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Purpose: The ZEPHIR clinical trial evaluated the role of [89Zr]trastuzumab-PET/CT (HER2-PET/CT) and 2-[18F]fluoro-2-deoxy-D-glucose PET/CT ([18F]FDG-PET/CT) in predicting outcomes in patients with advanced HER2-positive breast cancer treated with trastuzumab emtansine (T-DM1). In this study, we combined molecular/metabolic imaging and transcriptomic data to investigate the biological processes associated with [89Zr]trastuzumab and [18F]FDG uptake and to dissect the mechanisms involved in T-DM1 resistance., Experimental Design: RNA was extracted from metastasis biopsies obtained in the ZEPHIR trial. HER2-PET/CT and [18F]FDG-PET/CT imaging data of biopsied lesions were integrated with transcriptomic data. Lesions were compared based on the level of [89Zr]trastuzumab uptake as well as on the presence/absence of metabolic response, defined comparing baseline and on-treatment [18F]FDG-PET/CT., Results: We analyzed matched transcriptomic and molecular/metabolic imaging data for 24 metastases. Genes and pathways involved in extracellular matrix (ECM) organization and glycosylphosphatidylinositol synthesis were enriched in lesions presenting low [89Zr]trastuzumab uptake. [18F]FDG uptake at baseline correlated with proliferation and immune-related processes. Hypoxia and ECM-related processes were enriched in lesions showing no metabolic response to T-DM1, whereas immune-related processes were associated with high [89Zr]trastuzumab uptake and metabolic response. Gene signatures including differentially expressed genes according to [89Zr]trastuzumab uptake and metabolic response showed predictive value in an external cohort., Conclusions: To the best of our knowledge, this study represents the first correlative analysis between [89Zr]trastuzumab tumor uptake and gene expression profiling in humans. Our findings suggest a role for ECM in impairing [89Zr]trastuzumab tumor uptake and T-DM1 metabolic response in advanced HER2-positive breast cancer, highlighting the potential of molecular imaging to depict tumor microenvironment features., (©2024 American Association for Cancer Research.)

In preclinical experiments, cyclic fasting-mimicking diets (FMDs) showed broad anticancer effects in combination with chemotherapy. Among different tumor types, triple-negative breast cancer (TNBC) is exquisitely sensitive to FMD. However, the antitumor activity and efficacy of cyclic FMD in TNBC patients remain unclear. Here, we show that a severely calorie-restricted, triweekly, 5-day FMD regimen results in excellent pathologic complete response (pCR) rates (primary endpoint) and long-term clinical outcomes (secondary endpoints) when combined with preoperative chemotherapy in 30 patients with early-stage TNBC enrolled in the phase 2 trial BREAKFAST. Bulk and single-cell RNA sequencing analysis revealed that highly glycolytic cancer cells, myeloid cells, and pericytes from tumors achieving pCR undergo a significant, early downmodulation of pathways related to glycolysis and pyruvate metabolism. Our findings pave the wave for conducting larger clinical trials to investigate the efficacy of cyclic FMD in early-stage TNBC patients and to validate early changes of intratumor glycolysis as a predictor of clinical benefit from nutrient restriction. This study was registered at Clinicaltrials.gov (NCT04248998)., Competing Interests: Declaration of interests The authors declare the following competing interests: G.V.B., speaker/advisory board: Novartis, Eli Lilly, Daichi/Astrazeneca, Roche, MSD, and Seagen; G.P., consulting fees: Roche, Bayer, and Astra Zeneca; C.V., consulting fees/advisory board: Novartis, Pfizer, Eli Lilly, Daiichi Sankyo, and Menarini Stemline; C.V., honoraria as speaker: Novartis, Eli Lilly, Istituto Gentili, Accademia Nazionale di Medicina, MSD, Research grant: Roche; F.d.B., consulting fees/advisory board: Roche, EMD Serono, NMS Nerviano Medical Science, Sanofi, MSD, Novartis, Incyte, BMS, Menarini, Astra Zeneca, Pierre Fabre, Mattioli 1885, MCCann Health, Taiho; F.d.B., IQVIA Speaker Bureau: BMS, Healthcare Research & Pharmacoepidemiology, Merck Group, MSD, Pfizer, Servier, Sanofi, Roche, AMGEN, Incyte, Dephaforum, Seagen, Nadirex, BMS, Ambrosetti, and Itanet; and F.d.B., research grant/funding: Novartis, F.Hoffmann-LaRoche Ltd, BMS, Ignyta Inc., Merck Sharp & Dohme Spa, Kymab, Pfizer, Tesaro, MSD, MedImmune LCC, Exelixis Inc., LOXO Oncology Inc., DAICHI SANKIO Dev. Ltd, Basilea Pharmaceutica International AG, Janssen-Cilag International NV, and Merck KGAA. C.V. and F.d.B. are co-inventors of the FMD regimen used in this study. The Italian patent (no. 102019000009954) has been released and was first deposited on June 24(th), 2019, with an extension granted under PCT WO 2020/261131 on June 24(th), 2020. The European patent (no. 207403399), Canadian patent (no. 2144217), and USA patent are pending., (Copyright © 2024 Elsevier Inc. All rights reserved.)

In HER2-positive breast cancer, clinical outcome and sensitivity to HER2-targeted therapies are influenced by both tumor and microenvironment features. However, we are currently unable to depict the molecular heterogeneity of this disease with sufficient granularity. Here, by performing gene expression profiling in HER2-positive breast cancers from patients receiving adjuvant trastuzumab in the ALTTO clinical trial (NCT00490139), we identify and characterize five molecular subtypes associated with the risk of distant recurrence: immune-enriched, proliferative/metabolic-enriched, mesenchymal/stroma-enriched, luminal, and ERBB2-dependent. Additionally, we validate the biological profiles of the subtypes and explore their prognostic/predictive value in external cohorts, namely the NeoALTTO trial (NCT00553358), SCAN-B (NCT02306096), I-SPY2 (NCT01042379), METABRIC and TCGA. Immune-enriched tumors present better survival outcomes, in contrast to mesenchymal/stroma-enriched and proliferative/metabolic-enriched tumors, while luminal and ERBB2-dependent tumors are characterized by low and high rates of pathological complete response, respectively. Of note, these molecular subtypes provide the rationale for treatment approaches leveraging the heterogeneous biology of HER2-positive breast cancer., Competing Interests: Competing interests: The authors declare the following competing interests. S.EA.: grants via the affiliation from Novartis for the submitted work and from Roche/Genentech, Astra Zeneca, Pfizer, and BCRF outside the submitted work. S.DC.: consultation fees from Pierre-Fabre, IQVIA, and Medica Scientia Innovation Research (MEDSIR); institutional grant from Fondazione Associazione Italiana Ricerca contro il Cancro (AIRC); and Cancer Can.Heal European EU4 Health Programme 101080009-European Commission. T.U.: honoraria from Astra Zeneca, Novartis Pharma K.K., Eisai Co., Ltd., Chugai Pharmaceutical Co. Ltd; research grant from Eli Lilly Japan K.K. M.I.: employee of Novartis, owner of Novartis shares. M.P.: invited speaker for AstraZeneca, Lilly, MSD, Novartis, Pfizer, Roche-Genentech; consultant for Roche-Genentech; advisory board for Frame Therapeutics, Gilead, Menarini, NBE Therapeutics, Odonate, Roche-Genentech, SeaGen, Seattle Genetics; member of boards of directors, scientific board for Oncolytics; research grants to her Institution from AstraZeneca, Lilly, Gilead; funding to her Institution from Menarini, MSD, Novartis, Pfizer, Radius, Roche-Genentech, Servier, Synthon. L.P.: consulting fees and honoraria for advisory board participation from Pfizer, Astra Zeneca, Merck, Novartis, Bristol-Myers Squibb, Stemline-Menarini, GlaxoSmithKline, Genentech/Roche, Personalis, Daiichi, Natera, Exact Sciences and institutional research funding from Seagen, GlaxoSmithKline, AstraZeneca, Merck, Pfizer and Bristol Myers Squibb. S.L.: research funding to institution from Novartis, Bristol Myers Squibb, MSD, Puma Biotechnology, Eli Lilly, Nektar Therapeutics, Astra Zeneca/Daiichi Sankyo and Seattle Genetics; consultant (not compensated) to Seattle Genetics, Novartis, Bristol Myers Squibb, MSD, AstraZeneca/Daiichi Sankyo, Eli Lilly, Pfizer, Gilead Therapeutics, Nektar Therapeutics, PUMA Biotechnologies, and Roche-Genentech; consultant (paid to institution) to Novartis, GlaxoSmithKline, Roche-Genentech, Astra Zeneca/Daiichi Sankyo, Pfizer, Gilead Therapeutics, Seattle Genetics, MSD, Tallac Therapeutics, Eli Lilly and Bristol Myers Squibb. R.S.: non-financial support from Merck, Case 45, and Bristol Myers Squibb (BMS); research support from Merck, Puma Biotechnology, and Roche; personal fees from Roche, BMS, Astra Zeneca, Daiichi Sankyo and Exact Sciences for advisory boards. G.V.: grants/research supports from Roche/Genentech, Ventana Medical Systems, Dako/Agilent Technologies; honoraria or consultation fees from Ventana, Dako/Agilent, Roche, MSD Oncology, AstraZeneca, Daiichi Sankyo, Pfizer, Gilead. C.S.: advisory board (receipt of honoraria or consultations fees) for Astellas, Cepheid, Vertex, Seattle genetics, Puma, Amgen, Exact Sciences, INC, Merck & Co; invited speaker for Eisai, Prime Oncology, Teva, Foundation Medicine, Exact Sciences; advisory equity from Signatur Biosciences; other support (travel, accommodation expenses) from Roche, Genentech, Pfizer. The remaining authors declare no non-financial or financial competing interests., (© 2024. The Author(s).)

While triple-negative breast cancer (TNBC) is known to be heterogeneous at the genomic and transcriptomic levels, spatial information on tumor organization and cell composition is still lacking. Here, we investigate TNBC tumor architecture including its microenvironment using spatial transcriptomics on a series of 92 patients. We perform an in-depth characterization of tumor and stroma organization and composition using an integrative approach combining histomorphological and spatial transcriptomics. Furthermore, a detailed molecular characterization of tertiary lymphoid structures leads to identify a gene signature strongly associated to disease outcome and response to immunotherapy in several tumor types beyond TNBC. A stepwise clustering analysis identifies nine TNBC spatial archetypes, further validated in external datasets. Several spatial archetypes are associated with disease outcome and characterized by potentially actionable features. In this work, we provide a comprehensive insight into the complexity of TNBC ecosystem with potential clinical relevance, opening avenues for treatment tailoring including immunotherapy., Competing Interests: Competing interests: J.L., S.S., K.T., E.G.V. and N.B. are scientific advisors for 10xGenomics Inc. The remaining authors declare no competing interests., (© 2024. The Author(s).)

Importance: Biologic features may affect pathologic complete response (pCR) and event-free survival (EFS) after neoadjuvant chemotherapy plus ERBB2/HER2 blockade in ERBB2/HER2-positive early breast cancer (EBC)., Objective: To define the quantitative association between pCR and EFS by intrinsic subtype and by other gene expression signatures in a pooled analysis of 3 phase 3 trials: CALGB 40601, NeoALTTO, and NSABP B-41., Design, Setting, and Participants: In this retrospective pooled analysis, 1289 patients with EBC received chemotherapy plus either trastuzumab, lapatinib, or the combination, with a combined median follow-up of 5.5 years. Gene expression profiling by RNA sequencing was obtained from 758 samples, and intrinsic subtypes and 618 gene expression signatures were calculated. Data analyses were performed from June 1, 2020, to January 1, 2023., Main Outcomes and Measures: The association of clinical variables and gene expression biomarkers with pCR and EFS were studied by logistic regression and Cox analyses., Results: In the pooled analysis, of 758 women, median age was 49 years, 12% were Asian, 6% Black, and 75% were White. Overall, pCR results were associated with EFS in the ERBB2-enriched (hazard ratio [HR], 0.45; 95% CI, 0.29-0.70; P < .001) and basal-like (HR, 0.19; 95% CI, 0.04-0.86; P = .03) subtypes but not in luminal A or B tumors. Dual trastuzumab plus lapatinib blockade over trastuzumab alone had a trend toward EFS benefit in the intention-to-treat population; however, in the ERBB2-enriched subtype there was a significant and independent EFS benefit of trastuzumab plus lapatinib vs trastuzumab alone (HR, 0.47; 95% CI, 0.27-0.83; P = .009). Overall, 275 of 618 gene expression signatures (44.5%) were significantly associated with pCR and 9 of 618 (1.5%) with EFS. The ERBB2/HER2 amplicon and multiple immune signatures were significantly associated with pCR. Luminal-related signatures were associated with lower pCR rates but better EFS, especially among patients with residual disease and independent of hormone receptor status. There was significant adjusted HR for pCR ranging from 0.45 to 0.81 (higher pCR) and 1.21-1.94 (lower pCR rate); significant adjusted HR for EFS ranged from 0.71 to 0.94., Conclusions and Relevance: In patients with ERBB2/HER2-positive EBC, the association between pCR and EFS differed by tumor intrinsic subtype, and the benefit of dual ERBB2/HER2 blockade was limited to ERBB2-enriched tumors. Immune-activated signatures were concordantly associated with higher pCR rates and better EFS, whereas luminal signatures were associated with lower pCR rates.

Purpose: To explore whether specific triple-negative breast cancer (TNBC) molecular subtypes are predictive for a benefit from maintenance low-dose cyclophosphamide and methotrexate (CM) in the adjuvant IBCSG 22-00 phase III clinical trial., Experimental Design: RNA sequencing was performed on a selection of 347 TNBC formalin-fixed paraffin-embedded (FFPE) tumor samples following a case-cohort-like sampling. TNBC subtypes were computed on gene expression data. The association between TNBC subtypes and treatment outcome was assessed using a Cox proportional-hazards interaction test., Results: Immunomodulatory (IM) and basal-like/immune activated (BLIA) molecular subtypes showed a significant survival benefit when treated with low-dose CM [disease-free survival (DFS): HR, 0.5; 95% confidence interval (CI), 0.28-0.89; Pinteraction = 0.018 and HR, 0.49; 95% CI, 0.27-0.9; Pinteraction = 0.021]. Moreover, a high expression of regulatory T-cell immune signature was associated with a better prognosis in the CM arm, in line with a potential immunomodulating role of cyclophosphamide. In contrast, a worse outcome was observed in tumors with a mesenchymal (M) subtype treated with low-dose CM (DFS: HR, 1.9; 95% CI, 1.2-3; Pinteraction = 0.0044)., Conclusions: Our results show a differential benefit of low-dose CM therapy across different TNBC subtypes. Low-dose CM therapy could be considered as a potential strategy for TNBC tumors with IM subtype in the early-disease setting., (©2023 American Association for Cancer Research.)

The identification of prognostic markers in patients receiving neoadjuvant therapy is crucial for treatment optimization in HER2-positive breast cancer, with the immune microenvironment being a key factor. Here, we investigate the complexity of B and T cell receptor (BCR and TCR) repertoires in the context of two phase III trials, NeoALTTO and CALGB 40601, evaluating neoadjuvant paclitaxel with trastuzumab and/or lapatinib in women with HER2-positive breast cancer. BCR features, particularly the number of reads and clones, evenness and Gini index, are heterogeneous according to hormone receptor status and PAM50 subtypes. Moreover, BCR measures describing clonal expansion, namely evenness and Gini index, are independent prognostic factors. We present a model developed in NeoALTTO and validated in CALGB 40601 that can predict event-free survival (EFS) by integrating hormone receptor and clinical nodal status, breast pathological complete response (pCR), stromal tumor-infiltrating lymphocyte levels (%) and BCR repertoire evenness. A prognostic score derived from the model and including those variables, HER2-EveNT, allows the identification of patients with 5-year EFS > 90%, and, in those not achieving pCR, of a subgroup of immune-enriched tumors with an excellent outcome despite residual disease., (© 2023. The Author(s).)

Triple negative breast cancer (TNBC) is a highly heterogeneous disease with a poor prognosis and a paucity of therapeutic options. In recent years, immunotherapy has emerged as a new treatment option for patients with TNBC. However, this therapeutic evolution is paralleled by a growing need for biomarkers which allow for a better selection of patients who are most likely to benefit from this immune checkpoint inhibitor (ICI)-based regimen. These biomarkers will not only facilitate a better optimization of treatment strategies, but they will also avoid unnecessary side effects in non-responders, and limit the increasing financial toxicity linked to the use of these agents. Huge efforts have been deployed to identify predictive biomarkers for the ICI, but until now, the fruits of this labor remained largely unsatisfactory. Among clinically validated biomarkers, only programmed death-ligand 1 protein (PD-L1) expression has been prospectively assessed in TNBC trials. In addition to this, microsatellite instability and a high tumor mutational burden are approved as tumor agnostic biomarkers, but only a small percentage of TNBC fits this category. Furthermore, TNBC should no longer be approached as a single biological entity, but rather as a complex disease with different molecular, clinicopathological, and tumor microenvironment subgroups. This review provides an overview of the validated and evolving predictive biomarkers for a response to ICI in TNBC.

Background: Late distant recurrence is a challenge for the treatment of invasive lobular carcinoma (ILC) of the breast. Despite in-depth characterisation of primary ILC, the molecular landscape of metastatic ILC is still only partially understood., Methods: We retrospectively identified 38 ILC patients from the tissue banks of six European institutions. DNA extracted from patient matched primary and metastatic FFPE tissue blocks was whole genome sequenced to compute somatic copy number aberrations. This, in turn, was used to infer the evolutionary history of these patients., Findings: The data show different metastatic seeding patterns, with both an early and late divergence of the metastatic lineage observed in ILC. Additionally, cascading dissemination from a metastatic precursor was a dominant rule. Alterations in key cancer driver genes, such as TP53 or CCND1, were acquired early while additional aberrations were present only in the metastatic branch. In about 30% of the patients, the metastatic lineage harboured less aberrations than the primary tumour suggesting a period of tumour dormancy or prolonged adaptation at the distant site. This phenomenon was mostly observed in tumours from de novo metastatic patients., Interpretation: Our results provide insights into ILC evolution and offer potential paths for optimised ILC care., Funding: This work has received financial support from Les Amis de l'Institut Bordet, MEDIC, the Breast Cancer Research Foundation (BCRF) and the Belgian Fonds National de la Recherche Scientifique (F.R.S-FNRS)., Competing Interests: Declaration of interests C.S.: advisory board (receipt of honoraria or consultations fees): Astellas, Cepheid, Vertex, Seattle genetics, Puma, Amgen. Participation in company sponsored speaker's bureau: Eisai, Prime Oncology, Teva, Foundation Medicine. Other support (travel, accommodation expenses): Roche, Genentech, Pfizer (outside the submitted work). C.M. has received personal consultancy fees from Bayer, Roche, AstraZeneca, Daiichi Sankyo outside the scope of the submitted work; Grants from Italian Association for Cancer Research (AIRC); honoraria for lectures, presentations from Novartis. R.S. reports funding for research not related to the current manuscript from Breast Cancer Research Foundation; honoraria for lectures unrelated to the current manuscript from Bristol Myers Squibb; congress registration and travel not related to the current manuscript from Merck and Bristol Myers Squibb; participation on advisory boards unrelated to the current manuscript from Roche and Bristol Myers Squibb. R.S. has no conflicts of interests related to this project. G.E. reports consulting fees as general medical affairs consultancy from Thermofisher; role as secretary on the board of the scientific working group of the Belgian Society of Pathology and board member of the Belgian Society of Pathology not reimbursed. All other authors have no conflicts of interest., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Single cell technologies allow the interrogation of tumor heterogeneity, providing insights into tumor evolution and treatment resistance. To better understand whether circulating tumor cells (CTCs) could complement metastatic biopsies for tumor genomic profiling, we characterized 11 single CTCs and 10 pooled CTC samples at the mutational and copy number aberration (CNA) levels, and compared these results with matched synchronous tumor biopsies from 3 metastatic breast cancer patients with triple-negative (TNBC), HER2-positive and estrogen receptor-positive (ER+) tumors. Similar CNA profiles and the same patient-specific driver mutations were found in bulk tissue and CTCs for the HER2-positive and TNBC tumors, whereas different CNA profiles and driver mutations were identified for the ER+ tumor, which presented two distinct clones in CTCs defined by mutations in ESR1 Y537N and TP53, respectively. Furthermore, de novo mutational signatures derived from CTCs described patient-specific biological processes. These data suggest that tumor tissue and CTCs provide complementary clinically relevant information to map tumor heterogeneity and tumor evolution., (© 2022. The Author(s).)

Purpose: The heterogeneity of response to anti-HER2 agents represents a major challenge in patients with HER2-positive breast cancer. To better understand the sensitivity and resistance to trastuzumab and lapatinib, we investigated the role of copy number aberrations (CNA) in predicting pathologic complete response (pCR) and survival outcomes in the NeoALTTO trial., Experimental Design: The neoadjuvant phase III NeoALTTO trial enrolled 455 patients with HER2-positive early-stage breast cancer. DNA samples from 269 patients were assessed for genome-wide copy number profiling. Recurrent CNAs were found with GISTIC2.0., Results: CNA estimates were obtained for 184 patients included in NeoALTTO. Among those, matched transcriptome and whole-exome data were available for 154 and 181 patients, respectively. A significant association between gene copy number and pCR was demonstrated for ERBB2 amplification. Nevertheless, ERBB2 amplification ceased to be predictive once ERBB2 expression level was considered. GISTIC2.0 analysis revealed 159 recurrent CNA regions. Lower copy number levels of the 6q23-24 locus predicted absence of pCR in the whole cohort and in the estrogen receptor-positive subgroup. 6q23-24 deletion was significantly more frequent in TP53 wild-type (WT) compared with TP53 -mutated, resulting in copy number levels significantly associated with lack of pCR only in the TP53 WT subgroup. Interestingly, a gene-ontology analysis highlighted several immune processes correlated to 6q23-24 copy number., Conclusions: Our analysis identified ERBB2 copy number as well as 6q23-24 CNAs as predictors of response to anti-HER2-based treatment. ERBB2 expression outperformed ERBB2 amplification. The complexity of the 6q23-24 region warrants further investigation., (©2021 American Association for Cancer Research.)

Background: We aimed to determine the distribution of intrinsic subtypes within HER2-low breast cancer (BC), and to describe the prognostic impact of HER2-low status on survival outcomes., Methods: This is a retrospective, observational study of primary BC extracted from The Cancer Genome Atlas dataset. We described the distribution of PAM50 intrinsic subtypes within HER2-low BC subtype according to hormonal receptor status (positive (HR+) and negative (HR-)). Secondly, we assessed the impact of HER2-low on survival outcomes (progression-free interval (PFI), disease-free interval (DFI), and overall survival (OS))., Results: We analyzed 804 primary BCs, including 410 (51%) HER2-low BCs (336 HR+ and 74 HR-). The proportion of HER2-enriched tumors was higher in the HER2-low/HR- group compared to HER2-low/HR+ (13.7% versus 1.2%, respectively). HER2-enriched tumors were more frequent in HER2-low/HR- and HER2-low/HR+ subtypes, compared to HER2-negative/HR- and HER2-negative/HR+ subtypes, respectively (13.7% versus 1.6% and 1.2% versus 0.5%, respectively). We observed no significant differences in PFI, DFI, and OS between HER2-low subtypes and each non-HER2-low subtype paired by HR status., Conclusions: Our characterization of PAM50 intrinsic subtypes within HER2-low breast cancer may explain the different clinical behaviors and responses to treatment, and ultimately support further investigation of new treatment strategies in the HER2-low category. Moreover, it highlights the importance of considering HR status in the HER2-low category.

Purpose: Cyclin-dependent kinase 12 (CDK12) aberrations have been reported as a biomarker of response to immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). Herein, we characterize CDK12-mutated mCRPC, presenting clinical, genomic, and tumor-infiltrating lymphocyte (TIL) data., Experimental Design: Patients with mCRPC consented to the molecular analyses of diagnostic and mCRPC biopsies. Genomic analyses involved targeted next-generation (MiSeq; Illumina) and exome sequencing (NovaSeq; Illumina). TILs were assessed by validated immunocytochemistry coupled with deep learning-based artificial intelligence analyses including multiplex immunofluorescence assays for CD4, CD8, and FOXP3 evaluating TIL subsets. The control group comprised a randomly selected mCRPC cohort with sequencing and clinical data available., Results: Biopsies from 913 patients underwent targeted sequencing between February 2015 and October 2019. Forty-three patients (4.7%) had tumors with CDK12 alterations. CDK12-altered cancers had distinctive features, with some revealing high chromosomal break numbers in exome sequencing. Biallelic CDK12-aberrant mCRPCs had shorter overall survival from diagnosis than controls [5.1 years (95% confidence interval (CI), 4.0-7.9) vs. 6.4 years (95% CI, 5.7-7.8); hazard ratio (HR), 1.65 (95% CI, 1.07-2.53); P = 0.02]. Median intratumoral CD3 + cell density was higher in CDK12 cancers, although this was not statistically significant (203.7 vs. 86.7 cells/mm 2 ; P = 0.07). This infiltrate primarily comprised of CD4 + FOXP3 - cells (50.5 vs. 6.2 cells/mm 2 ; P < 0.0001), where high counts tended to be associated with worse survival from diagnosis (HR, 1.64; 95% CI, 0.95-2.84; P = 0.077) in the overall population., Conclusions: CDK12-altered mCRPCs have worse prognosis, with these tumors surprisingly being primarily enriched for CD4 + FOXP3 - cells that seem to associate with worse outcome and may be immunosuppressive. See related commentary by Lotan and Antonarakis, p. 380 ., (©2020 American Association for Cancer Research.)

Despite a proportion of renal cancer patients can experiment marked and durable responses to immune-checkpoint inhibitors, the treatment efficacy is widely variable and identifying the patient who will benefit from immunotherapy remains an issue. We performed a prospective study to investigate if soluble forms of the immune-checkpoints PD-1 (sPD-1), PD-L1 (sPD-L1), pan-BTN3As, BTN3A1, and BTN2A1, could be candidate to predict the response to immune-checkpoint blockade therapy. We evaluated the plasma levels in a learning cohort of metastatic clear cell renal carcinoma (mccRCC) patients treated with the anti-PD-1 agent nivolumab by ad hoc developed ELISA's. Using specific cut-offs determined through ROC curves, we showed that high baseline levels of sPD-1 (>2.11 ng/ml), sPD-L1 (>0.66 ng/ml), and sBTN3A1 (>6.84 ng/ml) were associated with a longer progression-free survival (PFS) to nivolumab treatment [median PFS, levels above thresholds: sPD-1, 20.7 months ( p < .0001); sPD-L1, 19 months ( p < .0001); sBTN3A1, 17.5 months ( p = .002)]. High sPD-1 and sBTN3A1 levels were also associated with best overall response by RECIST and objective response of >20%. The results were confirmed in a validation cohort of 20 mccRCC patients. The analysis of plasma dynamic changes after nivolumab showed a statistically significant decrease of sPD-1 after 2 cycles (Day 28) in the long-responder patients. Our study revealed that the plasma levels of sPD-1, sPD-L1, and sBTN3A1 can predict response to nivolumab, discriminating responders from non-responders already at therapy baseline, with the advantages of non-invasive sample collection and real-time monitoring that allow to evaluate the dynamic changes during cancer evolution and treatment., (© 2020 The Author(s). Published with license by Taylor & Francis Group, LLC.)

Background: Declines in prostate-specific antigen (PSA) levels at 12wk are used to evaluate treatment response in metastatic castration-resistant prostate cancer (mCRPC). PSA fall by ≥30% at 4wk (PSA4w30) has been reported to be associated with better outcome in a single-centre cohort study., Objective: To evaluate clinical relevance of early PSA decline in mCRPC patients treated with next-generation hormonal treatments (NGHTs) such as abiraterone and enzalutamide., Design, Setting, and Participants: This was a retrospective multicentre analysis. Eligible patients received NGHT for mCRPC between 6 January 2006 and 31 December 2017 in 13 cancer centres worldwide, and had PSA levels assessed at baseline and at 4 and/or 12wk after treatment. PSA response was defined as a ≥30% decline (progression as a ≥25% increase) from baseline., Outcome Measurements and Statistical Analysis: Association with overall survival (OS) was analysed using landmark multivariable Cox regression adjusting for previous chemotherapy, including cancer centre as a shared frailty term., Results and Limitations: We identified 1358 mCRPC patients treated with first-line NGHT (1133 had PSA available at 4wk, and 948 at both 4 and 12wk). Overall, 583 (52%) had a PSA4w30; it was associated with longer OS (median: 23; 95% confidence interval [CI]: 21-25) compared with no change (median: 17; 95% CI: 15-18) and progression (median: 13; 95% CI: 10-15). A PSA12w30 was associated with lower mortality (median OS 22 vs 14; hazard ratio=0.57; 95% CI=0.48-0.67; p<0.001). PSA4w30 strongly correlated with PSA12w30 (ρ=0.91; 95% CI=0.90-0.92; p<0.001). In total, 432/494 (87%) with a PSA4w30 achieved a PSA12w30. Overall, 11/152 (7%) patients progressing at 4wk had a PSA12w30 (1% of the overall population)., Conclusions: PSA changes in the first 4wk of NGHT therapies are strongly associated with clinical outcome from mCRPC and can help guide early treatment switch decisions., Patient Summary: Prostate-specific antigen changes at 4wk after abiraterone/enzalutamide treatment are important to determine patients' outcome and should be taken into consideration in clinical practice., (Copyright © 2019 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background: Gastrointestinal stromal tumors are uncommon intra-abdominal tumors. In fewer than 5% of cases, they originate primarily from the mesentery, omentum or peritoneum and these extra-gastrointestinal stromal tumors tend to have characteristics similar to gastrointestinal stromal., Case Report: We report a case of extra-gastrointestinal stromal tumor in a 76-year-old male, Eastern Cooperative Oncology Group (ECOG) performance status of 2. Abdominal Computed Tomography (CT) showed multiple non-homogeneous confluent nodules at the level of the greater omentum and mesentery, involving the bladder and rectum, with additional peritoneal nodules in the upper abdomen. In March 2008, the patient started imatinib mesylate at 400 mg/day. Instrumental examinations showed progressive response until thoracic-abdominal CT in February 2012 which documented a complete response. Follow-up ended in October 2013. Treatment with imatinib, in addition to pathological response, provided clinical benefit, a progressive regression of symptoms and improved the patient's ECOG performance status from 2 to 0.

Objectives: Sunitinib is the standard care for first-line treatment of metastatic renal cell carcinoma. The aim of this study was to determine whether a sunitinib regimen of 50 mg/day 2-weeks on/1-week off could maintain the same dose-intensity as the standard 4-weeks on/2-weeks off schedule, and provide the same efficacy in terms of objective response, progression-free survival and overall survival, while reducing drug-related toxicity., Methods: A total of 31 patients with metastatic renal cell carcinoma received sunitinib orally at the dose of 50 mg/day in a 2-weeks on/1-week off regimen until disease progression or intolerable toxicities occurred., Results: All enrolled patients were assessable in terms of toxicity and response. They received treatment for a median of 16 months (range 2.0-36.0+ months). A total of 13 patients (42%) obtained an objective response; disease stabilization was achieved in 10 patients (32%), whereas eight patients (26%) experienced disease progression. The most important toxicities were anemia, gastrointestinal effects, fatigue and hypertension, but they were all controlled., Conclusions: Sunitinib 50 mg given orally in a 2-weeks on/1-week off regimen can provide a high response rate and avoid drug-related toxicities, achieving the same dose intensity as the standard schedule, and probably longer disease control., (© 2012 The Japanese Urological Association.)