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Immunotherapy fails to cure most cancer patients. Preclinical studies indicate that radiotherapy synergizes with immunotherapy, promoting radiation-induced antitumor immunity. Most preclinical immunotherapy studies utilize transplant tumor models, which overestimate patient responses. Here, we show that transplant sarcomas are cured by PD-1 blockade and radiotherapy, but identical treatment fails in autochthonous sarcomas, which demonstrate immunoediting, decreased neoantigen expression, and tumor-specific immune tolerance. We characterize tumor-infiltrating immune cells from transplant and primary tumors, revealing striking differences in their immune landscapes. Although radiotherapy remodels myeloid cells in both models, only transplant tumors are enriched for activated CD8+ T cells. The immune microenvironment of primary murine sarcomas resembles most human sarcomas, while transplant sarcomas resemble the most inflamed human sarcomas. These results identify distinct microenvironments in murine sarcomas that coevolve with the immune system and suggest that patients with a sarcoma immune phenotype similar to transplant tumors may benefit most from PD-1 blockade and radiotherapy. Promising results of cancer therapies in transplant tumor models often fail to predict efficacy in clinical trials. Here the authors show that, while transplant tumors are cured by radiotherapy and PD-1 blockade, autochthonous sarcomas are resistant to the identical treatment, recapitulating the immune landscape and resistance to checkpoint blockade observed in most sarcoma patients.

In patients who had undergone stem-cell transplantation, lenalidomide maintenance therapy improved progression-free and overall survival, though at the expense of some increased hematologic toxicity and second malignant tumors. A goal of therapy for multiple myeloma, to induce complete remission and prolong survival, is usually accomplished with combination therapy. 1 , 2 Autologous hematopoietic stem-cell transplantation is often used after induction chemotherapy to improve the response or to consolidate complete remission. 1 , 2 However, since most patients with multiple myeloma have disease recurrence or progression after transplantation, maintenance therapies have been used to prolong complete remission and prevent relapse or progressive disease. Low-dose melphalan, interferon alfa, and glucocorticoids have been used for maintenance after primary therapy, but their long-term use is limited by toxicity and modest efficacy. 3 – 6 Five studies involving patients who . . .

Most single-cell RNA sequencing (scRNA-seq) analyses begin with cell clustering; thus, the clustering accuracy considerably impacts the validity of downstream analyses. In contrast with the abundance of clustering methods, the tools to assess the clustering accuracy are limited. We propose a new Clustering Deviation Index (CDI) that measures the deviation of any clustering label set from the observed single-cell data. We conduct in silico and experimental scRNA-seq studies to show that CDI can select the optimal clustering label set. As a result, CDI also informs the optimal tuning parameters for any given clustering method and the correct number of cluster components.

Most prostate cancers express the androgen receptor (AR), and tumor growth and progression are facilitated by exceptionally low levels of systemic or intratumorally produced androgens. Thus, absolute inhibition of the androgen signaling axis remains the goal of current therapeutic approaches to treat prostate cancer (PCa). Paradoxically, high dose androgens also exhibit considerable efficacy as a treatment modality in patients with late-stage metastatic PCa. Here we show that low levels of androgens, functioning through an AR monomer, facilitate a non-genomic activation of the mTOR signaling pathway to drive proliferation. Conversely, high dose androgens facilitate the formation of AR dimers/oligomers to suppress c-MYC expression, inhibit proliferation and drive a transcriptional program associated with a differentiated phenotype. These findings highlight the inherent liabilities in current approaches used to inhibit AR action in PCa and are instructive as to strategies that can be used to develop new therapeutics for this disease and other androgenopathies. The response of prostate cancer cells to androgens depends on the dose. Here, the authors show that low levels of androgens function through androgen receptor (AR) monomers to activate mTOR and promote cell proliferation, while high dose androgens induce AR dimerization to inhibit c-MYC expression and facilitate cell differentiation.

Longitudinal studies are crucial for understanding complex microbiome dynamics and their link to health. We introduce TEMPoral TEnsor Decomposition (TEMPTED), a time-informed dimensionality reduction method for high-dimensional longitudinal data that treats time as a continuous variable, effectively characterizing temporal information and handling varying temporal sampling. TEMPTED captures key microbial dynamics, facilitates beta-diversity analysis, and enhances reproducibility by transferring learned representations to new data. In simulations, it achieves 90% accuracy in phenotype classification, significantly outperforming existing methods. In real data, TEMPTED identifies vaginal microbial markers linked to term and preterm births, demonstrating robust performance across datasets and sequencing platforms.

Gastrointestinal stromal tumour is the most common sarcoma of the intestinal tract. Imatinib mesylate is a small molecule that inhibits activation of the KIT and platelet-derived growth factor receptor α proteins, and is effective in first-line treatment of metastatic gastrointestinal stromal tumour. We postulated that adjuvant treatment with imatinib would improve recurrence-free survival compared with placebo after resection of localised, primary gastrointestinal stromal tumour. We undertook a randomised phase III, double-blind, placebo-controlled, multicentre trial. Eligible patients had complete gross resection of a primary gastrointestinal stromal tumour at least 3 cm in size and positive for the KIT protein by immunohistochemistry. Patients were randomly assigned, by a stratified biased coin design, to imatinib 400 mg (n=359) or to placebo (n=354) daily for 1 year after surgical resection. Patients and investigators were blinded to the treatment group. Patients assigned to placebo were eligible to crossover to imatinib treatment in the event of tumour recurrence. The primary endpoint was recurrence-free survival, and analysis was by intention to treat. Accrual was stopped early because the trial results crossed the interim analysis efficacy boundary for recurrence-free survival. This study is registered with ClinicalTrials.gov, number NCT00041197. All randomised patients were included in the analysis. At median follow-up of 19·7 months (minimum–maximum 0–56·4), 30 (8%) patients in the imatinib group and 70 (20%) in the placebo group had had tumour recurrence or had died. Imatinib significantly improved recurrence-free survival compared with placebo (98% [95% CI 96–100] vs 83% [78–88] at 1 year; hazard ratio [HR] 0·35 [0·22–0·53]; one-sided p<0·0001). Adjuvant imatinib was well tolerated, with the most common serious events being dermatitis (11 [3%] vs 0), abdominal pain (12 [3%] vs six [1%]), and diarrhoea (ten [2%] vs five [1%]) in the imatinib group and hyperglycaemia (two [<1%] vs seven [2%]) in the placebo group. Adjuvant imatinib therapy is safe and seems to improve recurrence-free survival compared with placebo after the resection of primary gastrointestinal stromal tumour. US National Institutes of Health and Novartis Pharmaceuticals.

The survival and recurrence of residual tumor cells following therapy constitutes one of the biggest obstacles to obtaining cures in breast cancer, but it remains unclear how the clonal composition of tumors changes during relapse. We use cellular barcoding to monitor clonal dynamics during tumor recurrence in vivo. We find that clonal diversity decreases during tumor regression, residual disease, and recurrence. The recurrence of dormant residual cells follows several distinct routes. Approximately half of the recurrent tumors exhibit clonal dominance with a small number of subclones comprising the vast majority of the tumor; these clonal recurrences are frequently dependent upon Met gene amplification. A second group of recurrent tumors comprises thousands of subclones, has a clonal architecture similar to primary tumors, and is dependent upon the Jak/Stat pathway. Thus the regrowth of dormant tumors proceeds via multiple routes, producing recurrent tumors with distinct clonal composition, genetic alterations, and drug sensitivities. The cellular composition of recurrent tumors can provide insight into resistance to therapy and inform on second line therapies. Here, using a genetically modified mouse, the authors perform barcoding experiments of the primary tumors to allow them to study the clonal dynamics of tumor recurrence.

Breast ductal carcinoma in situ is a common non-invasive clinical finding that can progress to invasive breast cancer (IBC). Spatial proteomics can provide an additional dimension to our understanding of this disease and its capacity to progress. A subset ( n  = 103 patients) of a previously established cohort of primary DCIS specimens with known clinical outcomes was analyzed using a multiplexed proteomic platform (Nanostring GeoMx) for simultaneous quantitative measurement of 53 antigens. 1262 spatially distinct regions of interest (ROIs) (1226 ROIs after filtering) were collected, including inside DCIS epithelium, adjacent stroma, co-existing benign breast epithelium, and biopsy sites. We identified two predominant subgroups of DCIS, ER high/HER2 low and ER low/HER2 high. Levels of tumor associated proteins varied between benign and DCIS, between ER + and ER- patients, and between different regions within the DCIS epithelium. In addition, we identified several immune-related antigens (CD127, CD8, and PD-L2) within the DCIS epithelium that are associated with invasive progression. Comparison of antigen levels in matched ipsilateral breast events (both DCIS recurrences and IBC) demonstrates an effect of hormonal therapy on the phenotype of subsequent cancers. This study adds a spatially resolved proteomic dimension to our understanding of DCIS, its microenvironment, and its propensity to progress to IBC.

Purpose CALGB 40903 (Alliance) was a phase II single arm multicenter trial conducted in postmenopausal patients diagnosed with estrogen-receptor (ER) positive breast ductal carcinoma in situ (DCIS) without invasion. Patients were treated with the aromatase inhibitor (AI) letrozole for 6 months prior to surgery with change in magnetic resonance imaging (MRI) enhancement volume compared to baseline as the primary endpoint. In the current study, we performed sequence analysis of pre- and post-treatment specimens to determine gene expression and DNA copy number parameters associated with treatment and response. Experimental design Paraffin sections from pretreatment biopsies and post-treatment surgical specimens were evaluated for presence of DCIS. Proliferation based on KI67 staining was quantified by a study pathologist. Macrodissection of the DCIS components from thin sections was the source of RNA and DNA. Whole-transcriptome RNA and shallow whole-genome DNA sequencing were performed. PAM50 analysis to assign intrinsic subtypes with associated probability of class membership was performed. Differential gene expression comparing responders versus non-responders and pre- versus post-treatment specimens was performed using a two-tiered approach based on candidate genes and a whole genome survey with appropriate multiple testing corrections. Results Based on availability of specimens and presence of DCIS component, 29 patients (from the 70 who completed the treatment trial) were included in the final data set, including five who had a pathologic complete response (pCR). Response to treatment was qualified categorically based on a threshold of 10% KI67 in the post-treatment surgical specimen or pCR. Based on this criterion, six of the 29 DCIS were considered non-responders (> 10% KI67) and five subjects with pCR were assigned to the responder group. No standard clinical variables were associated with response. On the basis of gene expression analysis, 19 of the pre-treatment samples were classified as luminal A, all of which were classified as responders. PAM50 classification of the other ten pre-treatment samples included luminal B, HER2, basal, and normal-like, six of which were non-responders. PAM50 class membership shifted from baseline to post-treatment in eight cases, most often from luminal A to normal-like (five cases). Selected genes associated with estrogen receptor levels in invasive breast cancer were higher in AI responsive tumors. AI treatment resulted in reductions in estrogen and proliferation related genes. Conclusions Letrozole treatment produced an effective growth response, particularly in DCIS initially classified as luminal A. Study inclusion criteria of DCIS with at least 1% ER positive cells resulted in the inclusion of other subtypes that failed to respond. Treatment also induced both minor and major changes in intrinsic subtype based on PAM50 probabilities. Overall, these data indicate that response to AI treatment in ER( +) DCIS is variable and analogous to that observed in invasive breast cancers. Translational relevance Treatment for breast DCIS ranges from active surveillance to mastectomy, often combined with adjuvant endocrine therapy. The work presented here based on a unique neoadjuvant trial provides direct information on hormone therapy responsiveness of this disease and further couples the biology of invasive breast cancer to its non-obligate precursor. Trial registration : ClinicalTrials.gov Identifier: NCT01439711

BackgroundHypertension and proteinuria are common bevacizumab-induced toxicities. No validated biomarkers are available for identifying patients at risk of these toxicities.MethodsA genome-wide association study (GWAS) meta-analysis was performed in 1039 bevacizumab-treated patients of European ancestry in four clinical trials (CALGB 40502, 40503, 80303, 90401). Grade ≥2 hypertension and proteinuria were recorded (CTCAE v.3.0). Single-nucleotide polymorphism (SNP)-toxicity associations were determined using a cause-specific Cox model adjusting for age and sex.ResultsThe most significant SNP associated with hypertension with concordant effect in three out of the four studies (p-value <0.05 for each study) was rs6770663 (A > G) in KCNAB1, with the G allele increasing the risk of hypertension (p-value = 4.16 × 10−6). The effect of the G allele was replicated in ECOG-ACRIN E5103 in 582 patients (p-value = 0.005). The meta-analysis of all five studies for rs6770663 led to p-value = 7.73 × 10−8, close to genome-wide significance. The most significant SNP associated with proteinuria was rs339947 (C > A, between DNAH5 and TRIO), with the A allele increasing the risk of proteinuria (p-value = 1.58 × 10−7).ConclusionsThe results from the largest study of bevacizumab toxicity provide new markers of drug safety for further evaluations. SNP in KCNAB1 validated in an independent dataset provides evidence toward its clinical applicability to predict bevacizumab-induced hypertension.ClinicalTrials.gov Identifier: NCT00785291 (CALGB 40502); NCT00601900 (CALGB 40503); NCT00088894 (CALGB 80303) and NCT00110214 (CALGB 90401).