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Background Predicting treatment benefit and/or outcome before any therapeutic intervention has taken place would be clinically very useful. Herein, we evaluate the ability of the intrinsic subtypes and the risk of relapse score at diagnosis to predict survival and response following neoadjuvant chemotherapy. In addition, we evaluated the ability of the Claudin-low and 7-TNBCtype classifications to predict response within triple-negative breast cancer (TNBC). Methods Gene expression and clinical-pathological data were evaluated in a combined dataset of 957 breast cancer patients, including 350 with TNBC, treated with sequential anthracycline and anti-microtubule-based neoadjuvant regimens. Intrinsic subtype, risk of relapse score based on subtype and proliferation (ROR-P), the Claudin-low subtype and the 7-TNBCtype subtype classification were evaluated. Logistic regression models for pathological complete response (pCR) and Cox models for distant relapse-free survival (DRFS) were used. Results Basal-like, Luminal A, Luminal B, and HER2-enriched subtypes represented 32.7 %, 30.6 %, 18.2 %, and 10.3 % of cases, respectively. Intrinsic subtype was independently associated with pCR in all patients, in hormone receptor-positive/HER2-negative disease, in HER2-positive disease, and in TNBC. The pCR rate of Basal-like disease was >35 % across all clinical cohorts. Neither the Claudin-low nor the 7-TNBCtype subtype classifications predicted pCR within TNBCs after accounting for intrinsic subtype. Finally, intrinsic subtype and ROR-P provided independent prognostic information beyond clinicopathological variables and type of pathological response. A 5-year DRFS of 97.5 % (92.8–100.0 %) was observed in these neoadjuvant-treated and clinically node-negative patients predicted to be low risk by ROR-P (i.e. 57.4 % of Luminal A tumors with clinically node-negative disease). Conclusions Intrinsic subtyping at diagnosis provides prognostic and predictive information for patients receiving neoadjuvant chemotherapy. Although we could not exclude a survival benefit of neoadjuvant chemotherapy in patients with early breast cancer with clinically node-negative and ROR-low disease at diagnosis, the absolute benefit of cytotoxic therapy in this group might be rather small (if any).

Background The biological effect of oral metronomic vinorelbine (mVNB) alone or in combination with endocrine therapy in patients with hormone receptor-positive (HR+)/HER2-negative breast cancer has been scarcely addressed. Methods Postmenopausal women with untreated stage I–III HR+/HER2-negative breast cancer were randomized (1:1:1) to receive 3 weeks of letrozole (LTZ) 2.5 mg/day, oral mVNB 50 mg 3 days/week, or the combination. The primary objective was to evaluate, within PAM50 Luminal A/B disease, if the anti-proliferative effect of LTZ+mVNB was superior to monotherapy. An anti-proliferative effect was defined as the mean relative decrease of the PAM50 11-gene proliferation score in combination arm vs. both monotherapy arms. Secondary objectives included the evaluation of a comprehensive panel of breast cancer-related genes and safety. An unplanned analysis of stromal tumor-infiltrating lymphocytes (sTILs) was also performed. PAM50 analyses were performed using the nCounter®-based Breast Cancer 360™ gene panel, which includes 752 genes and 32 signatures. Results Sixty-one patients were randomized, and 54 paired samples (89%) were analyzed. The main patient characteristics were mean age of 67, mean tumor size of 1.7 cm, mean Ki67 of 14.3%, stage I (55.7%), and grades 1–2 (90%). Most baseline samples were PAM50 Luminal A (74.1%) or B (22.2%). The anti-proliferative effect of 3 weeks of LTZ+mVNB (− 73.2%) was superior to both monotherapy arms combined (− 49.9%; p  = 0.001) and mVNB (− 19.1%; p  < 0.001). The anti-proliferative effect of LTZ+mVNB (− 73.2%) was numerically higher compared to LTZ (− 65.7%) but did not reach statistical significance ( p  = 0.328). LTZ+mVNB induced high expression of immune-related genes and gene signatures, including CD8 T cell signature and PDL1 gene and low expression of ER-regulated genes (e.g., progesterone receptor) and cell cycle-related and DNA repair genes. In tumors with ≤ 10% sTILs at baseline, a statistically significant increase in sTILs was observed following LTZ (paired analysis p  = 0.049) and LTZ+mVNB ( p  = 0.012). Grade 3 adverse events occurred in 3.4% of the cases. Conclusions Short-term mVNB is well-tolerated and presents anti-proliferative activity alone and in combination with LTZ. The high expression of immune-related biological processes and sTILs observed with the combination opens the possibility of studying this combination with immunotherapy. Further investigation comparing these biological results with other metronomic schedules or drug combinations is warranted. Trial registration NCT02802748 , registered 16 June 2016.

As the catalog of oncogenic driver mutations is expanding, it becomes clear that alterations in a given gene might have different functions and should not be lumped into one class. The transcription factor GATA3 is a paradigm of this. We investigated the functions of the most common GATA3 mutation (X308_Splice) and five additional mutations, which converge into a neoprotein that we called “neoGATA3,” associated with excellent prognosis in patients. Analysis of available molecular data from >3000 breast cancer patients revealed a dysregulation of the ER-dependent transcriptional response in tumors carrying neoGATA3-generating mutations. Mechanistic studies in vitro showed that neoGATA3 interferes with the transcriptional programs controlled by estrogen and progesterone receptors, without fully abrogating them. ChIP-Seq analysis indicated that ER binding is reduced in neoGATA3-expressing cells, especially at distal regions, suggesting that neoGATA3 interferes with the fine tuning of ER-dependent gene expression. This has opposite outputs in distinct hormonal context, having pro- or anti-proliferative effects, depending on the estrogen/progesterone ratio. Our data call for functional analyses of putative cancer drivers to guide clinical application.

Background A colorectal tumor is not an isolated entity growing in a restricted location of the body. The patient’s gut environment constitutes the framework where the tumor evolves and this relationship promotes and includes a complex and tight correlation of the tumor with inflammation, blood vessels formation, nutrition, and gut microbiome composition. The tumor influence in the environment could both promote an anti-tumor or a pro-tumor response. Methods A set of 98 paired adjacent mucosa and tumor tissues from colorectal cancer (CRC) patients and 50 colon mucosa from healthy donors (246 samples in total) were included in this work. RNA extracted from each sample was hybridized in Affymetrix chips Human Genome U219. Functional relationships between genes were inferred by means of systems biology using both transcriptional regulation networks (ARACNe algorithm) and protein-protein interaction networks (BIANA software). Results Here we report a transcriptomic analysis revealing a number of genes activated in adjacent mucosa from CRC patients, not activated in mucosa from healthy donors. A functional analysis of these genes suggested that this active reaction of the adjacent mucosa was related to the presence of the tumor. Transcriptional and protein-interaction networks were used to further elucidate this response of normal gut in front of the tumor, revealing a crosstalk between proteins secreted by the tumor and receptors activated in the adjacent colon tissue; and vice versa. Remarkably, Slit family of proteins activated ROBO receptors in tumor whereas tumor-secreted proteins transduced a cellular signal finally activating AP-1 in adjacent tissue. Conclusions The systems-level approach provides new insights into the micro-ecology of colorectal tumorogenesis. Disrupting this intricate molecular network of cell-cell communication and pro-inflammatory microenvironment could be a therapeutic target in CRC patients.

Anaplastic lymphoma receptor tyrosine kinase ( ), ROS proto-oncogene 1, receptor tyrosine kinase ( ), and ret proto-oncogene ( ) fusions are present in 5%-7% of patients with advanced non-small-cell lung cancer (NSCLC); their accurate identification is critical to guide targeted therapies. FISH and immunohistochemistry (IHC) are considered the gold standards to determine gene fusions, but they have limitations. The nCounter platform is a potentially useful genomic tool for multiplexed detection of gene fusions, but has not been validated in the clinical setting. Formalin-fixed, paraffin embedded (FFPE) samples from 108 patients with advanced NSCLC were analyzed with an nCounter-based assay and the results compared with FISH, IHC, and reverse transcription PCR (RT-PCR). Data on response to fusion kinase inhibitors was retrospectively collected in a subset of 29 patients. Of 108 FFPE samples, 98 were successfully analyzed by nCounter (91%), which identified 55 fusion-positive cases (32 , 21 , and 2 ). nCounter results were highly concordant with IHC for ALK (98.5%, CI = 91.8-99.7), while 11 discrepancies were found compared with FISH (87.5% concordance, CI = 79.0-92.9). For , nCounter showed similar agreement with IHC and FISH (87.2% and 85.9%), but a substantial number of samples were positive only by 1 or 2 techniques. Of the 25 patients deriving clinical benefit from fusion kinase inhibitors, 24 were positive by nCounter and 22 by FISH. nCounter compares favorably with IHC and FISH and can be used for identifying patients with advanced NSCLC positive for / / fusion genes.

Purpose This study aimed to investigate the current therapeutic management of patients with early-stage HER2-positive (HER2+) breast cancer in Spain, while also exploring the perceptions surrounding HER2DX in terms of its credibility, clinical relevance, and impact on therapeutic decision-making. Understanding these aspects is crucial for optimizing treatment strategies and enhancing patient outcomes in the context of HER2+ breast cancer. Methods An online questionnaire was conducted by an independent third-party between April and May 2022 across 70 medical oncologists highly specialized in breast cancer management in Spain. The survey included 37 questions regarding treatment decision making in HER2+ early breast cancer. Results The management of patients with HER2+ early breast cancer exhibited a high degree of heterogeneity. Among the interviewed oncologists, 53% would recommend upfront surgery for node negative tumors measuring 1 cm or less. Interestingly, 69% and 56% of interviewers were open to deescalate the duration of adjuvant trastuzumab in pT1a and pT1b N0 tumors, respectively. Certain clinicopathological characteristics, such as high grade, high Ki-67, and young age, influenced the decision to prescribe neoadjuvant treatment for patients with clinical stage 1 disease. In cases where neoadjuvant treatment was prescribed for cT1-2 N0 tumors, there was a wide variation in the choice of chemotherapeutic and anti-HER2 regimens. Regarding the use of adjuvant trastuzumab emtansine (T-DM1) in patients with residual disease after neoadjuvant therapy, there was diversity in practice, and a common concern emerged that T-DM1 might be overtreating some patients. HER2DX, as a diagnostic tool, was deemed trustworthy, and the reported scores were considered clinically useful. However, 86% of interviewees believed that a prospective trial was necessary before fully integrating the test into routine clinical practice. Conclusion In the context of early-stage HER2+ breast cancer in Spain, a notable diversity in therapeutic approaches was observed. The majority of interviewed medical oncologists acknowledged HER2DX as a clinically valuable test for specific patients, in line with the 2022 SEOM-GEICAM-SOLTI clinical guidelines for early-stage breast cancer. To facilitate the full integration of HER2DX into clinical guidelines, conducting prospective studies to further validate its efficacy and utility was recommended.

HER2-positive breast cancer consists of four intrinsic molecular subtypes—luminal A, luminal B, HER2-enriched, and basal-like—and a normal-like subtype, with the HER2-enriched subtype having the highest activation of the EGFR–HER2 pathway. We aimed to test the hypothesis that patients with the HER2-enriched subtype benefit the most from dual HER2 blockade. PAMELA is an open-label, single-group, phase 2 trial done in 19 hospitals in Spain. We recruited female patients aged at least 18 years with previously untreated, centrally confirmed HER2-positive, stage I–IIIA invasive breast cancer regardless of hormone receptor status. Patients were given lapatinib (1000 mg per day orally) and trastuzumab (loading dose of 8 mg/kg, followed by 6 mg/kg every 3 weeks intravenously) for 18 weeks; hormone receptor-positive patients were additionally given letrozole (2·5 mg per day orally; if menopausal) or tamoxifen (20 mg per day orally; if premenopausal). Surgery was done 1–3 weeks after the last dose of study treatment. Intrinsic molecular subtypes of tumour biopsy samples taken at baseline (day 0) and day 14 were determined with the PAM50 predictor. The primary outcome was the ability of the HER2-enriched subtype to predict pathological complete response at the time of surgery. The primary outcome was assessed in the evaluable population (ie, all patients who had initial tumour biopsy samples available and who underwent definitive surgery) and safety was assessed in all patients who received at least one part of study treatment. This study is registered with ClinicalTrials.gov, number NCT01973660, and is completed. Between Oct 28, 2013, and Nov 26, 2015, we recruited 151 patients, of whom 14 (9%) discontinued treatment and 137 (91%) completed treatment as planned. At baseline, most patients had the HER2-enriched subtype (101 [67%]), followed by luminal A (22 [15%]), luminal B (16 [11%]), basal-like (nine [6%]), and normal-like (three [2%]) subtypes. At the time of surgery, 46 (30%, 95% CI 23–39) of 151 patients had pathological complete response in the breast. 41 (41%, 31–51) of 101 patients with the HER2-enriched subtype and five (10%, 4–23) of 50 patients with non-HER2-enriched subtypes achieved pathological complete response at the time of surgery (odds ratio 6·2, 95% CI 2·3–16·8; p=0·0004). The HER2-enriched subtype can identify patients with HER2-positive breast cancer who are likely to benefit from dual HER2 blockade therapies. GlaxoSmithKline, Susan Komen Foundation, CERCA Programme—Generalitat de Catalunya, Banco Bilbao Vizcaya Argentaria Foundation, Pas a Pas, and the Breast Cancer Research Foundation.

We previously reported algorithms based on clinical parameters and plasma cell characteristics to identify patients with smoldering multiple myeloma (SMM) with higher risk of progressing who could benefit from early treatment. In this work, we analyzed differences in the immune bone marrow (BM) microenvironment in SMM to better understand the role of immune surveillance in disease progression and to identify immune biomarkers associated to higher risk of progression. Gene expression analysis of BM cells from 28 patients with SMM, 22 patients with monoclonal gammopathy of undetermined significance (MGUS) and 22 patients with symptomatic MM was performed by using Nanostring Technology. BM cells in SMM compared to both MGUS and symptomatic MM showed upregulation of genes encoding for key molecules in cytotoxicity. However, some of these cytotoxic molecules positively correlated with inhibitory immune checkpoints, which may impair the effector function of BM cytotoxic cells. Analysis of 28 patients with SMM revealed 4 distinct clusters based on immune composition and activation markers. Patients in cluster 2 showed a significant increase in expression of cytotoxic molecules but also inhibitory immune checkpoints compared to cluster 3, suggesting the presence of cytotoxic cells with an exhausted phenotype. Accordingly, patients in cluster 3 had a significantly longer progression free survival. Finally, individual gene expression analysis showed that higher expression of TNF superfamily members (TNF, TNFAIP3, TNFRSF14) was associated with shorter progression free survival. Our results suggest that exhausted cytotoxic cells are associated to high-risk patients with SMM. Biomarkers overexpressed in patients with this immune gene profile in combination with clinical parameters and PC characterization may be useful to identify SMM patients with higher risk of progression.

Multi-gene prognostic signatures including the Oncotype® DX Recurrence Score (RS), EndoPredict® (EP) and Prosigna® (Risk Of Recurrence, ROR) are widely used to predict the likelihood of distant recurrence in patients with oestrogen-receptor-positive (ER+), HER2-negative breast cancer. Here, we describe the development and validation of methods to recapitulate RS, EP and ROR scores from NanoString expression data. RNA was available from 107 tumours from postmenopausal women with early-stage, ER+, HER2− breast cancer from the translational Arimidex, Tamoxifen, Alone or in Combination study (TransATAC) where previously these signatures had been assessed with commercial methodology. Gene expression was measured using NanoString nCounter. For RS and EP, conversion factors to adjust for cross-platform variation were estimated using linear regression. For ROR, the steps to perform subgroup-specific normalisation of the gene expression data and calibration factors to calculate the 46-gene ROR score were assessed and verified. Training with bootstrapping (n = 59) was followed by validation (n = 48) using adjusted, research use only (RUO) NanoString-based algorithms. In the validation set, there was excellent concordance between the RUO scores and their commercial counterparts (rc(RS) = 0.96, 95% CI 0.93–0.97 with level of agreement (LoA) of −7.69 to 8.12; rc(EP) = 0.97, 95% CI 0.96–0.98 with LoA of −0.64 to 1.26 and rc(ROR) = 0.97 (95% CI 0.94–0.98) with LoA of −8.65 to 10.54). There was also a strong agreement in risk stratification: (RS: κ = 0.86, p < 0.0001; EP: κ = 0.87, p < 0.0001; ROR: κ = 0.92, p < 0.001). In conclusion, the calibrated algorithms recapitulate the commercial RS and EP scores on individual biopsies and ROR scores on samples based on subgroup-centreing method using NanoString expression data.

Little is known regarding the interaction between immune microenvironment and tumor biology in hormone receptor (HR)+/HER2− breast cancer (BC). We here assess pretreatment gene-expression data from 66 HR+/HER2− early BCs from the LETLOB trial and show that non-luminal tumors (HER2-enriched, Basal-like) present higher tumor-infiltrating lymphocyte levels than luminal tumors. Moreover, significant differences in immune infiltrate composition, assessed by CIBERSORT, were observed: non-luminal tumors showed a more proinflammatory antitumor immune infiltrate composition than luminal ones.