multiple testing. CCND1, FGF3, FGF4 and FGF19 alterations were copy number amplifications, which may be consistent with 11q13 amplification. Further studies will provide insights into how these trends translate towards our understanding of CDK4/6i related resistance mechanisms. Citation Format: M Rosario Chica-Parrado, Chang-Ching Lin, Timothy Mahoney, Elizabeth Mauer, Ariella Hanker, Carlos Arteaga. Genomic Landscape of ER+/HER2- metastatic breast cancer as a function of prior treatment with a CDK4/6 inhibitor. [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 P5-02-02.
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