Publications by authors named "Carlos Caldas"

357 Publications

The temporal mutational and immune tumour microenvironment remodelling of HER2-negative primary breast cancers.

NPJ Breast Cancer 2021 Jun 7;7(1):73. Epub 2021 Jun 7.

Cancer Research UK Cambridge Institute, Robinson Way, Cambridge, UK.

The biology of breast cancer response to neoadjuvant therapy is underrepresented in the literature and provides a window-of-opportunity to explore the genomic and microenvironment modulation of tumours exposed to therapy. Here, we characterised the mutational, gene expression, pathway enrichment and tumour-infiltrating lymphocytes (TILs) dynamics across different timepoints of 35 HER2-negative primary breast cancer patients receiving neoadjuvant eribulin therapy (SOLTI-1007 NEOERIBULIN-NCT01669252). Whole-exome data (N = 88 samples) generated mutational profiles and candidate neoantigens and were analysed along with RNA-Nanostring 545-gene expression (N = 96 samples) and stromal TILs (N = 105 samples). Tumour mutation burden varied across patients at baseline but not across the sampling timepoints for each patient. Mutational signatures were not always conserved across tumours. There was a trend towards higher odds of response and less hazard to relapse when the percentage of subclonal mutations was low, suggesting that more homogenous tumours might have better responses to neoadjuvant therapy. Few driver mutations (5.1%) generated putative neoantigens. Mutation and neoantigen load were positively correlated (R = 0.94, p = <0.001); neoantigen load was weakly correlated with stromal TILs (R = 0.16, p = 0.02). An enrichment in pathways linked to immune infiltration and reduced programmed cell death expression were seen after 12 weeks of eribulin in good responders. VEGF was downregulated over time in the good responder group and FABP5, an inductor of epithelial mesenchymal transition (EMT), was upregulated in cases that recurred (p < 0.05). Mutational heterogeneity, subclonal architecture and the improvement of immune microenvironment along with remodelling of hypoxia and EMT may influence the response to neoadjuvant treatment.
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http://dx.doi.org/10.1038/s41523-021-00282-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8185105PMC
June 2021

Intestinal microbiota influences clinical outcome and side effects of early breast cancer treatment.

Cell Death Differ 2021 May 7. Epub 2021 May 7.

Gustave Roussy Cancer Center, Villejuif, France.

The prognosis of early breast cancer (BC) relies on cell autonomous and immune parameters. The impact of the intestinal microbiome on clinical outcome has not yet been evaluated. Shotgun metagenomics was used to determine the composition of the fecal microbiota in 121 specimens from 76 early BC patients, 45 of whom were paired before and after chemotherapy. These patients were enrolled in the CANTO prospective study designed to record the side effects associated with the clinical management of BC. We analyzed associations between baseline or post-chemotherapy fecal microbiota and plasma metabolomics with BC prognosis, as well as with therapy-induced side effects. We examined the clinical relevance of these findings in immunocompetent mice colonized with BC patient microbiota that were subsequently challenged with histo-compatible mouse BC and chemotherapy. We conclude that specific gut commensals that are overabundant in BC patients compared with healthy individuals negatively impact BC prognosis, are modulated by chemotherapy, and may influence weight gain and neurological side effects of BC therapies. These findings obtained in adjuvant and neoadjuvant settings warrant prospective validation.
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http://dx.doi.org/10.1038/s41418-021-00784-1DOI Listing
May 2021

Deciphering the signaling network of breast cancer improves drug sensitivity prediction.

Cell Syst 2021 May 30;12(5):401-418.e12. Epub 2021 Apr 30.

Department of Quantitative Biomedicine, University of Zürich, 8057 Zurich, Switzerland; Institute of Molecular Life Sciences, University of Zürich, 8057 Zurich, Switzerland. Electronic address:

One goal of precision medicine is to tailor effective treatments to patients' specific molecular markers of disease. Here, we used mass cytometry to characterize the single-cell signaling landscapes of 62 breast cancer cell lines and five lines from healthy tissue. We quantified 34 markers in each cell line upon stimulation by the growth factor EGF in the presence or absence of five kinase inhibitors. These data-on more than 80 million single cells from 4,000 conditions-were used to fit mechanistic signaling network models that provide insight into how cancer cells process information. Our dynamic single-cell-based models accurately predicted drug sensitivity and identified genomic features associated with drug sensitivity, including a missense mutation in DDIT3 predictive of PI3K-inhibition sensitivity. We observed similar trends in genotype-drug sensitivity associations in patient-derived xenograft mouse models. This work provides proof of principle that patient-specific single-cell measurements and modeling could inform effective precision medicine strategies.
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http://dx.doi.org/10.1016/j.cels.2021.04.002DOI Listing
May 2021

Characterisation of PALB2 tumours through whole-exome and whole-transcriptomic analyses.

NPJ Breast Cancer 2021 Apr 23;7(1):46. Epub 2021 Apr 23.

Cancer Research Malaysia, Subang Jaya, Malaysia.

Rare protein-truncating variants (PTVs) in PALB2 confer increased risk to breast cancer, but relatively few studies have reported the characteristics of tumours with PALB2 PTVs. In this study, we describe molecular characteristics of tumours with either germline or somatic alterations in PALB2. DNA from fresh frozen tumour tissues and matched peripheral blood lymphocytes for 560 breast cancer patients was subjected for whole-exome sequencing (WES), and RNA from tumour tissues was subjected to RNA sequencing (RNA-seq). We found six cases with germline and three with somatic protein-truncating variants in PALB2. The characteristics of tumours in patients with PALB2 PTVs were similar to those with BRCA1 and BRCA2 PTVs, having significantly more somatic alterations, and a high proportion of the mutational signature and genomic scar scores characteristic of deficiencies in homologous recombination (HR), compared to tumours arising in non-carriers. Unlike tumours arising in patients with BRCA1 and BRCA2 PTVs, PALB2 tumours did not have high prevalence of TP53 somatic alterations or an enriched immune microenvironment. In summary, PALB2 tumours show the homologous recombination deficiencies characteristic of BRCA1 and BRCA2 tumours, and highlight the potential clinical relevance of PALB2 mutational status in guiding therapeutic choices.
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http://dx.doi.org/10.1038/s41523-021-00254-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8065101PMC
April 2021

Landscapes of cellular phenotypic diversity in breast cancer xenografts and their impact on drug response.

Nat Commun 2021 03 31;12(1):1998. Epub 2021 Mar 31.

Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.

The heterogeneity of breast cancer plays a major role in drug response and resistance and has been extensively characterized at the genomic level. Here, a single-cell breast cancer mass cytometry (BCMC) panel is optimized to identify cell phenotypes and their oncogenic signalling states in a biobank of patient-derived tumour xenograft (PDTX) models representing the diversity of human breast cancer. The BCMC panel identifies 13 cellular phenotypes (11 human and 2 murine), associated with both breast cancer subtypes and specific genomic features. Pre-treatment cellular phenotypic composition is a determinant of response to anticancer therapies. Single-cell profiling also reveals drug-induced cellular phenotypic dynamics, unravelling previously unnoticed intra-tumour response diversity. The comprehensive view of the landscapes of cellular phenotypic heterogeneity in PDTXs uncovered by the BCMC panel, which is mirrored in primary human tumours, has profound implications for understanding and predicting therapy response and resistance.
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http://dx.doi.org/10.1038/s41467-021-22303-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8012607PMC
March 2021

PI3K activation promotes resistance to eribulin in HER2-negative breast cancer.

Br J Cancer 2021 Apr 15;124(9):1581-1591. Epub 2021 Mar 15.

Experimental Therapeutics Group, Vall d'Hebron Institute of Oncology, Barcelona, Spain.

Background: Eribulin is a microtubule-targeting agent approved for the treatment of advanced or metastatic breast cancer (BC) previously treated with anthracycline- and taxane-based regimens. PIK3CA mutation is associated with worse response to chemotherapy in oestrogen receptor-positive (ER+)/human epidermal growth factor receptor 2-negative (HER2-) metastatic BC. We aimed to evaluate the role of phosphoinositide 3-kinase (PI3K)/AKT pathway mutations in eribulin resistance.

Methods: Resistance to eribulin was evaluated in HER2- BC cell lines and patient-derived tumour xenografts, and correlated with a mutation in the PI3K/AKT pathway.

Results: Eleven out of 23 HER2- BC xenografts treated with eribulin exhibited disease progression. No correlation with ER status was detected. Among the resistant models, 64% carried mutations in PIK3CA, PIK3R1 or AKT1, but only 17% among the sensitive xenografts (P = 0.036). We observed that eribulin treatment induced AKT phosphorylation in vitro and in patient tumours. In agreement, the addition of PI3K inhibitors reversed primary and acquired resistance to eribulin in xenograft models, regardless of the genetic alterations in PI3K/AKT pathway or ER status. Mechanistically, PI3K blockade reduced p21 levels likely enabling apoptosis, thus sensitising to eribulin treatment.

Conclusions: PI3K pathway activation induces primary resistance or early adaptation to eribulin, supporting the combination of PI3K inhibitors and eribulin for the treatment of HER2- BC patients.
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http://dx.doi.org/10.1038/s41416-021-01293-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8076303PMC
April 2021

Time-resolved single-cell analysis of Brca1 associated mammary tumourigenesis reveals aberrant differentiation of luminal progenitors.

Nat Commun 2021 03 9;12(1):1502. Epub 2021 Mar 9.

University of Cambridge, Department of Pharmacology, Cambridge, UK.

It is unclear how genetic aberrations impact the state of nascent tumour cells and their microenvironment. BRCA1 driven triple negative breast cancer (TNBC) has been shown to arise from luminal progenitors yet little is known about how BRCA1 loss-of-function (LOF) and concomitant mutations affect the luminal progenitor cell state. Here we demonstrate how time-resolved single-cell profiling of genetically engineered mouse models before tumour formation can address this challenge. We found that perturbing Brca1/p53 in luminal progenitors induces aberrant alveolar differentiation pre-malignancy accompanied by pro-tumourigenic changes in the immune compartment. Unlike alveolar differentiation during gestation, this process is cell autonomous and characterised by the dysregulation of transcription factors driving alveologenesis. Based on our data we propose a model where Brca1/p53 LOF inadvertently promotes a differentiation program hardwired in luminal progenitors, highlighting the deterministic role of the cell-of-origin and offering a potential explanation for the tissue specificity of BRCA1 tumours.
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http://dx.doi.org/10.1038/s41467-021-21783-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7940427PMC
March 2021

FGFR1 amplification or overexpression and hormonal resistance in luminal breast cancer: rationale for a triple blockade of ER, CDK4/6, and FGFR1.

Breast Cancer Res 2021 Feb 12;23(1):21. Epub 2021 Feb 12.

Breast Cancer Clinical Research Unit, CNIO - Spanish National Cancer Research Center, Melchor Fernandez Almagro, 3, 28029, Madrid, Spain.

Background: FGFR1 amplification, but not overexpression, has been related to adverse prognosis in hormone-positive breast cancer (HRPBC). Whether FGFR1 overexpression and amplification are correlated, what is their distribution among luminal A or B HRPBC, and if there is a potential different prognostic role for amplification and overexpression are currently unknown features. The role of FGFR1 inhibitors in HRPBC is also unclear.

Methods: FGFR1 amplification (FISH) and overexpression (RNAscope) were investigated in a N = 251 HRPBC patients cohort and the METABRIC cohort; effects on survival and FISH-RNAscope concordance were determined. We generated hormonal deprivation resistant (LTED-R) and FGFR1-overexpressing cell line variants of the ER+ MCF7 and T47-D and the ER+, FGFR1-amplified HCC1428 cell lines. The role of ER, CDK4/6, and/or FGFR1 blockade alone or in combinations in Rb phosphorylation, cell cycle, and survival were studied.

Results: FGFR1 overexpression and amplification was non-concordant in > 20% of the patients, but both were associated to a similar relapse risk (~ 2.5-fold; P < 0.05). FGFR1 amplification or overexpression occurred regardless of the luminal subtype, but the incidence was higher in luminal B (16.3%) than A (6.6%) tumors; P < 0.05. The Kappa index for overexpression and amplification was 0.69 (P < 0.001). Twenty-four per cent of the patients showed either amplification and/or overexpression of FGFR1, what was associated to a hazard ratio for relapse of 2.6 (95% CI 1.44-4.62, P < 0.001). In vitro, hormonal deprivation led to FGFR1 overexpression. Primary FGFR1 amplification, engineered mRNA overexpression, or LTED-R-acquired FGFR1 overexpression led to resistance against hormonotherapy alone or in combination with the CDK4/6 inhibitor palbociclib. Blocking FGFR1 with the kinase-inhibitor rogaratinib led to suppression of Rb phosphorylation, abrogation of the cell cycle, and resistance-reversion in all FGFR1 models.

Conclusions: FGFR1 amplification and overexpression are associated to similar adverse prognosis in hormone-positive breast cancer. Capturing all the patients with adverse prognosis-linked FGFR1 aberrations requires assessing both features. Hormonal deprivation leads to FGFR1 overexpression, and FGFR1 overexpression and/or amplification are associated with resistance to hormonal monotherapy or in combination with palbociclib. Both resistances are reverted with triple ER, CDK4/6, and FGFR1 blockade.
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http://dx.doi.org/10.1186/s13058-021-01398-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7881584PMC
February 2021

Germline APOBEC3B deletion increases somatic hypermutation in Asian breast cancer that is associated with Her2 subtype, PIK3CA mutations, and immune activation.

Int J Cancer 2021 Jan 7. Epub 2021 Jan 7.

Cancer Research Malaysia, Subang Jaya, Malaysia.

A 30-kb deletion that eliminates the coding region of APOBEC3B (A3B) is >5 times more common in women of Asian compared to European descent. This polymorphism creates a chimera with the APOBEC3A (A3A) coding region and A3B 3'UTR, and is associated with an increased risk for breast cancer in Asian women. Here, we explored the relationship between the A3B deletion polymorphism with tumour characteristics in Asian women. Using whole exome and whole transcriptome sequencing data of 527 breast tumours, we report that germline A3B deletion polymorphism leads to expression of the A3A-B hybrid isoform and increased APOBEC-associated somatic hypermutation. Hypermutated tumours, regardless of A3B germline status, were associated with the Her2 molecular subtype and PIK3CA mutations. Compared to non-hypermutated tumours, hypermutated tumours also had higher neoantigen burden, tumour heterogeneity and immune activation. Taken together, our results suggest that the germline A3B deletion polymorphism, via the A3A-B hybrid isoform, contributes to APOBEC-mutagenesis in a significant proportion of Asian breast cancers. In addition, APOBEC somatic hypermutation, regardless of A3B background, may be an important clinical biomarker for Asian breast cancers. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/ijc.33463DOI Listing
January 2021

NRG1 fusions in breast cancer.

Breast Cancer Res 2021 Jan 7;23(1). Epub 2021 Jan 7.

Hutchison-MRC Research Centre, University of Cambridge, Cambridge, CB2 0XZ, UK.

Background: NRG1 gene fusions may be clinically actionable, since cancers carrying the fusion transcripts can be sensitive to tyrosine kinase inhibitors. The NRG1 gene encodes ligands for the HER2(ERBB2)-ERBB3 heterodimeric receptor tyrosine kinase, and the gene fusions are thought to lead to autocrine stimulation of the receptor. The NRG1 fusion expressed in the breast cancer cell line MDA-MB-175 serves as a model example of such fusions, showing the proposed autocrine loop and exceptional drug sensitivity. However, its structure has not been properly characterised, its oncogenic activity has not been fully explained, and there is limited data on such fusions in breast cancer.

Methods: We analysed genomic rearrangements and transcripts of NRG1 in MDA-MB-175 and a panel of 571 breast cancers.

Results: We found that the MDA-MB-175 fusion-originally reported as a DOC4(TENM4)-NRG1 fusion, lacking the cytoplasmic tail of NRG1-is in reality a double fusion, PPP6R3-TENM4-NRG1, producing multiple transcripts, some of which include the cytoplasmic tail. We hypothesise that many NRG1 fusions may be oncogenic not for lacking the cytoplasmic domain but because they do not encode NRG1's nuclear-localised form. The fusion in MDA-MB-175 is the result of a very complex genomic rearrangement, which we partially characterised, that creates additional expressed gene fusions, RSF1-TENM4, TPCN2-RSF1, and MRPL48-GAB2. We searched for NRG1 rearrangements in 571 breast cancers subjected to genome sequencing and transcriptome sequencing and found four cases (0.7%) with fusions, WRN-NRG1, FAM91A1-NRG1, ARHGEF39-NRG1, and ZNF704-NRG1, all splicing into NRG1 at the same exon as in MDA-MB-175. However, the WRN-NRG1 and ARHGEF39-NRG1 fusions were out of frame. We identified rearrangements of NRG1 in many more (8% of) cases that seemed more likely to inactivate than to create activating fusions, or whose outcome could not be predicted because they were complex, or both. This is not surprising because NRG1 can be pro-apoptotic and is inactivated in some breast cancers.

Conclusions: Our results highlight the complexity of rearrangements of NRG1 in breast cancers and confirm that some do not activate but inactivate. Careful interpretation of NRG1 rearrangements will therefore be necessary for appropriate patient management.
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http://dx.doi.org/10.1186/s13058-020-01377-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7788813PMC
January 2021

Deep Sequencing of B Cell Receptor Repertoires From COVID-19 Patients Reveals Strong Convergent Immune Signatures.

Front Immunol 2020 15;11:605170. Epub 2020 Dec 15.

Alchemab Therapeutics Ltd, London, United Kingdom.

Deep sequencing of B cell receptor (BCR) heavy chains from a cohort of 31 COVID-19 patients from the UK reveals a stereotypical naive immune response to SARS-CoV-2 which is consistent across patients. Clonal expansion of the B cell population is also observed and may be the result of memory bystander effects. There was a strong convergent sequence signature across patients, and we identified 1,254 clonotypes convergent between at least four of the COVID-19 patients, but not present in healthy controls or individuals following seasonal influenza vaccination. A subset of the convergent clonotypes were homologous to known SARS and SARS-CoV-2 spike protein neutralizing antibodies. Convergence was also demonstrated across wide geographies by comparison of data sets between patients from UK, USA, and China, further validating the disease association and consistency of the stereotypical immune response even at the sequence level. These convergent clonotypes provide a resource to identify potential therapeutic and prophylactic antibodies and demonstrate the potential of BCR profiling as a tool to help understand patient responses.
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http://dx.doi.org/10.3389/fimmu.2020.605170DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7769841PMC
January 2021

The molecular landscape of Asian breast cancers reveals clinically relevant population-specific differences.

Nat Commun 2020 12 22;11(1):6433. Epub 2020 Dec 22.

Cancer Research Malaysia, No. 1, Jalan SS12/1A, 47500, Subang Jaya, Malaysia.

Molecular profiling of breast cancer has enabled the development of more robust molecular prognostic signatures and therapeutic options for breast cancer patients. However, non-Caucasian populations remain understudied. Here, we present the mutational, transcriptional, and copy number profiles of 560 Malaysian breast tumours and a comparative analysis of breast cancers arising in Asian and Caucasian women. Compared to breast tumours in Caucasian women, we show an increased prevalence of HER2-enriched molecular subtypes and higher prevalence of TP53 somatic mutations in ER+ Asian breast tumours. We also observe elevated immune scores in Asian breast tumours, suggesting potential clinical response to immune checkpoint inhibitors. Whilst HER2-subtype and enriched immune score are associated with improved survival, presence of TP53 somatic mutations is associated with poorer survival in ER+ tumours. Taken together, these population differences unveil opportunities to improve the understanding of this disease and lay the foundation for precision medicine in different populations.
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http://dx.doi.org/10.1038/s41467-020-20173-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7755902PMC
December 2020

Metabolic Imaging Detects Resistance to PI3Kα Inhibition Mediated by Persistent FOXM1 Expression in ER Breast Cancer.

Cancer Cell 2020 10 24;38(4):516-533.e9. Epub 2020 Sep 24.

Cancer Research UK Cambridge Institute and Department of Oncology, Li Ka Shing Centre, University of Cambridge, Cambridge, UK; Cancer Research UK Cambridge Cancer Centre, Cambridge, UK; Department of Biochemistry, University of Cambridge, Cambridge UK. Electronic address:

PIK3CA, encoding the PI3Kα isoform, is the most frequently mutated oncogene in estrogen receptor (ER)-positive breast cancer. Isoform-selective PI3K inhibitors are used clinically but intrinsic and acquired resistance limits their utility. Improved selection of patients that will benefit from these drugs requires predictive biomarkers. We show here that persistent FOXM1 expression following drug treatment is a biomarker of resistance to PI3Kα inhibition in ER breast cancer. FOXM1 drives expression of lactate dehydrogenase (LDH) but not hexokinase 2 (HK-II). The downstream metabolic changes can therefore be detected using MRI of LDH-catalyzed hyperpolarized C label exchange between pyruvate and lactate but not by positron emission tomography measurements of HK-II-mediated trapping of the glucose analog 2-deoxy-2-[F]fluorodeoxyglucose. Rapid assessment of treatment response in breast cancer using this imaging method could help identify patients that benefit from PI3Kα inhibition and design drug combinations to counteract the emergence of resistance.
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http://dx.doi.org/10.1016/j.ccell.2020.08.016DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7562820PMC
October 2020

Trial watch : the gut microbiota as a tool to boost the clinical efficacy of anticancer immunotherapy.

Oncoimmunology 2020 06 3;9(1):1774298. Epub 2020 Jun 3.

Gustave Roussy Comprehensive Cancer Institute, Villejuif, France.

Accumulating evidence demonstrates the decisive role of the gut microbiota in determining the effectiveness of anticancer therapeutics such as immunogenic chemotherapy or immune checkpoint blockade in preclinical tumor models, as well as in cancer patients. In synthesis, it appears that a normal intestinal microbiota supports therapeutic anticancer responses, while a dysbiotic microbiota that lacks immunostimulatory bacteria or contains overabundant immunosuppressive species causes treatment failure. These findings have led to the design of clinical trials that evaluate the capacity of modulation of the gut microbiota to synergize with treatment and hence limit tumor progression. Along the lines of this Trial Watch, we discuss the rationale for harnessing the gut microbiome in support of cancer therapy and the progress of recent clinical trials testing this new therapeutic paradigm in cancer patients.
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http://dx.doi.org/10.1080/2162402X.2020.1774298DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7466862PMC
June 2020

Sex-Specific Genetic Associations for Barrett's Esophagus and Esophageal Adenocarcinoma.

Gastroenterology 2020 12 9;159(6):2065-2076.e1. Epub 2020 Sep 9.

Institute for Genomic Statistics and Bioinformatics, Medical Faculty, University of Bonn, Germany.

Background & Aims: Esophageal adenocarcinoma (EA) and its premalignant lesion, Barrett's esophagus (BE), are characterized by a strong and yet unexplained male predominance (with a male-to-female ratio in EA incidence of up to 6:1). Genome-wide association studies (GWAS) have identified more than 20 susceptibility loci for these conditions. However, potential sex differences in genetic associations with BE/EA remain largely unexplored.

Methods: Given strong genetic overlap, BE and EA cases were combined into a single case group for analysis. These were compared with population-based controls. We performed sex-specific GWAS of BE/EA in 3 separate studies and then used fixed-effects meta-analysis to provide summary estimates for >9 million variants for male and female individuals. A series of downstream analyses were conducted separately in male and female individuals to identify genes associated with BE/EA and the genetic correlations between BE/EA and other traits.

Results: We included 6758 male BE/EA cases, 7489 male controls, 1670 female BE/EA cases, and 6174 female controls. After Bonferroni correction, our meta-analysis of sex-specific GWAS identified 1 variant at chromosome 6q11.1 (rs112894788, KHDRBS2-MTRNR2L9, P = .039) that was statistically significantly associated with BE/EA risk in male individuals only, and 1 variant at chromosome 8p23.1 (rs13259457, PRSS55-RP1L1, P = 0.057) associated, at borderline significance, with BE/EA risk in female individuals only. We also observed strong genetic correlations of BE/EA with gastroesophageal reflux disease in male individuals and obesity in female individuals.

Conclusions: The identified novel sex-specific variants associated with BE/EA could improve the understanding of the genetic architecture of the disease and the reasons for the male predominance.
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http://dx.doi.org/10.1053/j.gastro.2020.08.052DOI Listing
December 2020

Older adult psychopathology: international comparisons of self-reports, collateral reports, and cross-informant agreement.

Int Psychogeriatr 2020 Sep 4:1-12. Epub 2020 Sep 4.

Department of Family and Community Health, University of Pennsylvania School of Nursing, Philadelphia, PA, USA.

Objectives: To conduct international comparisons of self-reports, collateral reports, and cross-informant agreement regarding older adult psychopathology.

Participants: We compared self-ratings of problems (e.g. I cry a lot) and personal strengths (e.g. I like to help others) for 10,686 adults aged 60-102 years from 19 societies and collateral ratings for 7,065 of these adults from 12 societies.

Measurements: Data were obtained via the Older Adult Self-Report (OASR) and the Older Adult Behavior Checklist (OABCL; Achenbach et al., 2004).

Results: Cronbach's alphas were .76 (OASR) and .80 (OABCL) averaged across societies. Across societies, 27 of the 30 problem items with the highest mean ratings and 28 of the 30 items with the lowest mean ratings were the same on the OASR and the OABCL. Q correlations between the means of the 0-1-2 ratings for the 113 problem items averaged across all pairs of societies yielded means of .77 (OASR) and .78 (OABCL). For the OASR and OABCL, respectively, analyses of variance (ANOVAs) yielded effect sizes (ESs) for society of 15% and 18% for Total Problems and 42% and 31% for Personal Strengths, respectively. For 5,584 cross-informant dyads in 12 societies, cross-informant correlations averaged across societies were .68 for Total Problems and .58 for Personal Strengths. Mixed-model ANOVAs yielded large effects for society on both Total Problems (ES = 17%) and Personal Strengths (ES = 36%).

Conclusions: The OASR and OABCL are efficient, low-cost, easily administered mental health assessments that can be used internationally to screen for many problems and strengths.
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http://dx.doi.org/10.1017/S1041610220001532DOI Listing
September 2020

Six versus 12 months' adjuvant trastuzumab in patients with HER2-positive early breast cancer: the PERSEPHONE non-inferiority RCT.

Health Technol Assess 2020 08;24(40):1-190

Warwick Clinical Trials Unit, University of Warwick, Coventry, UK.

Background: The addition of adjuvant trastuzumab to chemotherapy has significantly improved outcomes for people with human epidermal growth factor receptor 2 (HER2)-positive, early, potentially curable breast cancer. Twelve months' trastuzumab, tested in registration trials, was adopted as standard adjuvant treatment in 2006. Subsequently, similar outcomes were demonstrated using 9 weeks of trastuzumab. Shorter durations were therefore tested for non-inferiority.

Objectives: To establish whether or not 6 months' adjuvant trastuzumab is non-inferior to 12 months' in the treatment of HER2-positive early breast cancer using a primary end point of 4-year disease-free survival.

Design: This was a Phase III randomised controlled non-inferiority trial.

Setting: The setting was 152 NHS hospitals.

Participants: A total of 4088 patients with HER2-positive early breast cancer who it was planned would receive both chemotherapy and trastuzumab took part.

Intervention: Randomisation (1 : 1) to 6 months' or 12 months' trastuzumab treatment.

Main Outcomes: The primary end point was disease-free survival. The secondary end points were overall survival, cost-effectiveness and cardiac function during treatment with trastuzumab. Assuming a 4-year disease-free survival rate of 80% with 12 months' trastuzumab, 4000 patients were required to demonstrate non-inferiority of 6 months' trastuzumab (5% one-sided significance, 85% power), defining the non-inferiority limit as no worse than 3% below the standard arm. Costs and quality-adjusted life-years were estimated using a within-trial analysis and a lifetime decision-analytic model.

Results: Between 4 October 2007 and 31 July 2015, 2045 patients were randomised to 12 months' trastuzumab and 2043 were randomised to 6 months' trastuzumab. Sixty-nine per cent of patients had ER-positive disease; 90% received anthracyclines (49% with taxanes; 41% without taxanes); 10% received taxanes without anthracyclines; 54% received trastuzumab sequentially after chemotherapy; and 85% received adjuvant chemotherapy (58% were node negative). At 6.1 years' median follow-up, with 389 (10%) deaths and 566 (14%) disease-free survival events, the 4-year disease-free survival rates for the 4088 patients were 89.5% (95% confidence interval 88.1% to 90.8%) in the 6-month group and 90.3% (95% confidence interval 88.9% to 91.5%) in the 12-month group (hazard ratio 1.10, 90% confidence interval 0.96 to 1.26; non-inferiority  = 0.01), demonstrating non-inferiority of 6 months' trastuzumab. Congruent results were found for overall survival (non-inferiority  = 0.0003) and landmark analyses 6 months from starting trastuzumab [non-inferiority  = 0.03 (disease-free-survival) and  = 0.006 (overall survival)]. Six months' trastuzumab resulted in fewer patients reporting adverse events of severe grade [365/1929 (19%) vs. 460/1935 (24%) for 12-month patients;  = 0.0003] or stopping early because of cardiotoxicity [61/1977 (3%) vs. 146/1941 (8%) for 12-month patients;  < 0.0001]. Health economic analysis showed that 6 months' trastuzumab resulted in significantly lower lifetime costs than and similar lifetime quality-adjusted life-years to 12 months' trastuzumab, and thus there is a high probability that 6 months' trastuzumab is cost-effective compared with 12 months' trastuzumab. Patient-reported experiences in the trial highlighted fatigue and aches and pains most frequently.

Limitations: The type of chemotherapy and timing of trastuzumab changed during the recruitment phase of the study as standard practice altered.

Conclusions: PERSEPHONE demonstrated that, in the treatment of HER2-positive early breast cancer, 6 months' adjuvant trastuzumab is non-inferior to 12 months'. Six months' treatment resulted in significantly less cardiac toxicity and fewer severe adverse events.

Future Work: Ongoing translational work investigates patient and tumour genetic determinants of toxicity, and trastuzumab efficacy. An individual patient data meta-analysis with PHARE and other trastuzumab duration trials is planned.

Trial Registration: Current Controlled Trials ISRCTN52968807, EudraCT 2006-007018-39 and ClinicalTrials.gov NCT00712140.

Funding: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in ; Vol. 24, No. 40. See the NIHR Journals Library website for further project information.
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http://dx.doi.org/10.3310/hta24400DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7505360PMC
August 2020

Hyperpolarized C MRI of Tumor Metabolism Demonstrates Early Metabolic Response to Neoadjuvant Chemotherapy in Breast Cancer.

Radiol Imaging Cancer 2020 07 31;2(4):e200017. Epub 2020 Jul 31.

Departments of Radiology (R.W., A.B.G., J.T.G., A.J.P., S.U., F.Z., M.L., M.C.L., S.H., A.F., L.B., L.R., E.S., M.J.G., F.J.G., F.A.G.), Oncology (J.K., H.B., E.H., B.B., R.B., J.E.A., C.C.), and Biochemistry (K.M.B.), the Cambridge Breast Cancer Research Unit (E.P., J.K., H.B., E.H., R.B., J.E.A., C.C.), University of Cambridge, Cambridge, England; Departments of Radiology (A.J.P., I.P., R.S., M.J.G., F.J.G., F.A.G.) and Histopathology (E.P.), Addenbrooke's Hospital, Cambridge University Hospitals NHS Foundation Trust, Cambridge, England; Cancer Research UK Cambridge Centre, Cambridge, England (R.W., M.A.M., E.P., T.T., L.B., L.R., E.S., J.E.A., C.C., K.M.B., F.A.G.); Department of Biomedical Imaging and Image-guided Therapy, Medical University of Vienna, Waehringer Guertel 18-20, Vienna 1090, Austria (R.W., L.B.); Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, England (M.A.M., T.T., C.C., K.M.B.); and RAPID Biomedical, Rimpar, Germany (T.L.).

Purpose: To compare hyperpolarized carbon 13 (C) MRI with dynamic contrast material-enhanced (DCE) MRI in the detection of early treatment response in breast cancer.

Materials And Methods: In this institutional review board-approved prospective study, a woman with triple-negative breast cancer (age, 49 years) underwent C MRI after injection of hyperpolarized [1-carbon 13 {C}]-pyruvate and DCE MRI at 3 T at baseline and after one cycle of neoadjuvant therapy. The C-labeled lactate-to-pyruvate ratio derived from hyperpolarized C MRI and the pharmacokinetic parameters transfer constant () and washout parameter () derived from DCE MRI were compared before and after treatment.

Results: Exchange of the C label between injected hyperpolarized [1-C]-pyruvate and the endogenous lactate pool was observed, catalyzed by the enzyme lactate dehydrogenase. After one cycle of neoadjuvant chemotherapy, a 34% reduction in the C-labeled lactate-to-pyruvate ratio resulted in correct identification of the patient as a responder to therapy, which was subsequently confirmed via a complete pathologic response. However, DCE MRI showed an increase in mean (132%) and mean (31%), which could be incorrectly interpreted as a poor response to treatment.

Conclusion: Hyperpolarized C MRI enabled successful identification of breast cancer response after one cycle of neoadjuvant chemotherapy and may improve response prediction when used in conjunction with multiparametric proton MRI.Published under a CC BY 4.0 license.
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http://dx.doi.org/10.1148/rycan.2020200017DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7398116PMC
July 2020

Serial Analysis of Circulating Tumor Cells in Metastatic Breast Cancer Receiving First-Line Chemotherapy.

J Natl Cancer Inst 2021 Apr;113(4):443-452

Department of Medical Oncology, Institut Curie, PSL Research University, Paris, France.

Background: We examined the prognostic significance of circulating tumor cell (CTC) dynamics during treatment in metastatic breast cancer (MBC) patients receiving first-line chemotherapy.

Methods: Serial CTC data from 469 patients (2202 samples) were used to build a novel latent mixture model to identify groups with similar CTC trajectory (tCTC) patterns during the course of treatment. Cox regression was used to estimate hazard ratios for progression-free survival (PFS) and overall survival (OS) in groups based on baseline CTCs, combined CTC status at baseline to the end of cycle 1, and tCTC. Akaike information criterion was used to select the model that best predicted PFS and OS.

Results: Latent mixture modeling revealed 4 distinct tCTC patterns: undetectable CTCs (56.9% ), low (23.7%), intermediate (14.5%), or high (4.9%). Patients with low, intermediate, and high tCTC patterns had statistically significant inferior PFS and OS compared with those with undetectable CTCs (P < .001). Akaike Information Criterion indicated that the tCTC model best predicted PFS and OS compared with baseline CTCs and combined CTC status at baseline to the end of cycle 1 models. Validation studies in an independent cohort of 1856 MBC patients confirmed these findings. Further validation using only a single pretreatment CTC measurement confirmed prognostic performance of the tCTC model.

Conclusions: We identified 4 novel prognostic groups in MBC based on similarities in tCTC patterns during chemotherapy. Prognostic groups included patients with very poor outcome (intermediate + high CTCs, 19.4%) who could benefit from more effective treatment. Our novel prognostic classification approach may be used for fine-tuning of CTC-based risk stratification strategies to guide future prospective clinical trials in MBC.
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http://dx.doi.org/10.1093/jnci/djaa113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8023821PMC
April 2021

Towards a cancer mission in Horizon Europe: recommendations.

Mol Oncol 2020 08;14(8):1589-1615

European Cancer Patient Coalition, Brussels, Belgium.

A comprehensive translational cancer research approach focused on personalized and precision medicine, and covering the entire cancer research-care-prevention continuum has the potential to achieve in 2030 a 10-year cancer-specific survival for 75% of patients diagnosed in European Union (EU) member states with a well-developed healthcare system. Concerted actions across this continuum that spans from basic and preclinical research through clinical and prevention research to outcomes research, along with the establishment of interconnected high-quality infrastructures for translational research, clinical and prevention trials and outcomes research, will ensure that science-driven and social innovations benefit patients and individuals at risk across the EU. European infrastructures involving comprehensive cancer centres (CCCs) and CCC-like entities will provide researchers with access to the required critical mass of patients, biological materials and technological resources and can bridge research with healthcare systems. Here, we prioritize research areas to ensure a balanced research portfolio and provide recommendations for achieving key targets. Meeting these targets will require harmonization of EU and national priorities and policies, improved research coordination at the national, regional and EU level and increasingly efficient and flexible funding mechanisms. Long-term support by the EU and commitment of Member States to specialized schemes are also needed for the establishment and sustainability of trans-border infrastructures and networks. In addition to effectively engaging policymakers, all relevant stakeholders within the entire continuum should consensually inform policy through evidence-based advice.
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http://dx.doi.org/10.1002/1878-0261.12763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400777PMC
August 2020

Landscape of G-quadruplex DNA structural regions in breast cancer.

Nat Genet 2020 09 3;52(9):878-883. Epub 2020 Aug 3.

Cancer Research UK Cambridge Institute, Li Ka Shing Centre, University of Cambridge, Cambridge, UK.

Response and resistance to anticancer therapies vary due to intertumor and intratumor heterogeneity. Here, we map differentially enriched G-quadruplex (G4) DNA structure-forming regions (∆G4Rs) in 22 breast cancer patient-derived tumor xenograft (PDTX) models. ∆G4Rs are associated with the promoters of highly amplified genes showing high expression, and with somatic single-nucleotide variants. Differences in ΔG4R landscapes reveal seven transcription factor programs across PDTXs. ∆G4R abundance and locations stratify PDTXs into at least three G4-based subtypes. ∆G4Rs in most PDTXs (14 of 22) were found to associate with more than one breast cancer subtype, which we also call an integrative cluster (IC). This suggests the frequent coexistence of multiple breast cancer states within a PDTX model, the majority of which display aggressive triple-negative IC10 gene activity. Short-term cultures of PDTX models with increased ∆G4R levels are more sensitive to small molecules targeting G4 DNA. Thus, G4 landscapes reveal additional IC-related intratumor heterogeneity in PDTX biopsies, improving breast cancer stratification and potentially identifying new treatment strategies.
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http://dx.doi.org/10.1038/s41588-020-0672-8DOI Listing
September 2020

Association of Sperm-Associated Antigen 5 and Treatment Response in Patients With Estrogen Receptor-Positive Breast Cancer.

JAMA Netw Open 2020 07 1;3(7):e209486. Epub 2020 Jul 1.

Department of Clinical Oncology, Nottingham University Hospitals NHS Trust, Nottingham, United Kingdom.

Importance: There is no proven test that can guide the optimal treatment, either endocrine therapy or chemotherapy, for estrogen receptor-positive breast cancer.

Objective: To investigate the associations of sperm-associated antigen 5 (SPAG5) transcript and SPAG5 protein expressions with treatment response in systemic therapy for estrogen receptor-positive breast cancer.

Design, Settings, And Participants: This retrospective cohort study included patients with estrogen receptor-positive breast cancer who received 5 years of adjuvant endocrine therapy with or without neoadjuvant anthracycline-based combination chemotherapy (NACT) derived from 11 cohorts from December 1, 1986, to November 28, 2019. The associations of SPAG5 transcript and SPAG5 protein expression with pathological complete response to NACT were evaluated, as was the association of SPAG5 mRNA expression with response to neoadjuvant endocrine therapy. The associations of distal relapse-free survival with SPAG5 transcript or SPAG5 protein expressions were analyzed. Data were analyzed from September 9, 2015, to November 28, 2019.

Main Outcomes And Measures: The primary outcomes were breast cancer-specific survival, distal relapse-free survival, pathological complete response, and clinical response. Outcomes were examined using Kaplan-Meier, multivariable logistic, and Cox regression models.

Results: This study included 12 720 women aged 24 to 78 years (mean [SD] age, 58.46 [12.45] years) with estrogen receptor-positive breast cancer, including 1073 women with SPAG5 transcript expression and 361 women with SPAG5 protein expression of locally advanced disease stage IIA through IIIC. Women with SPAG5 transcript and SPAG5 protein expressions achieved higher pathological complete response compared with those without SPAG5 transcript or SPAG5 protein expressions (transcript: odds ratio, 2.45 [95% CI, 1.71-3.51]; P < .001; protein: odds ratio, 7.32 [95% CI, 3.33-16.22]; P < .001). Adding adjuvant anthracycline chemotherapy to adjuvant endocrine therapy for SPAG5 mRNA expression in estrogen receptor-positive breast cancer was associated with prolonged 5-year distal relapse-free survival in patients without lymph node involvement (hazard ratio, 0.34 [95% CI, 0.14-0.87]; P = .03) and patients with lymph node involvement (hazard ratio, 0.35 [95% CI, 0.18-0.68]; P = .002) compared with receiving 5-year endocrine therapy alone. Mean (SD) SPAG5 transcript was found to be downregulated after 2 weeks of neoadjuvant endocrine therapy compared with pretreatment levels in 68 of 92 patients (74%) (0.23 [0.18] vs 0.34 [0.24]; P < .001).

Conclusions And Relevance: These findings suggest that SPAG5 transcript and SPAG5 protein expressions could be used to guide the optimal therapies for estrogen receptor-positive breast cancer. Retrospective and prospective clinical trials are warranted.
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http://dx.doi.org/10.1001/jamanetworkopen.2020.9486DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7341179PMC
July 2020

The GATA3 X308_Splice breast cancer mutation is a hormone context-dependent oncogenic driver.

Oncogene 2020 08 25;39(32):5455-5467. Epub 2020 Jun 25.

Institute of Cancer Research, Medical University Vienna, Comprehensive Cancer Center, Vienna, Austria.

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.
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http://dx.doi.org/10.1038/s41388-020-1376-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410826PMC
August 2020

ctDNA monitoring using patient-specific sequencing and integration of variant reads.

Sci Transl Med 2020 06;12(548)

Cambridge University Hospitals NHS Foundation Trust, Cambridge CB2 0QQ, UK.

Circulating tumor-derived DNA (ctDNA) can be used to monitor cancer dynamics noninvasively. Detection of ctDNA can be challenging in patients with low-volume or residual disease, where plasma contains very few tumor-derived DNA fragments. We show that sensitivity for ctDNA detection in plasma can be improved by analyzing hundreds to thousands of mutations that are first identified by tumor genotyping. We describe the INtegration of VAriant Reads (INVAR) pipeline, which combines custom error-suppression methods and signal-enrichment approaches based on biological features of ctDNA. With this approach, the detection limit in each sample can be estimated independently based on the number of informative reads sequenced across multiple patient-specific loci. We applied INVAR to custom hybrid-capture sequencing data from 176 plasma samples from 105 patients with melanoma, lung, renal, glioma, and breast cancer across both early and advanced disease. By integrating signal across a median of >10 informative reads, ctDNA was routinely quantified to 1 mutant molecule per 100,000, and in some cases with high tumor mutation burden and/or plasma input material, to parts per million. This resulted in median area under the curve (AUC) values of 0.98 in advanced cancers and 0.80 in early-stage and challenging settings for ctDNA detection. We generalized this method to whole-exome and whole-genome sequencing, showing that INVAR may be applied without requiring personalized sequencing panels so long as a tumor mutation list is available. As tumor sequencing becomes increasingly performed, such methods for personalized cancer monitoring may enhance the sensitivity of cancer liquid biopsies.
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http://dx.doi.org/10.1126/scitranslmed.aaz8084DOI Listing
June 2020

Transcriptional profiling reveals a subset of human breast tumors that retain wt TP53 but display mutant p53-associated features.

Mol Oncol 2020 08 23;14(8):1640-1652. Epub 2020 Jun 23.

Department of Molecular Cell Biology, The Weizmann Institute of Science, Rehovot, Israel.

TP53 gene mutations are very common in human cancer. While such mutations abrogate the tumor suppressive activities of the wild-type (wt) p53 protein, some of them also endow the mutant (mut) protein with oncogenic gain of function (GOF), facilitating cancer progression. Yet, p53 may acquire altered functionality even without being mutated; in particular, experiments with cultured cells revealed that wtp53 can be rewired to adopt mut-like features in response to growth factors or cancer-mimicking genetic manipulations. To assess whether such rewiring also occurs in human tumors, we interrogated gene expression profiles and pathway deregulation patterns in the METABRIC breast cancer (BC) dataset as a function of TP53 gene mutation status. Harnessing the power of machine learning, we optimized a gene expression classifier for ER+Her2- patients that distinguishes tumors carrying TP53 mutations from those retaining wt TP53. Interestingly, a small subset of wt TP53 tumors displayed gene expression and pathway deregulation patterns markedly similar to those of TP53-mutated tumors. Moreover, similar to TP53-mutated tumors, these 'pseudomutant' cases displayed a signature for enhanced proliferation and had worse prognosis than typical wtp53 tumors. Notably, these tumors revealed upregulation of genes which, in BC cell lines, were reported to be positively regulated by p53 GOF mutants. Thus, such tumors may benefit from mut p53-associated activities without having to accrue TP53 mutations.
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http://dx.doi.org/10.1002/1878-0261.12736DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400784PMC
August 2020

Caring for patients with cancer in the COVID-19 era.

Nat Med 2020 05 16;26(5):665-671. Epub 2020 Apr 16.

Division of Molecular Oncology & Immunology, The Netherlands Cancer Institute, Amsterdam, the Netherlands.

The current COVID-19 pandemic challenges oncologists to profoundly re-organize oncological care in order to dramatically reduce hospital visits and admissions and therapy-induced immune-related complications without compromising cancer outcomes. Since COVID-19 is a novel disease, guidance by scientific evidence is often unavailable, and impactful decisions are inevitably made on the basis of expert opinions. Here we report how the seven comprehensive cancer centers of Cancer Core Europe have organized their healthcare systems at an unprecedented scale and pace to make their operations 'pandemic proof'. We identify and discuss many commonalities, but also important local differences, and pinpoint critical research priorities to enable evidence-based remodeling of cancer care during the COVID-19 pandemic. Also, we discuss how the current situation offers a unique window of opportunity for assessing the effects of de-escalating anticancer regimens, which may fast-forward the development of more-refined and less-toxic treatments. By sharing our joint experiences, we offer a roadmap for proceeding and aim to mobilize the global research community to generate the data that are critically needed to offer the best possible care to patients.
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http://dx.doi.org/10.1038/s41591-020-0874-8DOI Listing
May 2020

DNA copy number motifs are strong and independent predictors of survival in breast cancer.

Commun Biol 2020 04 2;3(1):153. Epub 2020 Apr 2.

Department of Cancer Genetics, Institute for Cancer Research, Oslo University Hospital, Ullernchausseen 70 N-0310, Oslo, Norway.

Somatic copy number alterations are a frequent sign of genome instability in cancer. A precise characterization of the genome architecture would reveal underlying instability mechanisms and provide an instrument for outcome prediction and treatment guidance. Here we show that the local spatial behavior of copy number profiles conveys important information about this architecture. Six filters were defined to characterize regional traits in copy number profiles, and the resulting Copy Aberration Regional Mapping Analysis (CARMA) algorithm was applied to tumors in four breast cancer cohorts (n = 2919). The derived motifs represent a layer of information that complements established molecular classifications of breast cancer. A score reflecting presence or absence of motifs provided a highly significant independent prognostic predictor. Results were consistent between cohorts. The nonsite-specific occurrence of the detected patterns suggests that CARMA captures underlying replication and repair defects and could have a future potential in treatment stratification.
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http://dx.doi.org/10.1038/s42003-020-0884-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7118095PMC
April 2020

Genetic Alterations in the PI3K/AKT Pathway and Baseline AKT Activity Define AKT Inhibitor Sensitivity in Breast Cancer Patient-derived Xenografts.

Clin Cancer Res 2020 07 27;26(14):3720-3731. Epub 2020 Mar 27.

Department of Medical Oncology, Hospital Vall d'Hebron, Universitat Autònoma de Barcelona, Barcelona, Spain.

Purpose: AZD5363/capivasertib is a pan-AKT catalytic inhibitor with promising activity in combination with paclitaxel in triple-negative metastatic breast cancer harboring PI3K/AKT-pathway alterations and in estrogen receptor-positive breast cancer in combination with fulvestrant. Here, we aimed to identify response biomarkers and uncover mechanisms of resistance to AZD5363 and its combination with paclitaxel.

Experimental Design: Genetic and proteomic markers were analyzed in 28 HER2-negative patient-derived xenografts (PDXs) and in patient samples, and correlated to AZD5363 sensitivity as single agent and in combination with paclitaxel.

Results: Four PDX were derived from patients receiving AZD5363 in the clinic which exhibited concordant treatment response. Mutations in / and absence of mTOR complex 1 (mTORC1)-activating alterations, for example, in or , were associated with sensitivity to AZD5363 monotherapy. Interestingly, excluding from the composite biomarker increased its accuracy from 64% to 89%. Moreover, resistant PDXs exhibited low baseline pAKT S473 and residual pS6 S235 upon treatment, suggesting that parallel pathways bypass AKT/S6K1 signaling in these models. We identified two mechanisms of acquired resistance to AZD5363: cyclin D1 overexpression and loss of p.E17K.

Conclusions: This study provides insight into putative predictive biomarkers of response and acquired resistance to AZD5363 in HER2-negative metastatic breast cancer.
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http://dx.doi.org/10.1158/1078-0432.CCR-19-3324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7814659PMC
July 2020