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    Screening for breast cancer brain metastases - Authors' reply. The Lancet. Oncology 10.1016/S1470-2045(22)00211-X
    Screening for breast cancer brain metastases. The Lancet. Oncology 10.1016/S1470-2045(22)00201-7
    Electronic Health Interventions for Patients With Breast Cancer: Systematic Review and Meta-Analyses. Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:Ongoing supportive care using electronic health (eHealth) interventions has the potential to provide remote support and improve health outcomes for patients with breast cancer. This study aimed to evaluate the effectiveness of eHealth interventions on patient-reported outcomes (quality of life [QOL], self-efficacy, and mental or physical health) for patients during and after breast cancer treatment and patient-reported experience measures (acceptability and engagement). METHODS:Systematic review with meta-analyses (random-effects model) of randomized controlled trials was conducted following Preferred Reporting Items for Systematic Reviews and Meta-Analysis guidelines. Nine databases were searched using a prespecified search strategy. Patient-directed eHealth interventions for adult patients during or after active breast cancer treatment measuring QOL, self-efficacy, and mental (depressive, anxiety, and distress symptoms) or physical (physical activity, nutrition, and fatigue) health outcomes were included. Data from eligible full-text articles were independently extracted by six observers. RESULTS:Thirty-two unique studies (4,790 patients) were included. All were health self-management interventions, and most were multicomponent (videos, forums, and electronic reminder systems) websites. Meta-analyses revealed a significant effect of eHealth interventions on QOL (standardized mean difference [SMD], 0.20 [95% CI, 0.03 to 0.36]), self-efficacy (SMD, 0.45 [95% CI, 0.24 to 0.65]), distress (SMD, -0.41 [95% CI,-0.63 to -0.20]), and fatigue (SMD, -0.37 [95% CI, -0.61 to -0.13]). Twenty-five studies (78.1%) measured patient-reported experience measures. Acceptability (n = 9) was high, with high ratings for satisfaction (range, 71%-100%), usefulness (range, 71%-95%), and ease-of-use (range, 73%-92%). Engagement (n = 25) decreased over time, but disease-focused information and interactive support were most engaging. CONCLUSION:eHealth interventions may provide an acceptable and effective strategy for improving QOL, distress, self-efficacy, and fatigue among patients with breast cancer. 10.1200/JCO.21.01171
    Pembrolizumab in Early Triple-Negative Breast Cancer. The New England journal of medicine 10.1056/NEJMc2203316
    Pembrolizumab in Early Triple-Negative Breast Cancer. Reply. The New England journal of medicine 10.1056/NEJMc2203316
    Albumin nanoparticle containing a PI3Kγ inhibitor and paclitaxel in combination with α-PD1 induces tumor remission of breast cancer in mice. Science translational medicine Immunomodulators that remodel the tumor immunosuppressive microenvironment have been combined with anti-programmed death 1 (α-PD1) or anti-programmed death ligand 1 (α-PDL1) immunotherapy but have shown limited success in clinical trials. However, therapeutic strategies to modulate the immunosuppressive microenvironment of lymph nodes have been largely overlooked. Here, we designed an albumin nanoparticle, Nano-PI, containing the immunomodulators PI3Kγ inhibitor (IPI-549) and paclitaxel (PTX). We treated two breast cancer mouse models with Nano-PI in combination with α-PD1, which remodeled the tumor microenvironment in both lymph nodes and tumors. This combination achieved long-term tumor remission in mouse models and eliminated lung metastases. PTX combined with IPI-549 enabled the formation of a stable nanoparticle and enhanced the repolarization of M2 to M1 macrophages. Nano-PI not only enhanced the delivery of both immunomodulators to lymph nodes and tumors but also improved the drug accumulation in the macrophages of these two tissues. Immune cell profiling revealed that the combination of Nano-PI with α-PD1 remodeled the immune microenvironment by polarizing M2 to M1 macrophages, increasing CD4 and CD8 T cells, B cells, and dendritic cells, decreasing regulatory T cells, and preventing T cell exhaustion. Our data suggest that Nano-PI in combination with α-PD1 modulates the immune microenvironment in both lymph nodes and tumors to achieve long-term remission in mice with metastatic breast cancer, and represents a promising candidate for future clinical trials. 10.1126/scitranslmed.abl3649
    Treatment Efficacy Score-continuous residual cancer burden-based metric to compare neoadjuvant chemotherapy efficacy between randomized trial arms in breast cancer trials. Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments. PATIENTS AND METHODS:The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test. RESULTS:In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival. CONCLUSIONS:TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone. 10.1016/j.annonc.2022.04.072
    Clinical and pathological features of breast cancer patients eligible for adjuvant abemaciclib. Annals of oncology : official journal of the European Society for Medical Oncology 10.1016/j.annonc.2022.04.069
    EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation. Nature communications Bone metastases occur in 50-70% of patients with late-stage breast cancers and effective therapies are needed. The expression of enhancer of zeste homolog 2 (EZH2) is correlated with breast cancer metastasis, but its function in bone metastasis hasn't been well-explored. Here we report that EZH2 promotes osteolytic metastasis of breast cancer through regulating transforming growth factor beta (TGFβ) signaling. EZH2 induces cancer cell proliferation and osteoclast maturation, whereas EZH2 knockdown decreases bone metastasis incidence and outgrowth in vivo. Mechanistically, EZH2 transcriptionally increases ITGB1, which encodes for integrin β1. Integrin β1 activates focal adhesion kinase (FAK), which phosphorylates TGFβ receptor type I (TGFβRI) at tyrosine 182 to enhance its binding to TGFβ receptor type II (TGFβRII), thereby activating TGFβ signaling. Clinically applicable FAK inhibitors but not EZH2 methyltransferase inhibitors effectively inhibit breast cancer bone metastasis in vivo. Overall, we find that the EZH2-integrin β1-FAK axis cooperates with the TGFβ signaling pathway to promote bone metastasis of breast cancer. 10.1038/s41467-022-30105-0
    A risk model for digital breast tomosynthesis to predict breast cancer and guide clinical care. Science translational medicine Screening with digital breast tomosynthesis (DBT) improves breast cancer detection and reduces false positives. However, currently, no breast cancer risk model takes advantage of the additional information generated by DBT imaging for breast cancer risk prediction. We developed and internally validated a DBT-based short-term risk model for predicting future late-stage and interval breast cancers after negative screening exams. We included the available 805 incident breast cancers and a random sample of 5173 healthy women matched on year of study entry in a nested case-control study from 154,200 multiethnic women, aged 35 to 74, attending DBT screening in the United States between 2014 and 2019. A relative risk model was trained using elastic net logistic regression and nested cross-validation to estimate risks for using imaging features and age. An absolute risk model was developed using derived risks and U.S. incidence and competing mortality rates. Absolute risks, discrimination performance, and risk stratification were estimated in the left-out validation set. The discrimination performance of 1-year risk was 0.82 (95% CI, 0.79 to 0.85) with good calibration ( = 0.7). Using the U.S. Preventive Service Task Force guidelines, 14% of the women were at high risk, 19.6 times higher compared to general risk. In this high-risk group, 76% of stage II and III cancers and 59% of stage 0 cancers were observed ( < 0.01). Using mammographic features generated from DBT screens, our image-based risk prediction model could guide radiologists in selecting women for clinical care, potentially leading to earlier detection and improved prognoses. 10.1126/scitranslmed.abn3971
    Treatment guideline concordance, initiation, and abandonment in patients with non-metastatic breast cancer from the African Breast Cancer-Disparities in Outcomes (ABC-DO) cohort in sub-Saharan Africa: a prospective cohort study. The Lancet. Oncology BACKGROUND:Comprehensive breast cancer management is essential to achieve high breast cancer survival; however, detailed reports of the treatment regimens received by patients are scarce in sub-Saharan Africa where survival is low. We aimed to examine treatment initiation, guideline concordance, and abandonment in patients with non-metastatic breast cancer in sub-Saharan Africa from the African Breast Cancer-Disparities in Outcomes (ABC-DO) prospective cohort. METHODS:The ABC-DO prospective cohort study recruited women (aged ≥18 years) with newly diagnosed invasive breast cancer in eight hospitals across five sub-Saharan African countries (Namibia, Nigeria, Uganda, South Africa, and Zambia). We analysed treatments received by women who were classified as non-metastatic (M0) at the initial presentation. Data on surgery, radiotherapy, and systemic therapies were obtained from medical records and a self-reported follow-up questionnaire at 6 months after the diagnosis, follow-up calls every 3 months, and a baseline questionnaire. Initiation, completion, and abandonment of treatment modalities and combined therapy regimens were examined overall, by country-specific groups, and by clinical factors relevant for guideline-based treatment. FINDINGS:Of 2313 women recruited into the ABC-DO study between Sept 10, 2014, and Dec 31, 2017, 2226 had histologically or clinically confirmed breast cancer. Of these 2226 women, 510 were excluded from the present analysis because 378 had metastatic disease, 37 were prevalent cases (defined as those previously diagnosed with breast cancer >2 years before baseline), 82 had unknown TNM stage, and 13 were White or Asian women in South Africa (number was too small for analysis). After a median follow-up of 5·2 years (IQR 4·6-5·9), 1163 (68%) of 1716 women underwent breast cancer surgery. Surgery and systemic therapy (ie, multimodality treatment) with radiotherapy was initiated in 370 (36%) of 1028 women with localised tumours versus 156 (23%) of 688 women with locally advanced tumours, whereas multimodality treatment without radiotherapy was initiated in 386 (38%) versus 167 (24%) women, respectively. Of 1530 patients requiring chemotherapy (which excludes 105 who died within 6 months after baseline), 1013 (66%) initiated treatment of neoadjuvant chemotherapy or surgery within 3 months after baseline, which was adequately completed by 359 (35%) of 1013 women, marginally completed by 284 (28%), abandoned by 200 (20%), and unknown in 151 (15%). 19 (2%) women died within 6 months after chemotherapy initiation. Of 1375 women in whom endocrine therapy was indicated, this treatment was initiated in 920, and lasted at least 3 years in 367 (40%) women. Treatment disparities between country-specific groups were substantial for all therapy regimens. INTERPRETATION:A high proportion of patients with non-metastatic breast cancer did not initiate, did not fully complete, or abandoned treatment with surgery, systemic therapy, radiotherapy, or an appropriate combination of these, highlighting the need for improved treatment access and completion in sub-Saharan Africa to potentially prevent premature breast cancer deaths. FUNDING:National Institutes of Health (National Cancer Institute), Susan G Komen, and the International Agency for Research on Cancer. 10.1016/S1470-2045(22)00198-X
    CDK12 promotes tumorigenesis but induces vulnerability to therapies inhibiting folate one-carbon metabolism in breast cancer. Nature communications Cyclin-dependent kinase 12 (CDK12) overexpression is implicated in breast cancer, but whether it has a primary or only a cooperative tumorigenic role is unclear. Here, we show that transgenic CDK12 overexpression in the mouse mammary gland per se is sufficient to drive the emergence of multiple and multifocal tumors, while, in cooperation with known oncogenes, it promotes earlier tumor onset and metastasis. Integrative transcriptomic, metabolomic and functional data reveal that hyperactivation of the serine-glycine-one-carbon network is a metabolic hallmark inherent to CDK12-induced tumorigenesis. Consistently, in retrospective patient cohort studies and in patient-derived xenografts, CDK12-overexpressing breast tumors show positive response to methotrexate-based chemotherapy targeting CDK12-induced metabolic alterations, while being intrinsically refractory to other types of chemotherapy. In a retrospective analysis of hormone receptor-negative and lymph node-positive breast cancer patients randomized in an adjuvant phase III trial to 1-year low-dose metronomic methotrexate-based chemotherapy or no maintenance chemotherapy, a high CDK12 status predicts a dramatic reduction in distant metastasis rate in the chemotherapy-treated vs. not-treated arm. Thus, by coupling tumor progression with metabolic reprogramming, CDK12 creates an actionable vulnerability for breast cancer therapy and might represent a suitable companion biomarker for targeted antimetabolite therapies in human breast cancers. 10.1038/s41467-022-30375-8
    Is Regional Nodal Radiotherapy Necessary for Patients With cN1 and ypN0 Breast Cancer After Neoadjuvant Chemotherapy? JAMA oncology 10.1001/jamaoncol.2022.0313
    Is Regional Nodal Radiotherapy Necessary for Patients With cN1 and ypN0 Breast Cancer After Neoadjuvant Chemotherapy?-Reply. JAMA oncology 10.1001/jamaoncol.2022.0316
    Treatment With Etirinotecan Pegol for Patients With Metastatic Breast Cancer and Brain Metastases: Final Results From the Phase 3 ATTAIN Randomized Clinical Trial. JAMA oncology Importance:Patients with breast cancer and brain metastases (BM) have a poor prognosis and high clinical need for novel treatments; however, historically, studies have often excluded these patients. Although the BEACON study did not meet its primary end point, treatment with etirinotecan pegol vs chemotherapy of the physician's choice for patients with advanced breast cancer demonstrated a significant improvement in overall survival (OS) for the prespecified patient subgroup with preexisting, pretreated, and nonprogressive BM. Objective:To compare clinical outcomes in patients with BM treated with etirinotecan pegol vs chemotherapy of the physician's choice in a confirmatory trial. Design, Setting, and Participants:This study was a phase 3, open-label, randomized clinical trial (ATTAIN) in patients with metastatic breast cancer and a history of stable pretreated BM who experienced disease progression while receiving chemotherapy in the metastatic setting. The trial took place at 47 sites in 10 countries, and patients were enrolled between March 7, 2017, and November 6, 2019. Interventions:Patients were randomized to receive etirinotecan pegol, 145 mg/m2, every 21 days or chemotherapy (eribulin, ixabepilone, vinorelbine, gemcitabine, paclitaxel, docetaxel, or nab-paclitaxel). Main Outcomes and Measures:The primary end point was OS. Key secondary end points included progression-free survival, objective response rate, duration of response, and the clinical benefit rate. Results:A total of 178 female patients (9 [5.1%] Asian, 8 [4.5%] Black or African American, and 123 [69.1] White individuals) were randomized to receive treatment with etirinotecan pegol (92 [51.7%]; median [range] age, 53 [27-79] years) or chemotherapy (86 [48.3%]; median [range] age, 52 [24-77] years). Median OS was similar in both groups (etirinotecan pegol, 7.8 months; chemotherapy, 7.5 months; hazard ratio [HR], 0.90; 95% CI, 0.61-1.33; P = .60). Median progression-free survival for non-central nervous system metastases per blinded independent central review for etirinotecan pegol vs chemotherapy was 2.8 and 1.9 months (HR, 0.72; 95% CI, 0.45-1.16; P = .18) and 3.9 vs 3.3 months, respectively, for central nervous system metastases (HR, 0.59; 95% CI, 0.33-1.05; P = .07). Safety profiles between the groups were largely comparable. Conclusions and Relevance:The results of the ATTAIN randomized clinical trial found no statistically significant difference in outcomes between treatment with etirinotecan pegol and chemotherapy in patients with BM. However, this study represents one of the largest published trials dedicated to patients with breast cancer and BM and may help to inform further research. Trial Registration:ClinicalTrials.gov Identifier: NCT02915744. 10.1001/jamaoncol.2022.0514
    N6-methyladenosine regulated FGFR4 attenuates ferroptotic cell death in recalcitrant HER2-positive breast cancer. Nature communications Intrinsic and acquired anti-HER2 resistance remains a major hurdle for treating HER2-positive breast cancer. Using genome-wide CRISPR/Cas9 screening in vitro and in vivo, we identify FGFR4 as an essential gene following anti-HER2 treatment. FGFR4 inhibition enhances susceptibility to anti-HER2 therapy in resistant breast cancer. Mechanistically, m6A-hypomethylation regulated FGFR4 phosphorylates GSK-3β and activates β-catenin/TCF4 signaling to drive anti-HER2 resistance. Notably, suppression of FGFR4 dramatically diminishes glutathione synthesis and Fe efflux efficiency via the β-catenin/TCF4-SLC7A11/FPN1 axis, resulting in excessive ROS production and labile iron pool accumulation. Ferroptosis, a unique iron-dependent form of oxidative cell death, is triggered after FGFR4 inhibition. Experiments involving patient-derived xenografts and organoids reveals a synergistic effect of anti-FGFR4 with anti-HER2 therapy in breast cancer with either intrinsic or acquired resistance. Together, these results pinpoint a mechanism of anti-HER2 resistance and provide a strategy for overcoming resistance via FGFR4 inhibition in recalcitrant HER2-positive breast cancer. 10.1038/s41467-022-30217-7
    Targeting HER2-AXL heterodimerization to overcome resistance to HER2 blockade in breast cancer. Science advances Anti-HER2 therapies have markedly improved prognosis of HER2-positive breast cancer. However, different mechanisms play a role in treatment resistance. Here, we identified AXL overexpression as an essential mechanism of trastuzumab resistance. AXL orchestrates epithelial-to-mesenchymal transition and heterodimerizes with HER2, leading to activation of PI3K/AKT and MAPK pathways in a ligand-independent manner. Genetic depletion and pharmacological inhibition of AXL restored trastuzumab response in vitro and in vivo. AXL inhibitor plus trastuzumab achieved complete regression in trastuzumab-resistant patient-derived xenograft models. Moreover, expression in HER2-positive primary tumors was able to predict prognosis. Data from the PAMELA trial showed a change in expression during neoadjuvant dual HER2 blockade, supporting its role in resistance. Therefore, our study highlights the importance of targeting AXL in combination with anti-HER2 drugs across HER2-amplified breast cancer patients with high expression. Furthermore, it unveils the potential value of AXL as a druggable prognostic biomarker in HER2-positive breast cancer. 10.1126/sciadv.abk2746
    Elacestrant Prolongs Progression-Free Survival in Advanced Breast Cancer. Cancer discovery Prolonged progression-free survival was seen with elacestrant versus standard-of-care endocrine therapy. 10.1158/2159-8290.CD-RW2022-095
    PRMT inhibition induces a viral mimicry response in triple-negative breast cancer. Nature chemical biology Triple-negative breast cancer (TNBC) is the most aggressive breast cancer subtype with the worst prognosis and few effective therapies. Here we identified MS023, an inhibitor of type I protein arginine methyltransferases (PRMTs), which has antitumor growth activity in TNBC. Pathway analysis of TNBC cell lines indicates that the activation of interferon responses before and after MS023 treatment is a functional biomarker and determinant of response, and these observations extend to a panel of human-derived organoids. Inhibition of type I PRMT triggers an interferon response through the antiviral defense pathway with the induction of double-stranded RNA, which is derived, at least in part, from inverted repeat Alu elements. Together, our results represent a shift in understanding the antitumor mechanism of type I PRMT inhibitors and provide a rationale and biomarker approach for the clinical development of type I PRMT inhibitors. 10.1038/s41589-022-01024-4
    Breast cancer: NICE recommends innovative magnetic technology for locating sentinel lymph nodes. BMJ (Clinical research ed.) 10.1136/bmj.o1226
    Elacestrant (oral selective estrogen receptor degrader) Versus Standard Endocrine Therapy for Estrogen Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Advanced Breast Cancer: Results From the Randomized Phase III EMERALD Trial. Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:Patients with pretreated estrogen receptor (ER)-positive/human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer have poor prognosis. Elacestrant is a novel, oral selective ER degrader that demonstrated activity in early studies. METHODS:This randomized, open-label, phase III trial enrolled patients with ER-positive/HER2-negative advanced breast cancer who had one-two lines of endocrine therapy, required pretreatment with a cyclin-dependent kinase 4/6 inhibitor, and ≤ 1 chemotherapy. Patients were randomly assigned to elacestrant 400 mg orally once daily or standard-of-care (SOC) endocrine monotherapy. Primary end points were progression-free survival (PFS) by blinded independent central review in all patients and patients with detectable mutations. RESULTS:Patients were randomly assigned to elacestrant (n = 239) or SOC (n = 238). mutation was detected in 47.8% of patients, and 43.4% received two prior endocrine therapies. PFS was prolonged in all patients (hazard ratio = 0.70; 95% CI, 0.55 to 0.88; = .002) and patients with mutation (hazard ratio = 0.55; 95% CI, 0.39 to 0.77; = .0005). Treatment-related grade 3/4 adverse events occurred in 7.2% receiving elacestrant and 3.1% receiving SOC. Treatment-related adverse events leading to treatment discontinuations were 3.4% in the elacestrant arm versus 0.9% in SOC. Nausea of any grade occurred in 35.0% receiving elacestrant and 18.8% receiving SOC (grade 3/4, 2.5% and 0.9%, respectively). CONCLUSION:Elacestrant is the first oral selective ER degrader demonstrating a significant PFS improvement versus SOC both in the overall population and in patients with mutations with manageable safety in a phase III trial for patients with ER-positive/HER2-negative advanced breast cancer. 10.1200/JCO.22.00338
    Clinical Validity of 16α-[F]Fluoro-17β-Estradiol Positron Emission Tomography/Computed Tomography to Assess Estrogen Receptor Status in Newly Diagnosed Metastatic Breast Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:Determining the estrogen receptor (ER) status is essential in metastatic breast cancer (MBC) management. Whole-body ER imaging with 16α-[F]fluoro-17β-estradiol positron emission tomography ([F]FES-PET) is increasingly used for this purpose. To establish the clinical validity of the [F]FES-PET, we studied the diagnostic accuracy of qualitative and quantitative [F]FES-PET assessment to predict ER expression by immunohistochemistry in a metastasis. METHODS:In a prospective multicenter trial, 200 patients with newly diagnosed MBC underwent extensive workup including molecular imaging. For this subanalysis, ER expression in the biopsied metastasis was related to qualitative whole-body [F]FES-PET evaluation and quantitative [F]FES uptake in the corresponding metastasis. A review and meta-analysis regarding [F]FES-PET diagnostic performance were performed. RESULTS:Whole-body [F]FES-PET assessment predicted ER expression in the biopsied metastasis with good accuracy: a sensitivity of 95% (95% CI, 89 to 97), a specificity of 80% (66 to 89), a positive predictive value (PPV) of 93% (87 to 96), and a negative predictive value (NPV) of 85% (72 to 92) in 181 of 200 evaluable patients. Quantitative [F]FES uptake predicted ER immunohistochemistry in the corresponding metastasis with a sensitivity/specificity of 91%/69% and a PPV/NPV of 90%/71% in 156 of 200 evaluable patients. For bone metastases, PPV/NPV was 92%/81%. Meta-analysis with addition of our data has increased diagnostic performance and narrowed the 95% CIs compared with previous studies with a sensitivity/specificity of both 86% (81 to 90 and 73 to 93, respectively). CONCLUSION:In this largest prospective series so far, we established the clinical validity of [F]FES-PET to determine tumor ER status in MBC. In view of the high diagnostic accuracy of qualitatively assessed whole-body [F]FES-PET, this noninvasive imaging modality can be considered a valid alternative to a biopsy of a metastasis to determine ER status in newly MBC (ClinicalTrials.gov identifier: NCT01957332). 10.1200/JCO.22.00400
    Effect of Denosumab Added to 2 Different nab-Paclitaxel Regimens as Neoadjuvant Therapy in Patients With Primary Breast Cancer: The GeparX 2 × 2 Randomized Clinical Trial. JAMA oncology Importance:Adjuvant denosumab might improve disease-free survival in hormone receptor (HR)-positive primary breast cancer (BC). The optimal neoadjuvant nab-paclitaxel schedule in terms of efficacy and safety is unclear. Objective:To determine whether adding denosumab to anthracycline/taxane-containing neoadjuvant chemotherapy (NACT) increases the pathological complete response (pCR) rate and which nab-paclitaxel schedule is more effective in the NACT setting. Design, Setting, and Participants:The GeparX was a multicenter, prospective, open-label, phase 2b, 2 × 2 randomized clinical trial conducted by GBG and AGO-B at 38 German sites between February 2017 and March 2019. The analysis data set was locked September 4, 2020; analysis was completed November 13, 2020. Patients had unilateral or bilateral primary BC, stage cT2-cT4a-d or cT1c, with either clinically node-positive or pathologically node-positive or HR-negative disease, or Ki-67 proliferation index greater than 20%, or ERBB2 (formerly HER2)-positive BC. Interventions:Patients were randomized to receive or not receive denosumab, 120 mg subcutaneously every 4 weeks for 6 cycles, and either nab-paclitaxel, 125 mg/m2 weekly for 12 weeks or days 1 and 8 every 3 weeks for 4 cycles (8 doses), followed by 4 cycles of epirubicin/cyclophosphamide, 90/600 mg/m2 (every 2 weeks or every 3 weeks). Carboplatin was given in triple-negative BC (TNBC), and trastuzumab biosimilar ABP980 plus pertuzumab was given in ERBB2-positive BC (ERBB2-positive substudy). Main Outcomes and Measures:The primary outcome was pCR rates between arms for each randomization. Results:A total of 780 female (n = 779) and male (n = 1) patients (median [range] age, 49.0 [22-80] years) were randomized to the 4 treatment groups. The pCR (ypT0 ypN0) rate was 41.0% (90% CI, 37%-45%) with denosumab vs 42.8% (90% CI, 39%-47%) (P = .58) without denosumab, irrespective of BC subtype. Nab-paclitaxel weekly resulted in a significantly (significance level of α = .10) higher pCR rate of 44.9% (90% CI, 41%-49%) vs 39.0% (90% CI, 35%-43%) (P = .06) with nab-paclitaxel days 1 and 8 every 3 weeks. The pCR rates for nab-paclitaxel schedules in subgroups were only significantly different for TNBC (60.4% vs 50.0%; P = .06). Grade 3 to 4 toxic effects did not differ with or without denosumab. Nonhematologic toxic effects of grade 3 to 4 were higher with nab-paclitaxel weekly (33.7% vs 24.1%; P = .004). Conclusions and Relevance:In this randomized clinical trial, denosumab added to anthracycline/taxane-based NACT did not improve pCR rates. Nab-paclitaxel at a dosage of 125 mg/m2 weekly significantly increased the pCR rate compared with the days 1 and 8, every-3-weeks schedule overall and in TNBC, but generated higher toxicity. Trial Registration:ClinicalTrials.gov Identifier: NCT02682693. 10.1001/jamaoncol.2022.1059
    A Digital Breast Tomosynthesis Risk Model Can Guide Clinical Care in Breast Cancer. Cancer discovery A digital breast tomosynthesis (DBT)-based risk model was developed and improved breast cancer risk stratification. 10.1158/2159-8290.CD-RW2022-094
    Everolimus Added to Adjuvant Endocrine Therapy in Patients With High-Risk Hormone Receptor-Positive, Human Epidermal Growth Factor Receptor 2-Negative Primary Breast Cancer. Journal of clinical oncology : official journal of the American Society of Clinical Oncology PURPOSE:Everolimus, an oral inhibitor of the mammalian target of rapamycin, improves progression-free survival in combination with endocrine therapy (ET) in postmenopausal women with aromatase inhibitor-resistant metastatic breast cancer. However, the benefit of adding everolimus to ET in the adjuvant setting in early breast cancer is unknown. PATIENTS AND METHODS:In this randomized double-blind phase III study, women with high-risk, hormone receptor-positive, human epidermal growth factor receptor 2-negative primary breast cancer were randomly assigned to everolimus or placebo for 2 years combined with standard ET. Stratification factors included ET agent, receipt of neoadjuvant versus adjuvant chemotherapy, progesterone receptor status, duration of ET before random assignment, and lymph node involvement. The primary end point was disease-free survival (DFS). The trial is registered with ClinicalTrials.gov identifier: NCT01805271. RESULTS:Between June 2013 and March 2020, 1,278 patients were randomly allocated to receive everolimus or placebo. At the first interim analysis, the trial was stopped for futility and a full analysis undertaken once data snapshot complete. One hundred forty-seven patients have had a DFS event reported and at 3 years, DFS did not differ between patients who received ET plus everolimus (88% [95% CI, 85 to 91]) or ET plus placebo (89% [95% CI, 86 to 91; hazard ratio = 0.95, 95% CI, 0.69 to 1.32, = .77]). Grade ≥ 3 adverse events were reported in 22.9% of patients (29.9% with everolimus 15.9% with placebo, < .001). 53.4% everolimus-treated patients permanently discontinued experimental treatment early compared with placebo-treated 22.3%. CONCLUSION:Among high-risk patients, everolimus added to adjuvant ET did not improve DFS. Tolerability was a concern, with more than half of patients stopping everolimus before study completion. Everolimus cannot be recommended in the adjuvant setting. 10.1200/JCO.21.02179
    Current and future diagnostic and treatment strategies for patients with invasive lobular breast cancer. Annals of oncology : official journal of the European Society for Medical Oncology BACKGROUND:Invasive Lobular breast cancer (ILC) is the second most common type of breast cancer after invasive breast cancer of no special type (NST), representing up to 15% of all breast cancers. DESIGN:Latest data on ILC are presented, focusing on diagnosis, molecular make-up according to the ESMO Scale for Clinical Actionability of molecular Targets (ESCAT) guidelines, treatment in the early and metastatic setting and ILC-focused clinical trials. RESULTS:At the imaging level, MRI-based and novel PET/CT-based techniques can overcome the limitations of currently used imaging techniques for diagnosing ILC. At the pathology level, E-cadherin immunohistochemistry could help improving inter-pathologist agreement. The majority of patients with ILC do not seem to benefit as much from (neo-)adjuvant chemotherapy as patients with NST, although chemotherapy might be required in a subset of high-risk patients. No differences in treatment efficacy are seen for anti-HER2 therapies in the adjuvant setting and CDK4/6 inhibitors in the metastatic setting. The clinical utility of the commercially-available prognostic gene expression-based tests is unclear for patients with ILC. Several ESCAT alterations differ in frequency between ILC and NST. Germline BRCA1 and PALB2 alterations are less frequent in patients with ILC, while germline CDH1 (gene coding for E-cadherin) alterations are more frequent in patients with ILC. Somatic HER2 mutations are more frequent in ILC, especially in metastases (15% ILC versus 5% NST). A high tumour mutational burden, relevant for immune checkpoint inhibition, is more frequent in ILC metastases (16%) than NST metastases (5%). Tumours with somatic inactivating CDH1 mutations may be vulnerable for treatment with ROS1 inhibitors, a concept currently investigated in early and metastatic ILC. CONCLUSIONS:ILC is a unique malignancy based on its pathological and biological features leading to differences in diagnosis as well as in treatment response, resistance and targets as compared to NST. 10.1016/j.annonc.2022.05.006
    Effect of Metformin vs Placebo on Invasive Disease-Free Survival in Patients With Breast Cancer: The MA.32 Randomized Clinical Trial. JAMA Importance:Metformin, a biguanide commonly used to treat type 2 diabetes, has been associated with potential beneficial effects across breast cancer subtypes in observational and preclinical studies. Objective:To determine whether the administration of adjuvant metformin (vs placebo) to patients with breast cancer without diabetes improves outcomes. Design, Setting, and Participants:MA.32, a phase 3 randomized, placebo-controlled, double-blind trial, conducted in Canada, Switzerland, US, and UK, enrolled 3649 patients with high-risk nonmetastatic breast cancer receiving standard therapy between August 2010 and March 2013, with follow-up to October 2020. Interventions:Patients were randomized (stratified for hormone receptor [estrogen receptor and/or progesterone receptor {ER/PgR}] status, positive vs negative; body mass index, ≤30 vs >30; human epidermal growth factor receptor 2 [ERBB2, formerly HER2 or HER2/neu], positive vs negative; and any vs no chemotherapy) to 850 mg of oral metformin twice a day (n = 1824) or oral placebo twice a day (n = 1825) for 5 years. Main Outcomes and Measures:The primary outcome was invasive disease-free survival in hormone receptor-positive breast cancer. Of the 8 secondary outcomes, overall survival, distant relapse-free survival, and breast cancer-free interval were analyzed. Results:Of the 3649 randomized patients (mean age, 52.4 years; 3643 women [99.8%]), all (100%) were included in analyses. After a second interim analysis, futility was declared for patients who were ER/PgR-, so the primary analysis was conducted for 2533 patients who were ER/PgR+. The median duration of follow-up in the ER/PgR+ group was 96.2 months (range, 0.2-121 months). Invasive disease-free survival events occurred in 465 patients who were ER/PgR+. The incidence rates for invasive disease-free survival events were 2.78 per 100 patient-years in the metformin group vs 2.74 per 100 patient-years in the placebo group (hazard ratio [HR], 1.01; 95% CI, 0.84-1.21; P = .93), and the incidence rates for death were 1.46 per 100 patient-years in the metformin group vs 1.32 per 100 patient-years in the placebo group (HR, 1.10; 95% CI, 0.86-1.41; P = .47). Among patients who were ER/PgR-, followed up for a median of 94.1 months, incidence of invasive disease-free survival events was 3.58 vs 3.60 per 100 patient-years, respectively (HR, 1.01; 95% CI, 0.79-1.30; P = .92). None of the 3 secondary outcomes analyzed in the ER/PgR+ group had statistically significant differences. Grade 3 nonhematological toxic events occurred more frequently in patients taking metformin than in patients taking placebo (21.5% vs 17.5%, respectively, P = .003). The most common grade 3 or higher adverse events in the metformin vs placebo groups were hypertension (2.4% vs 1.9%), irregular menses (1.5% vs 1.4%), and diarrhea (1.9% vs 7.0%). Conclusions and Relevance:Among patients with high-risk operable breast cancer without diabetes, the addition of metformin vs placebo to standard breast cancer treatment did not significantly improve invasive disease-free survival. Trial Registration:ClinicalTrials.gov Identifier: NCT01101438. 10.1001/jama.2022.6147
    NICE allows immunotherapy treatment for small group of patients with advanced triple negative breast cancer. BMJ (Clinical research ed.) 10.1136/bmj.o1311
    AZD5305 More Tolerable than 1st-Generation PARP Inhibitors. Cancer discovery Findings from the phase I/IIa trial of AZD5305, a next-generation, highly selective PARP1 inhibitor, indicate that the drug is better tolerated in patients with ovarian, HER2-negative breast, pancreatic, and prostate cancers with BRCA1/2, PALB2, and RAD51C mutations compared with first-generation PARP inhibitors. In addition, 25% of 40 evaluable patients had a partial response. 10.1158/2159-8290.CD-NB2022-0039
    Effect of Supine vs Prone Breast Radiotherapy on Acute Toxic Effects of the Skin Among Women With Large Breast Size: A Randomized Clinical Trial. JAMA oncology Importance:Women with large breast size treated with adjuvant breast radiotherapy (RT) have a high rate of acute toxic effects of the skin. Breast RT in the prone position is one strategy that may decrease these toxic effects. Objective:To determine if breast RT in the prone position reduces acute toxic effects of the skin when compared with treatment in the supine position. Design, Setting, and Participants:This phase 3, multicenter, single-blind randomized clinical trial accrued patients from 5 centers across Canada from April 2013 to March 2018 to compare acute toxic effects of breast RT for women with large breast size (bra band ≥40 in and/or ≥D cup) in the prone vs supine positions. A total of 378 patients were referred for adjuvant RT and underwent randomization. Seven patients randomized to supine position were excluded (5 declined treatment and 2 withdrew consent), and 14 patients randomized to prone position were excluded (4 declined treatment, 3 had unacceptable cardiac dose, and 7 were unable to tolerate being prone). Data were analyzed from April 2019 through September 2020. Interventions:Patients were randomized to RT in the supine or prone position. From April 2013 until June 2016, all patients (n = 167) received 50 Gy in 25 fractions (extended fractionation) with or without boost (range, 10-16 Gy). After trial amendment in June 2016, the majority of patients (177 of 190 [93.2%]) received the hypofractionation regimen of 42.5 Gy in 16 fractions. Main Outcomes and Measures:Main outcome was moist desquamation (desquamation). Results:Of the 357 women (mean [SD] age, 61 [9.9] years) included in the analysis, 182 (51.0%) were treated in the supine position and 175 (49.0%) in prone. There was statistically significantly more desquamation in patients treated in the supine position compared with prone (72 of 182 [39.6%] patients vs 47 of 175 [26.9%] patients; OR, 1.78; 95% CI, 1.24-2.56; P = .002), which was confirmed on multivariable analysis (OR, 1.99; 95% CI, 1.48-2.66; P < .001), along with other independent factors: use of boost (OR, 2.71; 95% CI, 1.95-3.77; P < .001), extended fractionation (OR, 2.85; 95% CI, 1.41-5.79; P = .004), and bra size (OR, 2.56; 95% CI, 1.50-4.37; P < .001). Conclusions and Relevance:This randomized clinical trial confirms that treatment in the prone position decreases desquamation in women with large breast size receiving adjuvant RT. It also shows increased toxic effects using an RT boost and conventional fractionation. Trial Registration:ClinicalTrials.gov Identifier: NCT01815476. 10.1001/jamaoncol.2022.1479
    Breast cancer chemotherapy induces vascular dysfunction and hypertension through a NOX4-dependent mechanism. The Journal of clinical investigation Cardiovascular disease is the major cause of morbidity and mortality in breast cancer survivors. Chemotherapy contributes to this risk. We aimed to define the mechanisms of long-term vascular dysfunction caused by neoadjuvant chemotherapy (NACT) and identify novel therapeutic targets. We studied arteries from postmenopausal women who had undergone breast cancer treatment using docetaxel, doxorubicin, and cyclophosphamide (NACT) and from women with no history of such treatment matched for key clinical parameters. We explored mechanisms in WT and Nox4-/- mice and in human microvascular endothelial cells. Endothelium-dependent, NO-mediated vasodilatation was severely impaired in patients after NACT, while endothelium-independent responses remained normal. This was mimicked by a 24-hour exposure of arteries to NACT agents ex vivo. When applied individually, only docetaxel impaired endothelial function in human vessels. Mechanistic studies showed that NACT increased inhibitory eNOS phosphorylation of threonine 495 in a Rho-associated protein kinase-dependent (ROCK-dependent) manner and augmented vascular superoxide and hydrogen peroxide production and NADPH oxidase activity. Docetaxel increased expression of the NADPH oxidase NOX4 in endothelial and smooth muscle cells and NOX2 in the endothelium. A NOX4 increase in human arteries may be mediated epigenetically by diminished DNA methylation of the NOX4 promoter. Docetaxel induced endothelial dysfunction and hypertension in mice, and these were prevented in Nox4-/- mice and by pharmacological inhibition of Nox4 or Rock. Commonly used chemotherapeutic agents and, in particular, docetaxel alter vascular function by promoting the inhibitory phosphorylation of eNOS and enhancing ROS production by NADPH oxidases. 10.1172/JCI149117
    Redefining breast cancer subtypes to guide treatment prioritization and maximize response: Predictive biomarkers across 10 cancer therapies. Cancer cell Using pre-treatment gene expression, protein/phosphoprotein, and clinical data from the I-SPY2 neoadjuvant platform trial (NCT01042379), we create alternative breast cancer subtypes incorporating tumor biology beyond clinical hormone receptor (HR) and human epidermal growth factor receptor-2 (HER2) status to better predict drug responses. We assess the predictive performance of mechanism-of-action biomarkers from ∼990 patients treated with 10 regimens targeting diverse biology. We explore >11 subtyping schemas and identify treatment-subtype pairs maximizing the pathologic complete response (pCR) rate over the population. The best performing schemas incorporate Immune, DNA repair, and HER2/Luminal phenotypes. Subsequent treatment allocation increases the overall pCR rate to 63% from 51% using HR/HER2-based treatment selection. pCR gains from reclassification and improved patient selection are highest in HR subsets (>15%). As new treatments are introduced, the subtyping schema determines the minimum response needed to show efficacy. This data platform provides an unprecedented resource and supports the usage of response-based subtypes to guide future treatment prioritization. 10.1016/j.ccell.2022.05.005