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    Tumor ENPP1 (CD203a)/Haptoglobin Axis Exploits Myeloid-Derived Suppressor Cells to Promote Post-Radiotherapy Local Recurrence in Breast Cancer. Cancer discovery ABSTRACT:Locoregional failure (LRF) in patients with breast cancer post-surgery and post-irradiation is linked to a dismal prognosis. In a refined new model, we identified ectonucleotide pyrophosphatase/phosphodiesterase 1/CD203a (ENPP1) to be closely associated with LRF. ENPP1hi circulating tumor cells (CTC) contribute to relapse by a self-seeding mechanism. This process requires the infiltration of polymorphonuclear myeloid-derived suppressor cells and neutrophil extracellular trap (NET) formation. Genetic and pharmacologic ENPP1 inhibition or NET blockade extends relapse-free survival. Furthermore, in combination with fractionated irradiation, ENPP1 abrogation obliterates LRF. Mechanistically, ENPP1-generated adenosinergic metabolites enhance haptoglobin (HP) expression. This inflammatory mediator elicits myeloid invasiveness and promotes NET formation. Accordingly, a significant increase in ENPP1 and NET formation is detected in relapsed human breast cancer tumors. Moreover, high ENPP1 or HP levels are associated with poor prognosis. These findings unveil the ENPP1/HP axis as an unanticipated mechanism exploited by tumor cells linking inflammation to immune remodeling favoring local relapse. SIGNIFICANCE:CTC exploit the ENPP1/HP axis to promote local recurrence post-surgery and post-irradiation by subduing myeloid suppressor cells in breast tumors. Blocking this axis impairs tumor engraftment, impedes immunosuppression, and obliterates NET formation, unveiling new opportunities for therapeutic intervention to eradicate local relapse and ameliorate patient survival. This article is highlighted in the In This Issue feature, p. 1171. 10.1158/2159-8290.CD-21-0932
    Stromal oncostatin M cytokine promotes breast cancer progression by reprogramming the tumor microenvironment. The Journal of clinical investigation The tumor microenvironment (TME) is reprogrammed by cancer cells and participates in all stages of tumor progression. The contribution of stromal cells to the reprogramming of the TME is not well understood. Here, we provide evidence of the role of the cytokine oncostatin M (OSM) as central node for multicellular interactions between immune and nonimmune stromal cells and the epithelial cancer cell compartment. OSM receptor (OSMR) deletion in a multistage breast cancer model halted tumor progression. We ascribed causality to the stromal function of the OSM axis by demonstrating reduced tumor burden of syngeneic tumors implanted in mice lacking OSMR. Single-cell and bioinformatic analysis of murine and human breast tumors revealed that OSM expression was restricted to myeloid cells, whereas OSMR was detected predominantly in fibroblasts and, to a lower extent, cancer cells. Myeloid-derived OSM reprogrammed fibroblasts to a more contractile and tumorigenic phenotype and elicited the secretion of VEGF and proinflammatory chemokines CXCL1 and CXCL16, leading to increased myeloid cell recruitment. Collectively, our data support the notion that the stromal OSM/OSMR axis reprograms the immune and nonimmune microenvironment and plays a key role in breast cancer progression. 10.1172/JCI148667
    PTPN2 elicits cell autonomous and non-cell autonomous effects on antitumor immunity in triple-negative breast cancer. Science advances The tumor-suppressor PTPN2 is diminished in a subset of triple-negative breast cancers (TNBCs). Paradoxically, PTPN2-deficiency in tumors or T cells in mice can facilitate T cell recruitment and/or activation to promote antitumor immunity. Here, we explored the therapeutic potential of targeting PTPN2 in tumor cells and T cells. PTPN2-deficiency in TNBC associated with T cell infiltrates and PD-L1 expression, whereas low associated with improved survival. PTPN2 deletion in murine mammary epithelial cells TNBC models, did not promote tumorigenicity but increased STAT-1-dependent T cell recruitment and PD-L1 expression to repress tumor growth and enhance the efficacy of anti-PD-1. Furthermore, the combined deletion of PTPN2 in tumors and T cells facilitated T cell recruitment and activation and further repressed tumor growth or ablated tumors already predominated by exhausted T cells. Thus, PTPN2-targeting in tumors and/or T cells facilitates T cell recruitment and/or alleviates inhibitory constraints on T cells to combat TNBC. 10.1126/sciadv.abk3338
    Effective drug combinations in breast, colon and pancreatic cancer cells. Jaaks Patricia,Coker Elizabeth A,Vis Daniel J,Edwards Olivia,Carpenter Emma F,Leto Simonetta M,Dwane Lisa,Sassi Francesco,Lightfoot Howard,Barthorpe Syd,van der Meer Dieudonne,Yang Wanjuan,Beck Alexandra,Mironenko Tatiana,Hall Caitlin,Hall James,Mali Iman,Richardson Laura,Tolley Charlotte,Morris James,Thomas Frances,Lleshi Ermira,Aben Nanne,Benes Cyril H,Bertotti Andrea,Trusolino Livio,Wessels Lodewyk,Garnett Mathew J Nature Combinations of anti-cancer drugs can overcome resistance and provide new treatments. The number of possible drug combinations vastly exceeds what could be tested clinically. Efforts to systematically identify active combinations and the tissues and molecular contexts in which they are most effective could accelerate the development of combination treatments. Here we evaluate the potency and efficacy of 2,025 clinically relevant two-drug combinations, generating a dataset encompassing 125 molecularly characterized breast, colorectal and pancreatic cancer cell lines. We show that synergy between drugs is rare and highly context-dependent, and that combinations of targeted agents are most likely to be synergistic. We incorporate multi-omic molecular features to identify combination biomarkers and specify synergistic drug combinations and their active contexts, including in basal-like breast cancer, and microsatellite-stable or KRAS-mutant colon cancer. Our results show that irinotecan and CHEK1 inhibition have synergistic effects in microsatellite-stable or KRAS-TP53 double-mutant colon cancer cells, leading to apoptosis and suppression of tumour xenograft growth. This study identifies clinically relevant effective drug combinations in distinct molecular subpopulations and is a resource to guide rational efforts to develop combinatorial drug treatments. 10.1038/s41586-022-04437-2
    A trispecific antibody targeting HER2 and T cells inhibits breast cancer growth via CD4 cells. Nature Effective antitumour immunity depends on the orchestration of potent T cell responses against malignancies. Regression of human cancers has been induced by immune checkpoint inhibitors, T cell engagers or chimeric antigen receptor T cell therapies. Although CD8 T cells function as key effectors of these responses, the role of CD4 T cells beyond their helper function has not been defined. Here we demonstrate that a trispecific antibody to HER2, CD3 and CD28 stimulates regression of breast cancers in a humanized mouse model through a mechanism involving CD4-dependent inhibition of tumour cell cycle progression. Although CD8 T cells directly mediated tumour lysis in vitro, CD4 T cells exerted antiproliferative effects by blocking cancer cell cycle progression at G1/S. Furthermore, when T cell subsets were adoptively transferred into a humanized breast cancer tumour mouse model, CD4 T cells alone inhibited HER2 breast cancer growth in vivo. RNA microarray analysis revealed that CD4 T cells markedly decreased tumour cell cycle progression and proliferation, and also increased pro-inflammatory signalling pathways. Collectively, the trispecific antibody to HER2 induced T cell-dependent tumour regression through direct antitumour and indirect pro-inflammatory/immune effects driven by CD4 T cells. 10.1038/s41586-022-04439-0
    HTR1A Inhibits the Progression of Triple-Negative Breast Cancer via TGF-β Canonical and Noncanonical Pathways. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Triple-negative breast cancer is the most aggressive subtype of breast cancer and the incidence of depression in breast cancer patients is high, which leading to worse survival and increased risk of recurrence. The effect of antidepressants on breast cancer patients remains contradictory, which might be due to variations in antidepression targets. Therefore, there is significant value to explore the antitumor potential of antidepressants and discover new therapeutic targets for breast patients. The authors screen antidepressant-related oncogenes or suppressors by using siRNAs. After combining functional experiments with online database analysis, 5-hydroxytryptamine receptor 1A (HTR1A is selected with antitumor potential in breast cancer cells in vivo and in vitro. RNA-seq analysis and coimmunoprecipitation assays indicate that HTR1A interacts with TRIM21 and PSMD7 to inhibit the degradation of TβRII through the ubiquitin-proteasome pathway, thereby inhibiting the transforming growth factor-β (TGF-β) canonical and noncanonical pathway. In addition, HTR1A is an independent predictive factor for breast cancer patients. The combined treatment of HTR1A agonists with demethylation drugs may significantly improve patient survival. It is of great significance to clarify the function and mechanism of the depression-related gene HTR1A in breast cancer, which might provide a new approach for triple-negative breast cancer patients. 10.1002/advs.202105672
    Cost-effectiveness Analysis of Pertuzumab With Trastuzumab in Patients With Metastatic Breast Cancer. JAMA oncology IMPORTANCE:The initial assessment of pertuzumab use for treatment of metastatic breast cancer by health technology assessment agencies suggested that pertuzumab was not cost-effective. In Ontario, Canada, pertuzumab became funded in November 2013 based on the substantial clinical benefit. To date, there is a paucity of analysis of pertuzumab using real-world data for cost-effectiveness. OBJECTIVE:To assess the cost-effectiveness of pertuzumab, trastuzumab, and chemotherapy vs trastuzumab and chemotherapy for patients with metastatic breast cancer. DESIGN, SETTING, AND PARTICIPANTS:A population-based retrospective economic evaluation was conducted in Ontario, Canada. Patients who received first-line treatments for metastatic breast cancer from January 1, 2008, to March 31, 2018, were identified. Patients were followed up from the start of treatment up to 5 years, with maximum follow-up to March 31, 2019. Patients were identified from the Ontario Cancer Registry and linked to the New Drug Funding Program database to identify receipt of first-line treatment (N = 1158). INTERVENTIONS:Treatment with pertuzumab, trastuzumab, and chemotherapy after public funding (November 25, 2013) compared with treatment with trastuzumab and chemotherapy before funding. MAIN OUTCOMES AND MEASURES:Cost-effectiveness, from a public payer perspective, was estimated from administrative data with a 5-year time horizon, adjusted for censoring, and discounted (1.5%). Incremental cost-effectiveness ratios for life-years gained and quality-adjusted life year (QALY) with bootstrapped 95% CIs were calculated. Sensitivity analysis with price reduction of pertuzumab alone or in combination with trastuzumab was conducted. RESULTS:A total of 579 pairs of matched patients receiving pertuzumab and controls were included. The mean (SD) age of the matched study cohort was 58 (12.97) years; 1151 were women (99.4%). Pertuzumab resulted in 0.61 life-years gained and 0.44 QALYs gained at an incremental cost of $192 139 (all costs measured in Canadian dollar values, CAD) with an incremental cost-effectiveness ratio of $316 203 per life-year gained and $436 679 per QALY. The main factors associated with cost included the cost of pertuzumab (60%), outpatient cancer treatment delivery (24%), and trastuzumab (15%). With 100% price reduction of pertuzumab, the incremental cost-effectiveness ratio was $174 027 per QALY. When the price of pertuzumab and trastuzumab were both reduced by more than 71%, the incremental cost-effectiveness ratio decreased below $100 000 per QALY. CONCLUSIONS AND RELEVANCE:The findings of this population-based study suggest that pertuzumab may increase survival for patients with metastatic breast cancer but would not be considered cost-effective, even after 100% price reduction, under conventional thresholds. 10.1001/jamaoncol.2021.8049
    Association of Residual Cancer Burden After Neoadjuvant Therapy and Event-Free Survival in Breast Cancer-Reply. JAMA oncology 10.1001/jamaoncol.2021.8000
    Improving Outcomes for High-Risk Hormone Receptor-Positive Breast Cancer With CDK Inhibition. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Journal Journal of Clinical Oncology, 10.1200/JCO.21.02850
    Transcriptional repression of estrogen receptor alpha by YAP reveals the Hippo pathway as therapeutic target for ER breast cancer. Nature communications Extensive knowledge has been gained on the transcription network controlled by ERα, however, the mechanism underlying ESR1 (encoding ERα) expression is less understood. We recently discovered that the Hippo pathway is required for the proper expression of ESR1. YAP/TAZ are transcription coactivators that are phosphorylated and inhibited by the Hippo pathway kinase LATS. Here we delineated the molecular mechanisms underlying ESR1 transcription repression by the Hippo pathway. Mechanistically, YAP binds to TEAD to increase local chromatin accessibility to stimulate transcription of nearby genes. Among the YAP target genes, Vestigial-Like Protein 3 (VGLL3) competes with YAP/TAZ for binding to TEAD transcription factor and recruits the NCOR2/SMRT repressor to the super-enhancer of ESR1 gene, leading to epigenetic alteration and transcriptional silencing. We developed a potent LATS inhibitor VT02956. Targeting the Hippo pathway by VT02956 represses ESR1 expression and inhibits the growth of ER breast cancer cells as well as patient-derived tumour organoids. Moreover, histone deacetylase inhibitors, such as Entinostat, induce VGLL3 expression to inhibit ER breast cancer cells. Our study suggests LATS as unexpected cancer therapeutic targets, especially for endocrine-resistant breast cancers. 10.1038/s41467-022-28691-0
    Late Breast Cancer Survivorship: Side Effects and Care Recommendations. Journal of clinical oncology : official journal of the American Society of Clinical Oncology Journal Journal of Clinical Oncology, 10.1200/JCO.22.00049
    A Combined Echocardiography Approach for the Diagnosis of Cancer Therapy-Related Cardiac Dysfunction in Women With Early-Stage Breast Cancer. JAMA cardiology IMPORTANCE:Diagnosis of cancer therapy-related cardiac dysfunction (CTRCD) remains a challenge. Cardiovascular magnetic resonance (CMR) provides accurate measurement of left ventricular ejection fraction (LVEF), but access to repeated scans is limited. OBJECTIVE:To develop a diagnostic model for CTRCD using echocardiographic LVEF and strain and biomarkers, with CMR as the reference standard. DESIGN, SETTING, AND PARTICIPANTS:In this prospective cohort study, patients were recruited from University of Toronto-affiliated hospitals from November 2013 to January 2019 with all cardiac imaging performed at a single tertiary care center. Women with human epidermal growth factor receptor 2 (HER2)-positive early-stage breast cancer were included. The main exclusion criterion was contraindication to CMR. A total of 160 patients were recruited, 136 of whom completed the study. EXPOSURES:Sequential therapy with anthracyclines and trastuzumab. MAIN OUTCOMES AND MEASURES:Patients underwent echocardiography, high-sensitivity troponin I (hsTnI), B-type natriuretic peptide (BNP), and CMR studies preanthracycline and postanthracycline every 3 months during and after trastuzumab therapy. Echocardiographic measures included 2-dimensional (2-D) LVEF, 3-D LVEF, peak systolic global longitudinal strain (GLS), and global circumferential strain (GCS). LVEF CTRCD was defined using the Cardiac Review and Evaluation Committee Criteria, GLS or GCS CTRCD as a greater than 15% relative change, and abnormal hsTnI and BNP as greater than 26 pg/mL and ≥ 35 pg/mL, respectively, at any follow-up point. Combinations of echocardiographic measures and biomarkers were examined to diagnose CMR CTRCD using conditional inference tree models. RESULTS:Among 136 women (mean [SD] age, 51.1 [9.2] years), CMR-identified CTRCD occurred in 37 (27%), and among those with analyzable images, in 30 of 131 (23%) by 2-D LVEF, 27 of 124 (22%) by 3-D LVEF, 53 of 126 (42%) by GLS, 61 of 123 (50%) by GCS, 32 of 136 (24%) by BNP, and 14 of 136 (10%) by hsTnI. In isolation, 3-D LVEF had greater sensitivity and specificity than 2-D LVEF for CMR CTRCD while GLS had greater sensitivity than 2-D or 3-D LVEF. Regression tree analysis identified a sequential algorithm using 3-D LVEF, GLS, and GCS for the optimal diagnosis of CTRCD (area under the receiver operating characteristic curve, 89.3%). The probability of CTRCD when results for all 3 tests were negative was 1.0%. When 3-D LVEF was replaced by 2-D LVEF in the model, the algorithm still performed well; however, its primary value was to rule out CTRCD. Biomarkers did not improve the ability to diagnose CTRCD. CONCLUSIONS AND RELEVANCE:Using CMR CTRCD as the reference standard, these data suggest that a sequential approach combining echocardiographic 3-D LVEF with 2-D GLS and 2-D GCS may provide a timely diagnosis of CTRCD during routine CTRCD surveillance with greater accuracy than using these measures individually. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT02306538. 10.1001/jamacardio.2021.5881
    Event-free Survival with Pembrolizumab in Early Triple-Negative Breast Cancer. The New England journal of medicine BACKGROUND:The addition of pembrolizumab to neoadjuvant chemotherapy led to a significantly higher percentage of patients with early triple-negative breast cancer having a pathological complete response (defined as no invasive cancer in the breast and negative nodes) at definitive surgery in an earlier analysis of this phase 3 trial of neoadjuvant and adjuvant therapy. The primary results regarding event-free survival in this trial have not been reported. METHODS:We randomly assigned, in a 2:1 ratio, patients with previously untreated stage II or III triple-negative breast cancer to receive neoadjuvant therapy with four cycles of pembrolizumab (at a dose of 200 mg) or placebo every 3 weeks plus paclitaxel and carboplatin, followed by four cycles of pembrolizumab or placebo plus doxorubicin-cyclophosphamide or epirubicin-cyclophosphamide. After definitive surgery, patients received adjuvant pembrolizumab (pembrolizumab-chemotherapy group) or placebo (placebo-chemotherapy group) every 3 weeks for up to nine cycles. The primary end points were pathological complete response (the results for which have been reported previously) and event-free survival, defined as the time from randomization to the date of disease progression that precluded definitive surgery, local or distant recurrence, occurrence of a second primary cancer, or death from any cause. Safety was also assessed. RESULTS:Of the 1174 patients who underwent randomization, 784 were assigned to the pembrolizumab-chemotherapy group and 390 to the placebo-chemotherapy group. The median follow-up at this fourth planned interim analysis (data cutoff, March 23, 2021) was 39.1 months. The estimated event-free survival at 36 months was 84.5% (95% confidence interval [CI], 81.7 to 86.9) in the pembrolizumab-chemotherapy group, as compared with 76.8% (95% CI, 72.2 to 80.7) in the placebo-chemotherapy group (hazard ratio for event or death, 0.63; 95% CI, 0.48 to 0.82; P<0.001). Adverse events occurred predominantly during the neoadjuvant phase and were consistent with the established safety profiles of pembrolizumab and chemotherapy. CONCLUSIONS:In patients with early triple-negative breast cancer, neoadjuvant pembrolizumab plus chemotherapy, followed by adjuvant pembrolizumab after surgery, resulted in significantly longer event-free survival than neoadjuvant chemotherapy alone. (Funded by Merck Sharp and Dohme, a subsidiary of Merck; KEYNOTE-522 ClinicalTrials.gov number, NCT03036488.). 10.1056/NEJMoa2112651
    Blocking breast cancer metastasis. Crunkhorn Sarah Nature reviews. Drug discovery 10.1038/d41573-022-00026-0
    Cancer statistics for African American/Black People 2022. CA: a cancer journal for clinicians African American/Black individuals have a disproportionate cancer burden, including the highest mortality and the lowest survival of any racial/ethnic group for most cancers. Every 3 years, the American Cancer Society estimates the number of new cancer cases and deaths for Black people in the United States and compiles the most recent data on cancer incidence (herein through 2018), mortality (through 2019), survival, screening, and risk factors using population-based data from the National Cancer Institute and the Centers for Disease Control and Prevention. In 2022, there will be approximately 224,080 new cancer cases and 73,680 cancer deaths among Black people in the United States. During the most recent 5-year period, Black men had a 6% higher incidence rate but 19% higher mortality than White men overall, including an approximately 2-fold higher risk of death from myeloma, stomach cancer, and prostate cancer. The overall cancer mortality disparity is narrowing between Black and White men because of a steeper drop in Black men for lung and prostate cancers. However, the decline in prostate cancer mortality in Black men slowed from 5% annually during 2010 through 2014 to 1.3% during 2015 through 2019, likely reflecting the 5% annual increase in advanced-stage diagnoses since 2012. Black women have an 8% lower incidence rate than White women but a 12% higher mortality; further, mortality rates are 2-fold higher for endometrial cancer and 41% higher for breast cancer despite similar or lower incidence rates. The wide breast cancer disparity reflects both later stage diagnosis (57% localized stage vs 67% in White women) and lower 5-year survival overall (82% vs 92%, respectively) and for every stage of disease (eg, 20% vs 30%, respectively, for distant stage). Breast cancer surpassed lung cancer as the leading cause of cancer death among Black women in 2019. Targeted interventions are needed to reduce stark cancer inequalities in the Black community. 10.3322/caac.21718
    Predicting the Likelihood of Carrying a or Mutation in Asian Patients With Breast Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:With the development of poly (ADP-ribose) polymerase inhibitors for treatment of patients with cancer with an altered or gene, there is an urgent need to ensure that there are appropriate strategies for identifying mutation carriers while balancing the increased demand for and cost of cancer genetics services. To date, the majority of mutation prediction tools have been developed in women of European descent where the age and cancer-subtype distributions are different from that in Asian women. METHODS:In this study, we built a new model (Asian Risk Calculator) for estimating the likelihood of carrying a pathogenic variant in or gene, using germline genetic testing results in a cross-sectional population-based study of 8,162 Asian patients with breast cancer. We compared the model performance to existing mutation prediction models. The models were evaluated for discrimination and calibration. RESULTS:Asian Risk Calculator included age of diagnosis, ethnicity, bilateral breast cancer, tumor biomarkers, and family history of breast cancer or ovarian cancer as predictors. The inclusion of tumor grade improved significantly the model performance. The full model was calibrated (Hosmer-Lemeshow value = .614) and discriminated well between and non- pathogenic variant carriers (area under receiver operating curve, 0.80; 95% CI, 0.75 to 0.84). Addition of grade to the existing clinical genetic testing criteria targeting patients with breast cancer age younger than 45 years reduced the proportion of patients referred for genetic counseling and testing from 37% to 33% ( value = .003), thereby improving the overall efficacy. CONCLUSION:Population-specific customization of mutation prediction models and clinical genetic testing criteria improved the accuracy of BRCA mutation prediction in Asian patients. 10.1200/JCO.21.01647
    Copy number amplification of ENSA promotes the progression of triple-negative breast cancer via cholesterol biosynthesis. Chen Yi-Yu,Ge Jing-Yu,Zhu Si-Yuan,Shao Zhi-Ming,Yu Ke-Da Nature communications Copy number alterations (CNAs) are pivotal genetic events in triple-negative breast cancer (TNBC). Here, our integrated copy number and transcriptome analysis of 302 TNBC patients reveals that gene alpha-endosulfine (ENSA) exhibits recurrent amplification at the 1q21.3 region and is highly expressed in TNBC. ENSA promotes tumor growth and indicates poor patient survival in TNBC. Mechanistically, we identify ENSA as an essential regulator of cholesterol biosynthesis in TNBC that upregulates the expression of sterol regulatory element-binding transcription factor 2 (SREBP2), a pivotal transcription factor in cholesterol biosynthesis. We confirm that ENSA can increase the level of p-STAT3 (Tyr705) and activated STAT3 binds to the promoter of SREBP2 to promote its transcription. Furthermore, we reveal the efficacy of STAT3 inhibitor Stattic in TNBC with high ENSA expression. In conclusion, the amplification of ENSA at the 1q21.3 region promotes TNBC progression and indicates sensitivity to STAT3 inhibitors. 10.1038/s41467-022-28452-z
    Somatic Mutations Show Immunogenicity in Metastatic Breast Cancer. Cancer discovery A natural immune response was generated to somatic mutations in metastatic breast cancer patients. 10.1158/2159-8290.CD-RW2022-025
    Nano-ultrasonic Contrast Agent for Chemoimmunotherapy of Breast Cancer by Immune Metabolism Reprogramming and Tumor Autophagy. Yang Xupeng,Zhao Meng,Wu Zhihua,Chen Chuanrong,Zhang Yanhua,Wang Liting,Guo Qianqian,Wang Quan,Liang Shunshun,Hu Suxian,Duan Yourong,Sun Ying ACS nano The functional status of innate immune cells is a considerable determinant of effective antitumor immune response. However, the triple-negative breast cancer tumor microenvironment with high lactic acid metabolism and high antioxidant levels limits immune cell survival, differentiation, and function. Here, we determine that the tumor microenvironment-responsive nano-ultrasonic contrast agent Pt(IV)/CQ/PFH NPs-PPA-1 boosts the ratio of mature dendritic cells (mDCs) and proinflammatory macrophages by reprogramming the metabolism of immature DCs (iDCs) and tumor-associated macrophages (TAMs). Specifically, platinum(IV) in cancer cells or iDCs was reduced to cisplatin, which can increase the intracellular content of ROS and therefore enhance the ratio of mDCs and apoptotic tumor cells. Meanwhile, chloroquine (CQ) released from nanoparticles (NPs) minimizes protective autophagy caused by cisplatin in tumor cells and reprograms the metabolism of TAMs to enhance the proportion of proinflammatory macrophages, achieving a superior synergistic effect of chemoimmunotherapy combined with Pt(IV) and anti-PD-L1 peptide (PPA-1). Furthermore, perfluorohexane (PFH) in NPs realizes monitoring treatment corresponding to ultrasound. Collectively, the nano-ultrasonic contrast agent supports a candidate for monitoring treatment and augmenting antitumor chemoimmunotherapy by suppressing tumor cell autophagy and reprogramming immunocyte metabolism. 10.1021/acsnano.2c00462
    Pain and health-related quality of life with olaparib versus physician's choice of next-generation hormonal drug in patients with metastatic castration-resistant prostate cancer with homologous recombination repair gene alterations (PROfound): an open-label, randomised, phase 3 trial. The Lancet. Oncology BACKGROUND:The PROfound study showed significantly improved radiographical progression-free survival and overall survival in men with metastatic castration-resistant prostate cancer with alterations in homologous recombination repair genes and disease progression on a previous next-generation hormonal drug who received olaparib then those who received control. We aimed to assess pain and patient-centric health-related quality of life (HRQOL) measures in patients in the trial. METHODS:In this open-label, randomised, phase 3 study, patients (aged ≥18 years) with metastatic castration-resistant prostate cancer and gene alterations to one of 15 genes (BRCA1, BRCA2, or ATM [cohort A] and BRIP1, BARD1, CDK12, CHEK1, CHEK2, FANCL, PALB2, PPP2R2A, RAD51B, RAD51C, RAD51D, and RAD54L [cohort B]) and disease progression after a previous next-generation hormonal drug were randomly assigned (2:1) to receive olaparib tablets (300 mg orally twice daily) or a control drug (enzalutamide tablets [160 mg orally once daily] or abiraterone tablets [1000 mg orally once daily] plus prednisone tablets [5 mg orally twice daily]), stratified by previous taxane use and measurable disease. The primary endpoint (radiographical progression-free survival in cohort A) has been previously reported. The prespecified secondary endpoints reported here are on pain, HRQOL, symptomatic skeletal-related events, and time to first opiate use for cancer-related pain in cohort A. Pain was assessed with the Brief Pain Inventory-Short Form, and HRQOL was assessed with the Functional Assessment of Cancer Therapy-Prostate (FACT-P). All endpoints were analysed in patients in cohort A by modified intention-to-treat. The study is registered with ClinicalTrials.gov, NCT02987543. FINDINGS:Between Feb 6, 2017, and June 4, 2019, 245 patients were enrolled in cohort A and received study treatment (162 [66%] in the olaparib group and 83 [34%] in the control group). Median duration of follow-up at data cutoff in all patients was 6·2 months (IQR 2·2-10·4) for the olaparib group and 3·5 months (1·7-4·9) for the control group. In cohort A, median time to pain progression was significantly longer with olaparib than with control (median not reached [95% CI not reached-not reached] with olaparib vs 9·92 months [5·39-not reached] with control; HR 0·44 [95% CI 0·22-0·91]; p=0·019). Pain interference scores were also better in the olaparib group (difference in overall adjusted mean change from baseline score -0·85 [95% CI -1·31 to -0·39]; p=0·0004). Median time to progression of pain severity was not reached in either group (95% CI not reached-not reached for both groups; HR 0·56 [95% CI 0·25-1·34]; p=0·17). In patients who had not used opiates at baseline (113 in the olaparib group, 58 in the control group), median time to first opiate use for cancer-related pain was 18·0 months (95% CI 12·8-not reached) in the olaparib group versus 7·5 months (3·2-not reached) in the control group (HR 0·61; 95% CI 0·38-0·99; p=0·044). The proportion of patients with clinically meaningful improvement in FACT-P total score during treatment was higher for the olaparib group than the control group: 15 (10%) of 152 evaluable patients had a response in the olaparib group compared with one (1%) of evaluable 77 patients in the control group (odds ratio 8·32 [95% CI 1·64-151·84]; p=0·0065). Median time to first symptomatic skeletal-related event was not reached for either treatment group (olaparib group 95% CI not reached-not reached; control group 7·8-not reached; HR 0·37 [95% CI 0·20-0·70]; p=0·0013). INTERPRETATION:Olaparib was associated with reduced pain burden and better-preserved HRQOL compared with the two control drugs in men with metastatic castration-resistant prostate cancer and homologous recombination repair gene alterations who had disease progression after a previous next-generation hormonal drug. Our findings support the clinical benefit of improved radiographical progression-free survival and overall survival identified in PROfound. FUNDING:AstraZeneca and Merck Sharp & Dohme. 10.1016/S1470-2045(22)00017-1
    Mitochondrial fission links ECM mechanotransduction to metabolic redox homeostasis and metastatic chemotherapy resistance. Nature cell biology Metastatic breast cancer cells disseminate to organs with a soft microenvironment. Whether and how the mechanical properties of the local tissue influence their response to treatment remains unclear. Here we found that a soft extracellular matrix empowers redox homeostasis. Cells cultured on a soft extracellular matrix display increased peri-mitochondrial F-actin, promoted by Spire1C and Arp2/3 nucleation factors, and increased DRP1- and MIEF1/2-dependent mitochondrial fission. Changes in mitochondrial dynamics lead to increased production of mitochondrial reactive oxygen species and activate the NRF2 antioxidant transcriptional response, including increased cystine uptake and glutathione metabolism. This retrograde response endows cells with resistance to oxidative stress and reactive oxygen species-dependent chemotherapy drugs. This is relevant in a mouse model of metastatic breast cancer cells dormant in the lung soft tissue, where inhibition of DRP1 and NRF2 restored cisplatin sensitivity and prevented disseminated cancer-cell awakening. We propose that targeting this mitochondrial dynamics- and redox-based mechanotransduction pathway could open avenues to prevent metastatic relapse. 10.1038/s41556-022-00843-w
    Earlier decisions on breast and ovarian surgery reduce cancer in women at high risk. Saul Helen,Gursul Deniz,Cassidy Samantha,Evans Gareth BMJ (Clinical research ed.) The studyMarcinkute R, Woodward ER, Gandhi A, et al. Uptake and efficacy of bilateral risk reducing surgery in unaffected female and carriers. 2021;0:1-8.To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/earlier-decisions-breast-ovarian-surgery-reduce-risk-cancer/. 10.1136/bmj.o258
    Biodegradable Nanoprobe for NIR-II Fluorescence Image-Guided Surgery and Enhanced Breast Cancer Radiotherapy Efficacy. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Positive resection margin frequently exists in breast-conserving treatment (BCT) of early-stage breast cancer, and insufficient therapeutic efficacy is common during radiotherapy (RT) in advanced breast cancer patients. Moreover, a multimodal nanotherapy platform is urgently required for precision cancer medicine. Therefore, a biodegradable cyclic RGD pentapeptide/hollow virus-like gadolinium (Gd)-based indocyanine green (R&HV-Gd@ICG) nanoprobe is developed to improve fluorescence image-guided surgery and breast cancer RT efficacy. R&HV-Gd exhibits remarkably improved aqueous stability, tumor retention, and target specificity of ICG, and achieves outstanding magnetic resonance/second near-infrared (NIR-II) window multimodal imaging in vivo. The nanoprobe-based NIR-II fluorescence image guidance facilitates complete tumor resection, improves the overall mouse survival rate, and effectively discriminates between benign and malignant breast tissues in spontaneous breast cancer transgenic mice (area under the curve = 0.978; 95% confidence interval: 0.952, 1.0). Moreover, introducing the nanoprobe to tumors generated more reactive oxygen species under X-ray irradiation, improved RT sensitivity, and reduced mouse tumor progression. Notably, the nanoprobe is biodegradable in vivo and exhibits accelerated bodily clearance, which is expected to reduce the potential long-term inorganic nanoparticle toxicity. Overall, the nanoprobe provides a basis for developing precision breast cancer treatment strategies. 10.1002/advs.202104728
    Mortality After Late Breast Cancer Recurrence in Denmark. Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:Late breast cancer (BC) recurrence (ie, ≥ 10 years after primary diagnosis) may have a more favorable prognosis than earlier recurrence. We investigated the risk of BC death after late recurrence, identified prognostic factors, and compared survival after early and late recurrence. METHODS:Using the Danish Breast Cancer Group and other nationwide databases, we identified women with early or late BC recurrence during 2004-2018, who were alive 6 months after recurrence. We followed them until BC death, death from other causes, emigration, 10 years, or December 31, 2018, whichever came first. We calculated mortality rates (MRs) per 1,000 person-years (PY) and cumulative BC mortality, for early versus late recurrence, and by characteristics of the primary tumor and the late recurrence. Using Cox regression, we calculated adjusted hazard ratios (HRs) for BC death, accounting for death from other causes as competing risks. RESULTS:Among 2,004 patients with late recurrence, 721 died of BC with a median survival time of 10 years (MR = 84.8 per 1,000 PY; 10-year cumulative mortality = 50%). Among 1,528 patients with early recurrence, 1,092 BC deaths occurred with a median survival time of 4 years (MR = 173.9 per 1,000 PY; 10-year cumulative mortality = 72%). We observed a lower hazard of BC-specific death among patients who developed late compared with early recurrence (hazard ratio = 0.72; 95% CI, 0.62 to 0.85). Advanced stage at primary diagnosis, distant metastases, adjuvant treatment for locoregional recurrence, and systemic treatment for distant recurrence were associated with increased mortality after late recurrence. Breast-conserving surgery at primary diagnosis, locoregional recurrence, and surgery for recurrence were associated with lower mortality after late recurrence. CONCLUSION:Patients with late recurrence had more favorable prognosis than patients with early recurrence. The localization of recurrent disease was the main prognostic factor for BC death. 10.1200/JCO.21.02062
    Mapping Systematic Reviews of Breast Cancer Survivorship Interventions: A Network Analysis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:Despite a large volume of research, breast cancer survivors continue to experience high levels of unmet need. To better understand the breadth of evidence, we mapped systematic review-level evidence across cancer survivorship domains and outcomes and conducted network analyses of breast cancer survivorship care interventions. METHODS:Umbrella review methodology was used to identify published systematic reviews reporting on survivorship care interventions for breast cancer survivors. Included reviews were mapped against domains and health care outcomes as specified by the Cancer Survivorship Quality Framework, and network analyses were conducted to determine the extent of clustering of reviews, and connectivity across domains and outcomes. RESULTS:Of 323 included reviews, most focused on management of physical (71.5%) or psychologic (65.3%) effects, health-related quality of life (55.1%), and physical activity (45.2%). Few focused on financial/employment effects, chronic conditions, health care delivery domains, or health service use or cost outcomes. Network analysis indicated 38.6% of reviews were connected to a single domain, 35.0% to two domains, and 16.5% to three domains, indicating a relatively siloed nature of research, with greater community clustering between health care delivery domains but limited connection between these and the other domains. Reviews published between 2011 and 2021 were more likely to examine financial toxicity and chronic conditions, but these domains remained under-represented compared with physical and psychologic effects. CONCLUSION:Despite vast volume of breast cancer survivorship intervention research, systematic review-level research is unevenly distributed, siloed, and with significant gaps in key domains and outcomes. Assessment of evidence gaps in primary research and strategic planning of future research, in consultation with survivors, is needed. 10.1200/JCO.21.02015
    Proteomic analysis of archival breast cancer clinical specimens identifies biological subtypes with distinct survival outcomes. Asleh Karama,Negri Gian Luca,Spencer Miko Sandra E,Colborne Shane,Hughes Christopher S,Wang Xiu Q,Gao Dongxia,Gilks C Blake,Chia Stephen K L,Nielsen Torsten O,Morin Gregg B Nature communications Despite advances in genomic classification of breast cancer, current clinical tests and treatment decisions are commonly based on protein level information. Formalin-fixed paraffin-embedded (FFPE) tissue specimens with extended clinical outcomes are widely available. Here, we perform comprehensive proteomic profiling of 300 FFPE breast cancer surgical specimens, 75 of each PAM50 subtype, from patients diagnosed in 2008-2013 (n = 178) and 1986-1992 (n = 122) with linked clinical outcomes. These two cohorts are analyzed separately, and we quantify 4214 proteins across all 300 samples. Within the aggressive PAM50-classified basal-like cases, proteomic profiling reveals two groups with one having characteristic immune hot expression features and highly favorable survival. Her2-Enriched cases separate into heterogeneous groups differing by extracellular matrix, lipid metabolism, and immune-response features. Within 88 triple-negative breast cancers, four proteomic clusters display features of basal-immune hot, basal-immune cold, mesenchymal, and luminal with disparate survival outcomes. Our proteomic analysis characterizes the heterogeneity of breast cancer in a clinically-applicable manner, identifies potential biomarkers and therapeutic targets, and provides a resource for clinical breast cancer classification. 10.1038/s41467-022-28524-0
    Assessment of Racial Disparity in Survival Outcomes for Early Hormone Receptor-Positive Breast Cancer After Adjusting for Insurance Status and Neighborhood Deprivation: A Post Hoc Analysis of a Randomized Clinical Trial. JAMA oncology IMPORTANCE:Racial disparities in survival outcomes among Black women with hormone receptor-positive breast cancer have been reported. However, the association between individual-level and neighborhood-level social determinants of health on such disparities has not been well studied. OBJECTIVE:To evaluate the association between race and clinical outcomes (ie, relapse-free interval and overall survival) adjusting for individual insurance coverage and neighborhood deprivation index (NDI), measured using zip code of residence, in women with breast cancer. DESIGN, SETTING, AND PARTICIPANTS:This was a post hoc analysis of 9719 women with breast cancer in the Trial Assigning Individualized Options for Treatment, a randomized clinical trial conducted from April 7, 2006, to October 6, 2010. All participants received a diagnosis of hormone receptor-positive, ERBB2-negative, axillary node-negative breast cancer. The present data analysis was conducted from April 1 to October 22, 2021. MAIN OUTCOMES AND MEASURES:A multivariate model was developed to evaluate the association between race and relapse-free interval and overall survival adjusting for insurance and NDI level at study entry, early discontinuation of endocrine therapy 4 years after initiation, and clinicopathologic characteristics of cancer. Median follow-up for clinical outcomes was 96 months. RESULTS:A total of 9719 women (4.2% [n = 405] Asian; 7.1% [n = 693] Black; 84.3% [n = 8189] White; 4.4% [n = 403] others/not specified) were included; 9.1% of included women [n = 889] were Hispanic or Latino. Median (SD) age was 56 (9.2) years. In multivariate models, Black race compared with White race was associated with statistically significant shorter relapse-free interval (hazard ratio [HR], 1.39; 95% CI, 1.05-1.84; P = .02) and overall survival (HR, 1.49; 95% CI, 1.10-2.99; P = .009), adjusting for insurance and NDI level at study entry and other factors. Although uninsured status was not associated with clinical outcomes, patients with Medicare (HR, 1.30; 95% CI, 1.01-1.68; P = .04) and Medicaid (HR, 1.44; 95% CI, 1.01-2.05; P = .05) had shorter overall survival compared with those with private insurance. Participants living in neighborhoods in the highest NDI quartile experienced shorter overall survival compared with those in the lowest quartile (HR, 1.34; 95% CI, 1.01-1.77; P = .04), regardless of self-identified race. CONCLUSIONS AND RELEVANCE:The findings of this post hoc analysis of a randomized clinical trial suggest that Black women with breast cancer have significantly shorter relapse-free interval and overall survival compared with White women. Early discontinuation of endocrine therapy, clinicopathologic characteristics, insurance coverage, and NDI do not fully explain the observed disparity. TRIAL REGISTRATION:ClinicalTrials.gov Identifier: NCT00310180. 10.1001/jamaoncol.2021.7656
    Breast Cancer Screening Strategies for Women With ATM, CHEK2, and PALB2 Pathogenic Variants: A Comparative Modeling Analysis. JAMA oncology IMPORTANCE:Screening mammography and magnetic resonance imaging (MRI) are recommended for women with ATM, CHEK2, and PALB2 pathogenic variants. However, there are few data to guide screening regimens for these women. OBJECTIVE:To estimate the benefits and harms of breast cancer screening strategies using mammography and MRI at various start ages for women with ATM, CHEK2, and PALB2 pathogenic variants. DESIGN, SETTING, AND PARTICIPANTS:This comparative modeling analysis used 2 established breast cancer microsimulation models from the Cancer Intervention and Surveillance Modeling Network (CISNET) to evaluate different screening strategies. Age-specific breast cancer risks were estimated using aggregated data from the Cancer Risk Estimates Related to Susceptibility (CARRIERS) Consortium for 32 247 cases and 32 544 controls in 12 population-based studies. Data on screening performance for mammography and MRI were estimated from published literature. The models simulated US women with ATM, CHEK2, or PALB2 pathogenic variants born in 1985. INTERVENTIONS:Screening strategies with combinations of annual mammography alone and with MRI starting at age 25, 30, 35, or 40 years until age 74 years. MAIN OUTCOMES AND MEASURES:Estimated lifetime breast cancer mortality reduction, life-years gained, breast cancer deaths averted, total screening examinations, false-positive screenings, and benign biopsies per 1000 women screened. Results are reported as model mean values and ranges. RESULTS:The mean model-estimated lifetime breast cancer risk was 20.9% (18.1%-23.7%) for women with ATM pathogenic variants, 27.6% (23.4%-31.7%) for women with CHEK2 pathogenic variants, and 39.5% (35.6%-43.3%) for women with PALB2 pathogenic variants. Across pathogenic variants, annual mammography alone from 40 to 74 years was estimated to reduce breast cancer mortality by 36.4% (34.6%-38.2%) to 38.5% (37.8%-39.2%) compared with no screening. Screening with annual MRI starting at 35 years followed by annual mammography and MRI at 40 years was estimated to reduce breast cancer mortality by 54.4% (54.2%-54.7%) to 57.6% (57.2%-58.0%), with 4661 (4635-4688) to 5001 (4979-5023) false-positive screenings and 1280 (1272-1287) to 1368 (1362-1374) benign biopsies per 1000 women. Annual MRI starting at 30 years followed by mammography and MRI at 40 years was estimated to reduce mortality by 55.4% (55.3%-55.4%) to 59.5% (58.5%-60.4%), with 5075 (5057-5093) to 5415 (5393-5437) false-positive screenings and 1439 (1429-1449) to 1528 (1517-1538) benign biopsies per 1000 women. When starting MRI at 30 years, initiating annual mammography starting at 30 vs 40 years did not meaningfully reduce mean mortality rates (0.1% [0.1%-0.2%] to 0.3% [0.2%-0.3%]) but was estimated to add 649 (602-695) to 650 (603-696) false-positive screenings and 58 (41-76) to 59 (41-76) benign biopsies per 1000 women. CONCLUSIONS AND RELEVANCE:This analysis suggests that annual MRI screening starting at 30 to 35 years followed by annual MRI and mammography at 40 years may reduce breast cancer mortality by more than 50% for women with ATM, CHEK2, and PALB2 pathogenic variants. In the setting of MRI screening, mammography prior to 40 years may offer little additional benefit. 10.1001/jamaoncol.2021.6204
    YAP Dictates Mitochondrial Redox Homeostasis to Facilitate Obesity-Associated Breast Cancer Progression. Advanced science (Weinheim, Baden-Wurttemberg, Germany) Dysregulation of hormones is considered a risk factor for obesity-mediated breast tumorigenesis; however, obesity is associated with poor outcomes among women diagnosed with triple-negative breast cancer (TNBC), which is a hormone-independent breast cancer subtype. Thus, identifying the driving force behind the obesity-breast cancer relationship is an urgent need. Here it is identified that diet-induced obesity (DIO) facilitates tumorigenesis of TNBC cells. Mechanistically, DIO induces a metabolic addiction to fatty acid oxidation (FAO), accompanied by coordinated activation of Yes-associated protein (YAP) signaling. Specifically, YAP governs mitochondrial redox homeostasis via transcriptional regulation of antioxidant-related enzymes, which renders tumor cells capable of extenuating FAO-elicited mitochondrial oxidative stress. Moreover, adipocytes-derived fatty acids are identified to be responsible for enhancing the FAO-YAP axis and antioxidative capacity, and higher expression of an obesity signature in breast cancer patients is positively correlated with YAP signaling and antioxidant genes. The findings uncover the crucial role of YAP in dictating mitochondrial redox homeostasis for obesity-mediated metabolic adaptation and breast tumor progression. 10.1002/advs.202103687
    Pathologic complete response (pCR) to neoadjuvant treatment with or without atezolizumab in triple-negative, early high-risk and locally advanced breast cancer: NeoTRIP Michelangelo randomized study. Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:High-risk triple-negative breast cancers (TNBCs) are characterized by poor prognosis, rapid progression to metastatic stage and onset of resistance to chemotherapy, thus representing an area in need of new therapeutic approaches. Programmed death-ligand 1 (PD-L1) expression is an adaptive mechanism of tumour resistance to tumour-infiltrating lymphocytes, which in turn are needed for response to chemotherapy. Overall, available data support the concept that blockade of PD-L1/programmed cell death protein 1 checkpoint may improve efficacy of classical chemotherapy. PATIENTS AND METHODS:Two hundred and eighty patients with TNBC were enrolled in this multicentre study (NCT002620280) and randomized to neoadjuvant carboplatin area under the curve 2 and nab-paclitaxel 125 mg/m intravenously (i.v.) on days 1 and 8, without (n = 142) or with (n = 138) atezolizumab 1200 mg i.v. on day 1. Both regimens were given q3 weeks for eight cycles before surgery followed by four cycles of an adjuvant anthracycline regimen. The primary aim of the study was to compare event-free survival (EFS), and an important secondary aim was the rate of pathological complete response (pCR defined as the absence of invasive cells in breast and lymph nodes). The primary population for all efficacy endpoints is the intention-to-treat (ITT) population. RESULTS:The ITT analysis revealed that pCR rate after treatment with atezolizumab (48.6%) did not reach statistical significance compared to no atezolizumab [44.4%: odds ratio (OR) 1.18; 95% confidence interval 0.74-1.89; P = 0.48]. Treatment-related adverse events were similar with either regimen except for a significantly higher overall incidence of serious adverse events and liver transaminase abnormalities with atezolizumab. CONCLUSIONS:The addition of atezolizumab to nab-paclitaxel and carboplatin did not significantly increase the rate of pCR in women with TNBC. In multivariate analysis, the presence of PD-L1 expression was the most significant factor influencing the rate of pCR (OR 2.08). Continuing follow-up for the EFS is ongoing, and molecular studies are under way. 10.1016/j.annonc.2022.02.004
    IAEA and Brazilian Navy to provide new arsenal to fight breast cancer: mammography on a ship. The Lancet. Oncology 10.1016/S1470-2045(22)00093-6
    The Lancet Breast Cancer Commission: tackling a global health, gender, and equity challenge. Coles Charlotte Elizabeth,Anderson Benjamin O,Cameron David,Cardoso Fatima,Horton Richard,Knaul Felicia Marie,Mutebi Miriam,Lee Naomi, Lancet (London, England) 10.1016/S0140-6736(22)00184-2
    Systematic review of Mendelian randomization studies on risk of cancer. Markozannes Georgios,Kanellopoulou Afroditi,Dimopoulou Olympia,Kosmidis Dimitrios,Zhang Xiaomeng,Wang Lijuan,Theodoratou Evropi,Gill Dipender,Burgess Stephen,Tsilidis Konstantinos K BMC medicine BACKGROUND:We aimed to map and describe the current state of Mendelian randomization (MR) literature on cancer risk and to identify associations supported by robust evidence. METHODS:We searched PubMed and Scopus up to 06/10/2020 for MR studies investigating the association of any genetically predicted risk factor with cancer risk. We categorized the reported associations based on a priori designed levels of evidence supporting a causal association into four categories, namely robust, probable, suggestive, and insufficient, based on the significance and concordance of the main MR analysis results and at least one of the MR-Egger, weighed median, MRPRESSO, and multivariable MR analyses. Associations not presenting any of the aforementioned sensitivity analyses were not graded. RESULTS:We included 190 publications reporting on 4667 MR analyses. Most analyses (3200; 68.6%) were not accompanied by any of the assessed sensitivity analyses. Of the 1467 evaluable analyses, 87 (5.9%) were supported by robust, 275 (18.7%) by probable, and 89 (6.1%) by suggestive evidence. The most prominent robust associations were observed for anthropometric indices with risk of breast, kidney, and endometrial cancers; circulating telomere length with risk of kidney, lung, osteosarcoma, skin, thyroid, and hematological cancers; sex steroid hormones and risk of breast and endometrial cancer; and lipids with risk of breast, endometrial, and ovarian cancer. CONCLUSIONS:Despite the large amount of research on genetically predicted risk factors for cancer risk, limited associations are supported by robust evidence for causality. Most associations did not present a MR sensitivity analysis and were thus non-evaluable. Future research should focus on more thorough assessment of sensitivity MR analyses and on more transparent reporting. 10.1186/s12916-022-02246-y
    Clinical Evidence of Chemotherapy or Endocrine Therapy Maintenance in Patients with Metastatic Breast Cancer: Meta-analysis from Randomized Clinical Trials and Propensity Score Matching of Multicentre Cohort Study. Cancer research and treatment PURPOSE:This study aims to comprehensively evaluate the clinical efficacy of chemotherapy or endocrine therapy maintenance in metastatic breast cancer (MBC) patients. MATERIALS AND METHODS:The meta-analysis of randomized clinical trials (RCTs) and propensity score matching of multicentre cohort study evaluated MBC patients who underwent first-line chemotherapy or endocrine therapy maintenance. This study is registered with PROSPERO: CRD42017071858, and ClinicalTrials.gov: NCT04258163. RESULTS:A total of 2,867 patients from 15 RCTs and 760 patients from multicentre cohort were included. The results from meta-analysis showed that chemotherapy maintenance improved progression-free survival (PFS) (hazard ratio [HR], 0.63; 95% confidence interval (CI) 0.54-0.73; p < 0.010; moderate-quality evidence) and overall survival (OS) (HR, 0.87; 95% CI 0.78-0.97; p=0.016; high-quality evidence) than observation. In the cohort study, for hormone receptor (HR)-positive MBC patients, chemotherapy maintenance improved PFS (HR, 0.67; 95% CI 0.52-0.85; p < 0.001) and OS (HR, 0.55; 95% CI 0.42-0.73; p < 0.001) compared with observation, and endocrine therapy maintenance also improved PFS (HR, 0.65; 95% CI 0.53-0.80; p < 0.001) and OS (HR, 0.55; 95% CI 0.44-0.69; p < 0.001). There were no differences between chemotherapy and endocrine therapy maintenance in PFS and OS (All p > 0.05). Regardless of the continuum or switch maintenance therapy, showed prolonged survival in MBC patients who were response to first-line treatment. CONCLUSION:This study provided evidences for survival benefits of chemotherapy and endocrine therapy maintenance in MBC patients, and there were no difference efficacy between chemotherapy and endocrine therapy maintenance for HR-positive patients. 10.4143/crt.2021.698
    Uptake of Recommendations for Posttreatment Cancer-Related Fatigue Among Breast Cancer Survivors. Di Meglio Antonio,Charles Cecile,Martin Elise,Havas Julie,Gbenou Arnauld,Flaysakier Jean-Daniel,Martin Anne-Laure,Everhard Sibille,Laas Enora,Chopin Nicolas,Vanlemmens Laurence,Jouannaud Christelle,Levy Christelle,Rigal Olivier,Fournier Marion,Soulie Patrick,Scotte Florian,Pistilli Barbara,Dumas Agnes,Menvielle Gwenn,André Fabrice,Michiels Stefan,Dauchy Sarah,Vaz-Luis Ines Journal of the National Comprehensive Cancer Network : JNCCN BACKGROUND:Physical activity (PA) and psychosocial interventions are recommended management strategies for cancer-related fatigue (CRF). Randomized trials support the use of mind-body techniques, whereas no data show benefit for homeopathy or naturopathy. METHODS:We used data from CANTO (ClinicalTrials.gov identifier: NCT01993498), a multicenter, prospective study of stage I-III breast cancer (BC). CRF, evaluated after primary treatment completion using the EORTC QLQ-C30 (global CRF) and QLQ-FA12 (physical, emotional, and cognitive dimensions), served as the independent variable (severe [score of ≥40/100] vs nonsevere). Outcomes of interest were adherence to PA recommendations (≥10 metabolic equivalent of task [MET] h/week [GPAQ-16]) and participation in consultations with a psychologist, psychiatrist, acupuncturist, or other complementary and alternative medicine (CAM) practitioner (homeopath and/or naturopath) after CRF assessment. Multivariable logistic regression examined associations between CRF and outcomes, adjusting for sociodemographic, psychologic, tumor, and treatment characteristics. RESULTS:Among 7,902 women diagnosed from 2012 through 2017, 36.4% reported severe global CRF, and 35.8%, 22.6%, and 14.1% reported severe physical, emotional, and cognitive CRF, respectively. Patients reporting severe global CRF were less likely to adhere to PA recommendations (60.4% vs 66.7%; adjusted odds ratio [aOR], 0.82; 95% CI, 0.71-0.94; P=.004), and slightly more likely to see a psychologist (13.8% vs 7.5%; aOR, 1.29; 95% CI, 1.05-1.58; P=.014), psychiatrist (10.4% vs 5.0%; aOR, 1.39; 95% CI, 1.10-1.76; P=.0064), acupuncturist (9.8% vs 6.5%; aOR, 1.46; 95% CI, 1.17-1.82; P=.0008), or CAM practitioner (12.5% vs 8.2%; aOR, 1.49; 95% CI, 1.23-1.82; P<.0001). There were differences in recommendation uptake by CRF dimension, including that severe physical CRF was associated with lower adherence to PA (aOR, 0.74; 95% CI, 0.63-0.86; P=.0001) and severe emotional CRF was associated with higher likelihood of psychologic consultations (aOR, 1.37; 95% CI, 1.06-1.79; P=.017). CONCLUSIONS:Uptake of recommendations to improve CRF, including adequate PA and use of psychosocial services, seemed suboptimal among patients with early-stage BC, whereas there was a nonnegligible interest in homeopathy and naturopathy. Findings of this large study indicate the need to implement recommendations for managing CRF in clinical practice. 10.6004/jnccn.2021.7051
    Randomized Trial of a Palliative Care Intervention to Improve End-of-Life Care Discussions in Patients With Metastatic Breast Cancer. Greer Joseph A,Moy Beverly,El-Jawahri Areej,Jackson Vicki A,Kamdar Mihir,Jacobsen Juliet,Lindvall Charlotta,Shin Jennifer A,Rinaldi Simone,Carlson Heather A,Sousa Angela,Gallagher Emily R,Li Zhigang,Moran Samantha,Ruddy Magaret,Anand Maya V,Carp Julia E,Temel Jennifer S Journal of the National Comprehensive Cancer Network : JNCCN BACKGROUND:Studies show that early, integrated palliative care (PC) improves quality of life (QoL) and end-of-life (EoL) care for patients with poor-prognosis cancers. However, the optimal strategy for delivering PC for those with advanced cancers who have longer disease trajectories, such as metastatic breast cancer (MBC), remains unknown. We tested the effect of a PC intervention on the documentation of EoL care discussions, patient-reported outcomes, and hospice utilization in this population. PATIENTS AND METHODS:Patients with MBC and clinical indicators of poor prognosis (n=120) were randomly assigned to receive an outpatient PC intervention (n=61) or usual care (n=59) between May 2, 2016, and December 26, 2018, at an academic cancer center. The intervention entailed 5 structured PC visits focusing on symptom management, coping, prognostic awareness, decision-making, and EoL planning. The primary outcome was documentation of EoL care discussions in the electronic health record (EHR). Secondary outcomes included patient-report of discussions with clinicians about EoL care, QoL, and mood symptoms at 6, 12, 18, and 24 weeks after baseline and hospice utilization. RESULTS:The rate of EoL care discussions documented in the EHR was higher among intervention patients versus those receiving usual care (67.2% vs 40.7%; P=.006), including a higher completion rate of a Medical Orders for Life-Sustaining Treatment form (39.3% vs 13.6%; P=.002). Intervention patients were also more likely to report discussing their EoL care wishes with their doctor (odds ratio [OR], 3.10; 95% CI, 1.21-7.94; P=.019) and to receive hospice services (OR, 4.03; 95% CI, 1.10-14.73; P=.035) compared with usual care patients. Study groups did not differ in patient-reported QoL or mood symptoms. CONCLUSIONS:This PC intervention significantly improved rates of discussion and documentation regarding EoL care and delivery of hospice services among patients with MBC, demonstrating that PC can be tailored to address the supportive care needs of patients with longer disease trajectories. ClinicalTrials.gov identifier: NCT02730858. 10.6004/jnccn.2021.7040
    Early and Integrated Palliative Care as Valuable Support in Patients With Metastatic Breast Cancer. Rohani Camelia Journal of the National Comprehensive Cancer Network : JNCCN 10.6004/jnccn.2022.7005
    Breast Cancers Are Immunogenic: Immunologic Analyses and a Phase II Pilot Clinical Trial Using Mutation-Reactive Autologous Lymphocytes. Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:Metastatic breast cancer (mBrCa) is most often an incurable disease with only modest responses to available immunotherapies. This study investigates the immunogenicity of somatic mutations in breast cancer and explores the therapeutic efficacy in a pilot trial of mutation-reactive tumor-infiltrating lymphocytes (TILs) in patients with metastatic disease. PATIENTS AND METHODS:Forty-two patients with mBrCa refractory to previous lines of treatment underwent surgical resection of a metastatic lesion(s), isolation of TIL cultures, identification of exomic nonsynonymous tumor mutations, and immunologic screening for neoantigen reactivity. Clinically eligible patients with appropriate reactivity were enrolled into one cohort of an ongoing phase II pilot trial of adoptive cell transfer of selected neoantigen-reactive TIL, with a short course of pembrolizumab (ClinicalTrials.gov identifier: NCT01174121). RESULTS:TILs were isolated and grown in culture from the resected lesions of all 42 patients with mBrCa, and a median number of 112 (range: 6-563) nonsynonymous mutations per patient were identified. Twenty-eight of 42 (67%) patients contained TIL that recognized at least one immunogenic somatic mutation (median: 3 neoantigens per patient, range: 1-11), and 13 patients demonstrated robust reactivity appropriate for adoptive transfer. Eight patients remained clinically eligible for treatment, and six patients were enrolled on a protocol of adoptive cell transfer of enriched neoantigen-specific TIL, in combination with pembrolizumab (≤ 4 doses). Objective tumor regression was noted in three patients, including one complete response (now ongoing over 5.5 years) and two partial responses (6 and 10 months). CONCLUSION:Most patients with breast cancer generated a natural immune response targeting the expressed products of their cancer mutations. Adoptive transfer of TIL is a highly personalized experimental option for patients with mBrCa shown to be capable of mediating objective responses in this pilot trial and deserves further study. 10.1200/JCO.21.02170
    The WID-BC-index identifies women with primary poor prognostic breast cancer based on DNA methylation in cervical samples. Nature communications Genetic and non-genetic factors contribute to breast cancer development. An epigenome-based signature capturing these components in easily accessible samples could identify women at risk. Here, we analyse the DNA methylome in 2,818 cervical, 357 and 227 matched buccal and blood samples respectively, and 42 breast tissue samples from women with and without breast cancer. Utilising cervical liquid-based cytology samples, we develop the DNA methylation-based Women's risk IDentification for Breast Cancer index (WID-BC-index) that identifies women with breast cancer with an AUROC (Area Under the Receiver Operator Characteristic) of 0.84 (95% CI: 0.80-0.88) and 0.81 (95% CI: 0.76-0.86) in internal and external validation sets, respectively. CpGs at progesterone receptor binding sites hypomethylated in normal breast tissue of women with breast cancer or in BRCA mutation carriers are also hypomethylated in cervical samples of women with poor prognostic breast cancer. Our data indicate that a systemic epigenetic programming defect is highly prevalent in women who develop breast cancer. Further studies validating the WID-BC-index may enable clinical implementation for monitoring breast cancer risk. 10.1038/s41467-021-27918-w
    Comprehensive metabolomics expands precision medicine for triple-negative breast cancer. Cell research Metabolic reprogramming is a hallmark of cancer. However, systematic characterizations of metabolites in triple-negative breast cancer (TNBC) are still lacking. Our study profiled the polar metabolome and lipidome in 330 TNBC samples and 149 paired normal breast tissues to construct a large metabolomic atlas of TNBC. Combining with previously established transcriptomic and genomic data of the same cohort, we conducted a comprehensive analysis linking TNBC metabolome to genomics. Our study classified TNBCs into three distinct metabolomic subgroups: C1, characterized by the enrichment of ceramides and fatty acids; C2, featured with the upregulation of metabolites related to oxidation reaction and glycosyl transfer; and C3, having the lowest level of metabolic dysregulation. Based on this newly developed metabolomic dataset, we refined previous TNBC transcriptomic subtypes and identified some crucial subtype-specific metabolites as potential therapeutic targets. The transcriptomic luminal androgen receptor (LAR) subtype overlapped with metabolomic C1 subtype. Experiments on patient-derived organoid and xenograft models indicate that targeting sphingosine-1-phosphate (S1P), an intermediate of the ceramide pathway, is a promising therapy for LAR tumors. Moreover, the transcriptomic basal-like immune-suppressed (BLIS) subtype contained two prognostic metabolomic subgroups (C2 and C3), which could be distinguished through machine-learning methods. We show that N-acetyl-aspartyl-glutamate is a crucial tumor-promoting metabolite and potential therapeutic target for high-risk BLIS tumors. Together, our study reveals the clinical significance of TNBC metabolomics, which can not only optimize the transcriptomic subtyping system, but also suggest novel therapeutic targets. This metabolomic dataset can serve as a useful public resource to promote precision treatment of TNBC. 10.1038/s41422-022-00614-0
    Intelligent Vacuum-Assisted Biopsy to Identify Breast Cancer Patients With Pathologic Complete Response (ypT0 and ypN0) After Neoadjuvant Systemic Treatment for Omission of Breast and Axillary Surgery. Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:Neoadjuvant systemic treatment (NST) elicits a pathologic complete response in 40%-70% of women with breast cancer. These patients may not need surgery as all local tumor has already been eradicated by NST. However, nonsurgical approaches, including imaging or vacuum-assisted biopsy (VAB), were not able to accurately identify patients without residual cancer in the breast or axilla. We evaluated the feasibility of a machine learning algorithm (intelligent VAB) to identify exceptional responders to NST. METHODS:We trained, tested, and validated a machine learning algorithm using patient, imaging, tumor, and VAB variables to detect residual cancer after NST (ypT+ or in situ or ypN+) before surgery. We used data from 318 women with cT1-3, cN0 or +, human epidermal growth factor receptor 2-positive, triple-negative, or high-proliferative Luminal B-like breast cancer who underwent VAB before surgery (ClinicalTrials.gov identifier: NCT02948764, RESPONDER trial). We used 10-fold cross-validation to train and test the algorithm, which was then externally validated using data of an independent trial (ClinicalTrials.gov identifier: NCT02575612). We compared findings with the histopathologic evaluation of the surgical specimen. We considered false-negative rate (FNR) and specificity to be the main outcomes. RESULTS:In the development set (n = 318) and external validation set (n = 45), the intelligent VAB showed an FNR of 0.0%-5.2%, a specificity of 37.5%-40.0%, and an area under the receiver operating characteristic curve of 0.91-0.92 to detect residual cancer (ypT+ or in situ or ypN+) after NST. Spiegelhalter's Z confirmed a well-calibrated model ( score -0.746, = .228). FNR of the intelligent VAB was lower compared with imaging after NST, VAB alone, or combinations of both. CONCLUSION:An intelligent VAB algorithm can reliably exclude residual cancer after NST. The omission of breast and axillary surgery for these exceptional responders may be evaluated in future trials. 10.1200/JCO.21.02439
    Prophylactic Use of Compression Sleeves Reduces the Incidence of Arm Swelling in Women at High Risk of Breast Cancer-Related Lymphedema: A Randomized Controlled Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:To determine whether prophylactic use of compression sleeves prevents arm swelling in women who had undergone axillary lymph node dissection for breast cancer surgery. METHODS:Women (n = 307) were randomly assigned to either a compression or control group. In addition to usual postoperative care, the compression group received two compression sleeves to wear postoperatively until 3 months after completing adjuvant treatments. Arm swelling was determined using bioimpedance spectroscopy (BIS) thresholds and relative arm volume increase (RAVI). Incidence and time free from arm swelling were compared using Kaplan-Meier analyses. Hazard ratios (HRs) were estimated from Cox regression models for BIS and RAVI thresholds independently. In addition, time to documentation of the first minimally important difference (MID) in four scales of the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30) and the breast cancer-specific (BR23) questionnaire was analyzed. RESULTS:The HR for developing arm swelling in the compression group relative to the control group was 0.61 (95% CI, 0.43 to 0.85; = .004) on the basis of BIS and 0.56 (95% CI, 0.33 to 0.96; = .034) on the basis of RAVI. The estimated cumulative incidence of arm swelling at 1 year was lower in the compression group than the control group on the basis of BIS (42% 52%) and RAVI (14% 25%). HRs for time from baseline to the first change of the minimally important difference were not statistically significant for any of the four scales of EORTC QLQ-30 and BR23 questionnaires. CONCLUSION:Prophylactic use of compression sleeves compared with the control group reduced and delayed the occurrence of arm swelling in women at high risk for lymphedema in the first year after surgery for breast cancer. 10.1200/JCO.21.02567
    CECR2 drives breast cancer metastasis by promoting NF-κB signaling and macrophage-mediated immune suppression. Science translational medicine Metastasis is the major cause of cancer-related deaths due to the lack of effective therapies. Emerging evidence suggests that certain epigenetic and transcriptional regulators drive cancer metastasis and could be targeted for metastasis treatment. To identify epigenetic regulators of breast cancer metastasis, we profiled the transcriptomes of matched pairs of primary breast tumors and metastases from human patients. We found that distant metastases are more immune inert with increased M2 macrophages compared to their matched primary tumors. The acetyl-lysine reader, cat eye syndrome chromosome region candidate 2 (CECR2), was the top up-regulated epigenetic regulator in metastases associated with an increased abundance of M2 macrophages and worse metastasis-free survival. CECR2 was required for breast cancer metastasis in multiple mouse models, with more profound effect in the immunocompetent setting. Mechanistically, the nuclear factor κB (NF-κB) family member v-rel avian reticuloendotheliosis viral oncogene homolog A (RELA) recruits CECR2 to increase chromatin accessibility and activate the expression of their target genes. These target genes include multiple metastasis-promoting genes, such as , , and , and cytokine genes and , which are critical for immunosuppression at metastatic sites. Consistent with these results, pharmacological inhibition of CECR2 bromodomain impeded NF-κB-mediated immune suppression by macrophages and inhibited breast cancer metastasis. These results reveal that targeting CECR2 may be a strategy to treat metastatic breast cancer. 10.1126/scitranslmed.abf5473
    Primary tumor associated macrophages activate programs of invasion and dormancy in disseminating tumor cells. Nature communications Metastases are initiated by disseminated tumor cells (DTCs) that colonize distant organs. Growing evidence suggests that the microenvironment of the primary tumor primes DTCs for dormant or proliferative fates. However, the manner in which this occurs remains poorly understood. Here, using the Window for High-Resolution Intravital Imaging of the Lung (WHRIL), we study the live lung longitudinally and follow the fate of individual DTCs that spontaneously disseminate from orthotopic breast tumors. We find that spontaneously DTCs have increased levels of retention, increased speed of extravasation, and greater survival after extravasation, compared to experimentally metastasized tumor cells. Detailed analysis reveals that a subset of macrophages within the primary tumor induces a pro-dissemination and pro-dormancy DTC phenotype. Our work provides insight into how specific primary tumor microenvironments prime a subpopulation of cells for expression of proteins associated with dissemination and dormancy. 10.1038/s41467-022-28076-3
    ERBB2-Low Breast Cancer-Is It a Fact or Fiction, and Do We Have the Right Assay? JAMA oncology 10.1001/jamaoncol.2021.7082
    Examination of Low ERBB2 Protein Expression in Breast Cancer Tissue. JAMA oncology IMPORTANCE:Trastuzumab deruxtecan (T-DXd) has shown efficacy in patients with breast cancer with ERBB2 immunohistochemistry (IHC) scores of 1+ or 2+ but not 0 as read in central pathology laboratories. The drug is currently being tested in large randomized clinical trials with registration intent for this patient population. OBJECTIVE:To determine the suitability of the current standard ERBB2 IHC assays to select patients with low ERBB2 positivity for treatment with T-DXd. DESIGN AND SETTING:Assessment of data from College of American Pathologists surveys and assessment of analytic data from a Yale University-based study of concordance of 18 pathologists reading 170 breast cancer biopsies. RESULTS:The total survey data set included scores over 2 years from 1391 to 1452 laboratories of 40 ERBB2 cores from each laboratory (20 cores twice a year for a total of 80). College of American Pathologists surveys show that 19% of cases read by the laboratories generate results with less than or equal to 70% concordance for IHC ERBB2 score 0 vs 1+. When 18 pathologists read the scanned slides from a selected set of breast cancer biopsies using a 4-point scale, there was only 26% concordance between 0 and 1+ compared with 58% concordance between 2+ and 3+. CONCLUSIONS AND RELEVANCE:In this study using a current standard ERBB2 IHC assay, the scoring accuracy for ERBB2 IHC in the low range (0 and 1+) was poor. This inaccuracy in the real world could lead to misassignment of many patients for treatment with T-DXd. 10.1001/jamaoncol.2021.7239
    Safety of adjuvant CDK4/6 inhibitors during the COVID-19 pandemic. Pfeiler Georg,DeMichele Angela,Dueck Amylou C,Fesl Christian,Gnant Michael,Mayer Erica L The Lancet. Oncology 10.1016/S1470-2045(21)00708-7
    MSF breast and cervical cancer screening programmes in Mali and Malawi. Devi Sharmila The Lancet. Oncology 10.1016/S1470-2045(22)00007-9
    Surgery No More? Managing the Primary Tumor in Stage IV Breast Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 10.1200/JCO.21.02706
    Regulation of Tumor Invasion by the Physical Microenvironment: Lessons from Breast and Brain Cancer. Annual review of biomedical engineering The success of anticancer therapies is often limited by heterogeneity within and between tumors. While much attention has been devoted to understanding the intrinsic molecular diversity of tumor cells, the surrounding tissue microenvironment is also highly complex and coevolves with tumor cells to drive clinical outcomes. Here, we propose that diverse types of solid tumors share common physical motifs that change in time and space, serving as universal regulators of malignancy. We use breast cancer and glioblastoma as instructive examples and highlight how invasion in both diseases is driven by the appropriation of structural guidance cues, contact-dependent heterotypic interactions with stromal cells, and elevated interstitial fluid pressure and flow. We discuss how engineering strategies show increasing value for measuring and modeling these physical propertiesfor mechanistic studies. Moreover, engineered systems offer great promise for developing and testing novel therapies that improve patient prognosis by normalizing the physical tumor microenvironment. 10.1146/annurev-bioeng-110220-115419
    New genomic technologies for multi-cancer early detection: Rethinking the scope of cancer screening. Hackshaw Allan,Clarke Christina A,Hartman Anne-Renee Cancer cell Cancers other than breast, colorectal, cervical, and lung do not have guideline-recommended screening. New multi-cancer early detection (MCED) tests-using a single blood sample-have been developed based on circulating cell-free DNA (cfDNA) or other analytes. In this commentary, we review the current evidence on these tests, provide several major considerations for new MCED tests, and outline how their evaluation will need to differ from that established for traditional single-cancer screening tests. 10.1016/j.ccell.2022.01.012
    Genomic characterization of metastatic patterns from prospective clinical sequencing of 25,000 patients. Cell Metastatic progression is the main cause of death in cancer patients, whereas the underlying genomic mechanisms driving metastasis remain largely unknown. Here, we assembled MSK-MET, a pan-cancer cohort of over 25,000 patients with metastatic diseases. By analyzing genomic and clinical data from this cohort, we identified associations between genomic alterations and patterns of metastatic dissemination across 50 tumor types. We found that chromosomal instability is strongly correlated with metastatic burden in some tumor types, including prostate adenocarcinoma, lung adenocarcinoma, and HR+/HER2+ breast ductal carcinoma, but not in others, including colorectal cancer and high-grade serous ovarian cancer, where copy-number alteration patterns may be established early in tumor development. We also identified somatic alterations associated with metastatic burden and specific target organs. Our data offer a valuable resource for the investigation of the biological basis for metastatic spread and highlight the complex role of chromosomal instability in cancer progression. 10.1016/j.cell.2022.01.003
    Aromatase inhibitors versus tamoxifen in premenopausal women with oestrogen receptor-positive early-stage breast cancer treated with ovarian suppression: a patient-level meta-analysis of 7030 women from four randomised trials. The Lancet. Oncology BACKGROUND:For women with early-stage oestrogen receptor (ER)-positive breast cancer, adjuvant tamoxifen reduces 15-year breast cancer mortality by a third. Aromatase inhibitors are more effective than tamoxifen in postmenopausal women but are ineffective in premenopausal women when used without ovarian suppression. We aimed to investigate whether premenopausal women treated with ovarian suppression benefit from aromatase inhibitors. METHODS:We did a meta-analysis of individual patient data from randomised trials comparing aromatase inhibitors (anastrozole, exemestane, or letrozole) versus tamoxifen for 3 or 5 years in premenopausal women with ER-positive breast cancer receiving ovarian suppression (goserelin or triptorelin) or ablation. We collected data on baseline characteristics, dates and sites of any breast cancer recurrence or second primary cancer, and dates and causes of death. Primary outcomes were breast cancer recurrence (distant, locoregional, or contralateral), breast cancer mortality, death without recurrence, and all-cause mortality. As distant recurrence invariably results in death from breast cancer several years after the occurrence, whereas locoregional recurrence and new contralateral breast cancer are not usually fatal, the distant recurrence analysis is shown separately. Standard intention-to-treat log-rank analyses estimated first-event rate ratios (RR) and their confidence intervals (CIs). FINDINGS:We obtained data from all four identified trials (ABCSG XII, SOFT, TEXT, and HOBOE trials), which included 7030 women with ER-positive tumours enrolled between June 17, 1999, and Aug 4, 2015. Median follow-up was 8·0 years (IQR 6·1-9·3). The rate of breast cancer recurrence was lower for women allocated to an aromatase inhibitor than for women assigned to tamoxifen (RR 0·79, 95% CI 0·69-0·90, p=0·0005). The main benefit was seen in years 0-4 (RR 0·68, 99% CI 0·55-0·85; p<0·0001), the period when treatments differed, with a 3·2% (95% CI 1·8-4·5) absolute reduction in 5-year recurrence risk (6·9% vs 10·1%). There was no further benefit, or loss of benefit, in years 5-9 (RR 0·98, 99% CI 0·73-1·33, p=0·89) or beyond year 10. Distant recurrence was reduced with aromatase inhibitor (RR 0·83, 95% CI 0·71-0·97; p=0·018). No significant differences were observed between treatments for breast cancer mortality (RR 1·01, 95% CI 0·82-1·24; p=0·94), death without recurrence (1·30, 0·75-2·25; p=0·34), or all-cause mortality (1·04, 0·86-1·27; p=0·68). There were more bone fractures with aromatase inhibitor than with tamoxifen (227 [6·4%] of 3528 women allocated to an aromatase inhibitor vs 180 [5·1%] of 3502 women allocated to tamoxifen; RR 1·27 [95% CI 1·04-1·54]; p=0·017). Non-breast cancer deaths (30 [0·9%] vs 24 [0·7%]; 1·30 [0·75-2·25]; p=0·36) and endometrial cancer (seven [0·2%] vs 15 [0·3%]; 0·52 [0·22-1·23]; p=0·14) were rare. INTERPRETATION:Using an aromatase inhibitor rather than tamoxifen in premenopausal women receiving ovarian suppression reduces the risk of breast cancer recurrence. Longer follow-up is needed to assess any impact on breast cancer mortality. FUNDING:Cancer Research UK, UK Medical Research Council. 10.1016/S1470-2045(21)00758-0
    Quantitative Detection of Aggregation Degree for Enhanced M2 Macrophage MR Imaging. Luo Lu-Jun,Liu Xiu-Mei,Zhang Xiao,Liu Jiao,Gao Yuanyuan,Sun Tong-Yi,Li Li-Li Nano letters self-assembly can be used in the enhanced diagnosis and therapy of major diseases such as cancer and bacterial infections on the basis of an assembly/aggregation-induced-retention (AIR) effect. However, the aggregation degree (α) is a significant parameter for determining the delivery efficiency to lesions in a complex physiological environment and a real-time quantitative calculation of the aggregation degree is still a great challenge. Here, we developed a magnetic resonance imaging (MRI) method for sensitive and quantitative calculation of α with a detection limit of 10 M and a bioactivated assembly (BIVA) magnetic resonance (MR) probe was optimized for enhanced -weighted MR imaging of M2 macrophages in tumors. Our MRI quantitative calculation method had a high fitting degree ( = 0.987) with the gold standard fluorescence (FL) method. On the basis of the BIVA mechanism of CD206 active targeting and cathepsin B specific tailoring to induce an nanofiber assembly, our optimized BIVA probe exhibited a high intracellular aggregation degree of over 70% and a high α value of over 55%. Finally, the aggregation-enhanced MR signal and the AIR effect both contributed to enhanced -weighted MR imaging of M2 macrophages in triple-negative breast cancer. We believe that our α real-time quantitative calculation method of MRI will help to further screen and optimize the enhanced imaging and treatment of the BIVA drug. 10.1021/acs.nanolett.1c04711