Spatial predictors of immunotherapy response in triple-negative breast cancer.

Immune checkpoint blockade (ICB) benefits some patients with triple-negative breast cancer, but what distinguishes responders from non-responders is unclear1. Because ICB targets cell-cell interactions2, we investigated the impact of multicellular spatial organization on response, and explored how ICB remodels the tumour microenvironment. We show that cell phenotype, activation state and spatial location are intimately linked, influence ICB effect and differ in sensitive versus resistant tumours early on-treatment. We used imaging mass cytometry3 to profile the in situ expression of 43 proteins in tumours from patients in a randomized trial of neoadjuvant ICB, sampled at three timepoints (baseline, n = 243; early on-treatment, n = 207; post-treatment, n = 210). Multivariate modelling showed that the fractions of proliferating CD8+TCF1+T cells and MHCII+ cancer cells were dominant predictors of response, followed by cancer-immune interactions with B cells and granzyme B+ T cells. On-treatment, responsive tumours contained abundant granzyme B+ T cells, whereas resistant tumours were characterized by CD15+ cancer cells. Response was best predicted by combining tissue features before and on-treatment, pointing to a role for early biopsies in guiding adaptive therapy. Our findings show that multicellular spatial organization is a major determinant of ICB effect and suggest that its systematic enumeration in situ could help realize precision immuno-oncology.

Duration of Adjuvant Aromatase-Inhibitor Therapy in Postmenopausal Breast Cancer.

BACKGROUND: For postmenopausal women with hormone-receptor-positive breast cancer, the most effective duration for adjuvant therapy with an aromatase inhibitor remains unclear. METHODS: In this prospective, phase 3 trial, we randomly assigned postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy to receive the aromatase inhibitor anastrozole for an additional 2 years (2-year group, receiving a total of 7 years) or an additional 5 years (5-year group, receiving a total of 10 years). The primary end point was disease-free survival. The primary analysis included all the patients who were still participating in the trial and who had no recurrence 2 years after randomization (i.e., when treatment in the 2-year group had ended). Secondary end points were overall survival, contralateral breast cancer, second primary cancer, and clinical bone fracture. RESULTS: Among the 3484 women who were enrolled in the trial, 3208 remained in the trial without disease progression after the first 2 years of extended anastrozole treatment following randomization. Among these women, disease progression or death occurred in 335 women in each treatment group in the primary-analysis set at 8 years (hazard ratio, 0.99; 95% confidence interval [CI], 0.85 to 1.15; P = 0.90). No between-group differences occurred in most secondary end points, and subgroup analyses did not indicate differences in any particular subgroup. The risk of clinical bone fracture was higher in the 5-year group than in the 2-year group (hazard ratio, 1.35; 95% CI, 1.00 to 1.84). CONCLUSIONS: In postmenopausal women with hormone-receptor-positive breast cancer who had received 5 years of adjuvant endocrine therapy, extending hormone therapy by 5 years provided no benefit over a 2-year extension but was associated with a greater risk of bone fracture. (Funded by AstraZeneca and the Austrian Breast and Colorectal Cancer Study Group; ABCSG-16/SALSA ClinicalTrials.gov number, NCT00295620.).

Is the CTS5 a helpful decision-making tool in the extended adjuvant therapy setting?

PURPOSE: The Clinical Treatment Score post-5 years (CTS5) is an easy-to-use tool estimating the late distant recurrence (LDR) risk in patients with hormone receptor-positive breast cancer after 5 years of endocrine therapy (ET). Apart from evaluating the prognostic value and calibration accuracy of CTS5, the aim of this study is to clarify if this score is able to identify patients at higher risk for LDR who will benefit from extended ET. METHODS: Prognostic power, calibration, and predictive value of the CTS5 was tested in patients of the prospective ABCSG-06 and -06a trials (n = 1254 and 860 patients, respectively). Time to LDR was analyzed with Cox regression models. RESULTS: Higher rates of LDR in the years five to ten were observed in high- and intermediate-risk patients compared to low-risk patients (HR 4.02, 95%CI 2.26-7.15, p < 0.001 and HR 1.93, 95%CI 1.05-3.56, p = 0.035). An increasing continuous CTS5 was associated with increasing LDR risk (HR 2.23, 95% CI 1.74-2.85, p < 0.001). Miscalibration of CTS5 in high-risk patients could be observed. Although not reaching significance, high-risk patients benefitted the most from prolonged ET with an absolute reduction of the estimated 5-year LDR of - 6.1% (95%CI - 14.4 to 2.3). CONCLUSION: The CTS5 is a reliable prognostic tool that is well calibrated in the lower and intermediate risk groups with a substantial difference of expected versus observed LDR rates in high-risk patients. While a numerical trend in favoring prolonged ET for patients with a higher CTS5 was found, a significantly predictive value for the score could not be confirmed. CLINICAL TRIAL REGISTRATION: ABCSG-06 trial (NCT00309491), ABCSG-06A7 1033AU/0001 (NCT00300508).

Impact of Imaging-Guided Localization on Performance of Tailored Axillary Surgery in Patients with Clinically Node-Positive Breast Cancer: Prospective Cohort Study Within TAXIS (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101).

BACKGROUND: Tailored axillary surgery (TAS) is a novel surgical concept for clinical node-positive breast cancer. It consists of the removal of the sentinel lymph nodes (LNs), as well as palpably suspicious nodes. The TAS technique can be utilized in both the upfront and neoadjuvant chemotherapy (NACT) setting. This study assessed whether/how imaging-guided localization (IGL) influenced TAS. PATIENTS AND METHODS: This was a prospective observational cohort study preplanned in the randomized phase-III OPBC-03/TAXIS trial. IGL was performed at the surgeon's discretion for targeted removal of LNs during TAS. Immediate back-up axillary lymph node dissection (ALND) followed TAS according to TAXIS randomization. RESULTS: Five-hundred patients were included from 44 breast centers in six countries, 151 (30.2%) of whom underwent NACT. IGL was performed in 84.4% of all patients, with significant variation by country (77.6-100%, p < 0.001). No difference in the median number of removed (5 vs. 4, p = 0.3) and positive (2 vs. 2, p = 0.6) LNs by use of IGL was noted. The number of LNs removed during TAS with IGL remained stable over time (p = 0.8), but decreased significantly without IGL, from six (IQR 4-6) in 2019 to four (IQR 3-4) in 2022 (p = 0.015). An ALND was performed in 249 patients, removing another 12 (IQR 9-17) LNs, in which a median number of 1 (IQR 0-4) was positive. There was no significant difference in residual nodal disease after TAS with or without IGL (68.0% vs. 57.6%, p = 0.2). CONCLUSIONS: IGL did not significantly change either the performance of TAS or the volume of residual nodal tumor burden. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03513614.

Study design for DESTINY-Breast Respond HER2-low Europe: T-DXd in patients with HER2-low advanced breast cancer.

Trastuzumab deruxtecan (T-DXd) is approved for the treatment of human epidermal growth factor receptor 2 (HER2)-low metastatic breast cancer (mBC). Results on T-DXd treatment in HER2-low mBC have so far been limited to clinical trials. DESTINY-Breast Respond HER2-low Europe (NCT05945732) is a multi-center, multi-country, observational, prospective, non-interventional study planning to enroll 1350 patients from 216 sites receiving T-DXd or conventional chemotherapy as their routine clinical care for advanced stage breast cancer in 12 European countries. This non-interventional study will provide real-world insight into T-DXd treatment for HER2-low mBC with data on effectiveness, safety and tolerability, patient-reported outcomes, treatment patterns, geriatric health status and HER2 testing. This will be beneficial for improving guidance to maximize patient treatment benefit.

Trastuzumab deruxtecan (T-DXd; Enhertu^®) is a medicine approved to treat cancers that produce a protein called HER2 on the surface of cancer cells. T-DXd works by targeting the HER2 protein to deliver chemotherapy directly to cancer cells. Until recently, breast cancers were classified as HER2-positive (high level of HER2 protein on cancer cells) or HER2-negative (very low level/no HER2 protein on cancer cells). T-DXd was approved for treating patients with HER2-positive advanced breast cancer in Europe in 2022. In 2023 the DESTINY-Breast04 clinical trial showed that T-DXd was more effective than current standard chemotherapies, when treating advanced breast cancer patients with low levels of the HER2 protein (historically classified as HER2-negative cancer). This trial led to the approval of T-DXd for treating advanced HER2-low breast cancer, providing a new treatment option for 50­60% of breast cancer patients. More information is needed about T-DXd treatment in the real world (for patients treated in the hospital, rather than in a clinical trial). This article describes the purpose and design of the DESTINY-Breast Respond HER2-low Europe study, which will collect and report more information about how effective T-DXd treatment is in the real world. This is a large study aiming to include 1350 eligible patients from 12 countries across Europe. Patients will report their experience of side effects (such as nausea and vomiting) to improve management of T-DXd treatment and maximize patient benefit. The study will also examine how elderly patients respond to T-DXd treatment, and how HER2 levels are being tested.Clinical Trial Registration: ICH CGP: NCT05945732, registered on 6 July 2023 (ClinicalTrials.gov).

Surface Topography, Microbial Adhesion, and Immune Responses in Silicone Mammary Implant-Associated Capsular Fibrosis.

Breast cancer is the most common cancer in women globally, often necessitating mastectomy and subsequent breast reconstruction. Silicone mammary implants (SMIs) play a pivotal role in breast reconstruction, yet their interaction with the host immune system and microbiome remains poorly understood. This study investigates the impact of SMI surface topography on host antimicrobial responses, wound proteome dynamics, and microbial colonization. Biological samples were collected from ten human patients undergoing breast reconstruction with SMIs. Mass spectrometry profiles were analyzed for acute and chronic wound proteomes, revealing a nuanced interplay between topography and antimicrobial response proteins. 16S rRNA sequencing assessed microbiome dynamics, unveiling topography-specific variations in microbial composition. Surface topography alterations influenced wound proteome composition. Microbiome analysis revealed heightened diversity around rougher SMIs, emphasizing topography-dependent microbial invasion. In vitro experiments confirmed staphylococcal adhesion, growth, and biofilm formation on SMI surfaces, with increased texture correlating positively with bacterial colonization. This comprehensive investigation highlights the intricate interplay between SMI topography, wound proteome dynamics, and microbial transmission. The findings contribute to understanding host-microbe interactions on SMI surfaces, essential for optimizing clinical applications and minimizing complications in breast reconstruction.

Trends in use of neoadjuvant systemic therapy in patients with clinically node-positive breast cancer in Europe: prospective TAXIS study (OPBC-03, SAKK 23/16, IBCSG 57-18, ABCSG-53, GBG 101).

PURPOSE: The aim of this study was to evaluate clinical practice heterogeneity in use of neoadjuvant systemic therapy (NST) for patients with clinically node-positive breast cancer in Europe. METHODS: The study was preplanned in the international multicenter phase-III OPBC-03/TAXIS trial (ClinicalTrials.gov Identifier: NCT03513614) to include the first 500 randomized patients with confirmed nodal disease at the time of surgery. The TAXIS study's pragmatic design allowed both the neoadjuvant and adjuvant setting according to the preferences of the local investigators who were encouraged to register eligible patients consecutively. RESULTS: A total of 500 patients were included at 44 breast centers in six European countries from August 2018 to June 2022, 165 (33%) of whom underwent NST. Median age was 57 years (interquartile range [IQR], 48-69). Most patients were postmenopausal (68.4%) with grade 2 and 3 hormonal receptor-positive and human epidermal growth factor receptor 2-negative breast cancer with a median tumor size of 28 mm (IQR 20-40). The use of NST varied significantly across the countries (p < 0.001). Austria (55.2%) and Switzerland (35.8%) had the highest percentage of patients undergoing NST and Hungary (18.2%) the lowest. The administration of NST increased significantly over the years (OR 1.42; p < 0.001) and more than doubled from 20 to 46.7% between 2018 and 2022. CONCLUSION: Substantial heterogeneity in the use of NST with HR+/HER2-breast cancer exists in Europe. While stringent guidelines are available for its use in triple-negative and HER2+ breast cancer, there is a need for the development of and adherence to well-defined recommendations for HR+/HER2-breast cancer.

Palbociclib with adjuvant endocrine therapy in early breast cancer (PALLAS): interim analysis of a multicentre, open-label, randomised, phase 3 study.

BACKGROUND: Palbociclib added to endocrine therapy improves progression-free survival in hormone-receptor-positive, HER2-negative, metastatic breast cancer. The PALLAS trial aimed to investigate whether the addition of 2 years of palbociclib to adjuvant endocrine therapy improves invasive disease-free survival over endocrine therapy alone in patients with hormone-receptor-positive, HER2-negative, early-stage breast cancer. METHODS: PALLAS is an ongoing multicentre, open-label, randomised, phase 3 study that enrolled patients at 406 cancer centres in 21 countries worldwide with stage II-III histologically confirmed hormone-receptor-positive, HER2-negative breast cancer, within 12 months of initial diagnosis. Eligible patients were aged 18 years or older with an Eastern Cooperative Oncology Group performance score of 0 or 1. Patients were randomly assigned (1:1) in permuted blocks of random size (4 or 6), stratified by anatomic stage, previous chemotherapy, age, and geographical region, by use of central telephone-based and web-based interactive response technology, to receive either 2 years of palbociclib (125 mg orally once daily on days 1-21 of a 28-day cycle) with ongoing standard provider or patient-choice adjuvant endocrine therapy (tamoxifen or aromatase inhibitor, with or without concurrent luteinising hormone-releasing hormone agonist), or endocrine therapy alone, without masking. The primary endpoint of the study was invasive disease-free survival in the intention-to-treat population. Safety was assessed in all randomly assigned patients who started palbociclib or endocrine therapy. This report presents results from the second pre-planned interim analysis triggered on Jan 9, 2020, when 67% of the total number of expected invasive disease-free survival events had been observed. The trial is registered with ClinicalTrials.gov (NCT02513394) and EudraCT (2014-005181-30). FINDINGS: Between Sept 1, 2015, and Nov 30, 2018, 5760 patients were randomly assigned to receive palbociclib plus endocrine therapy (n=2883) or endocrine therapy alone (n=2877). At the time of the planned second interim analysis, at a median follow-up of 23·7 months (IQR 16·9-29·2), 170 of 2883 patients assigned to palbociclib plus endocrine therapy and 181 of 2877 assigned to endocrine therapy alone had invasive disease-free survival events. 3-year invasive disease-free survival was 88·2% (95% CI 85·2-90·6) for palbociclib plus endocrine therapy and 88·5% (85·8-90·7) for endocrine therapy alone (hazard ratio 0·93 [95% CI 0·76-1·15]; log-rank p=0·51). As the test statistic comparing invasive disease-free survival between groups crossed the prespecified futility boundary, the independent data monitoring committee recommended discontinuation of palbociclib in patients still receiving palbociclib and endocrine therapy. The most common grade 3-4 adverse events were neutropenia (1742 [61·3%] of 2840 patients on palbociclib and endocrine therapy vs 11 [0·3%] of 2903 on endocrine therapy alone), leucopenia (857 [30·2%] vs three [0·1%]), and fatigue (60 [2·1%] vs ten [0·3%]). Serious adverse events occurred in 351 (12·4%) of 2840 patients on palbociclib plus endocrine therapy versus 220 (7·6%) of 2903 patients on endocrine therapy alone. There were no treatment-related deaths. INTERPRETATION: At the planned second interim analysis, addition of 2 years of adjuvant palbociclib to adjuvant endocrine therapy did not improve invasive disease-free survival compared with adjuvant endocrine therapy alone. On the basis of these findings, this regimen cannot be recommended in the adjuvant setting. Long-term follow-up of the PALLAS population and correlative studies are ongoing. FUNDING: Pfizer.

Landscape of HER2-low metastatic breast cancer (MBC): results from the Austrian AGMT_MBC-Registry.

BACKGROUND: About 50% of all primary breast cancers show a low-level expression of HER2 (HER2-low), defined as immunohistochemically 1+ or 2+ and lack of HER2 gene amplification measured by in situ hybridization. This low HER2 expression is a promising new target for antibody-drug conjugates (ADCs) currently under investigation. Until now, little is known about the frequency and the prognostic value of low HER2-expression in metastatic breast cancer (MBC). PATIENTS AND METHODS: The MBC-Registry of the Austrian Study Group of Medical Tumor Therapy (AGMT) is a multicenter nationwide ongoing registry for MBC patients in Austria. Unadjusted, univariate survival probabilities of progression-free survival (PFS) and overall survival (OS) were calculated by the Kaplan-Meier method and compared by the log-rank test. Multivariable adjusted hazard ratios were estimated by Cox regression models. In this analysis, only patients with known HER2 status and available survival data were included. RESULTS: As of 11/15/2020, 1,973 patients were included in the AGMT-MBC-Registry. Out of 1,729 evaluable patients, 351 (20.3%) were HER2-positive, 608 (35.2%) were HER2-low and 770 (44.5%) were completely HER2-negative (HER2-0). Low HER2-expression was markedly more frequent in the hormone-receptor(HR)+ subgroup compared to the triple-negative subgroup (40% vs. 23%). In multivariable analysis, low HER2 expression did not significantly influence OS neither in the HR+ (HR 0.89; 95% CI 0.74-1.05; P = 0.171) nor in the triple-negative subgroup (HR 0.92; 95% CI 0.68-1.25; P = 0.585), when compared to completely HER2-negative disease. Similar results were observed when HER2 IHC 2+ patients were compared to IHC 1+ or 0 patients. CONCLUSION: Low-HER2 expression did not have any impact on prognosis of metastatic breast cancer in this real-world population.

Conventional versus reverse sequence of neoadjuvant epirubicin/cyclophosphamide and docetaxel: sequencing results from ABCSG-34.

BACKGROUND: Preoperative chemotherapy containing anthracyclines and taxanes is well established in early-stage breast cancer. Previous studies have suggested that the chemotherapy sequence may matter but definitive evidence is missing. ABCSG trial 34 evaluated the activity of the MUC1 vaccine tecemotide when added to neoadjuvant treatment; the study provided the opportunity for the second randomisation to compare two different anthracycline/taxane sequences. METHODS: HER2-negative early-stage breast cancer patients were recruited to this randomised multicentre Phase 2 study. Patients in the chemotherapy cohort (n = 311) were additionally randomised to a conventional or reversed sequence of epirubicin/cyclophosphamide and docetaxel. Residual cancer burden (RCB) with/without tecemotide was defined as primary study endpoint; RCB in the two chemotherapy groups was a key secondary endpoint. RESULTS: No significant differences in terms of RCB 0/I (40.1% vs. 37.2%; P = 0.61) or pathologic complete response (pCR) rates (24.3% vs. 25%, P = 0.89) were observed between conventional or reverse chemotherapy sequence. No new safety signals were reported, and upfront docetaxel did not result in decreased rates of treatment delay or discontinuation. CONCLUSION: Upfront docetaxel did not improve chemotherapy activity or tolerability; these results suggest that upfront neoadjuvant treatment with anthracyclines remains a valid option.

Adjuvant denosumab in postmenopausal patients with hormone receptor-positive breast cancer (ABCSG-18): disease-free survival results from a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: In postmenopausal women with hormone receptor-positive, early-stage breast cancer, treatment with adjuvant aromatase inhibitors is the standard of care, but it increases risk for osteoporosis and fractures. Results from the ABCSG-18 trial showed that use of denosumab as an adjuvant to aromatase inhibitor therapy significantly reduced clinical fractures. Disease-free survival outcomes from ABCSG-18 have not yet been reported. METHODS: Postmenopausal patients with early, hormone receptor-positive, non-metastatic adenocarcinoma of the breast, who had completed their initial adjuvant treatment pathway (surgery, radiotherapy, or chemotherapy, or a combination) and were receiving adjuvant aromatase inhibitors, were enrolled at 58 trial centres in Austria and Sweden into this prospective, double-blind, placebo-controlled, phase 3 trial. With permuted block randomisation (block sizes 2 and 4, stratified by previous aromatase inhibitor use, total lumbar spine bone mineral density score at baseline, and type of centre), patients were assigned (1:1) to receive subcutaneous denosumab (60 mg) or matching placebo every 6 months during aromatase inhibitor therapy. The primary endpoint (previously reported) was the time to first clinical fracture after randomisation. The secondary endpoint reported here is disease-free survival (defined as time from randomisation to first evidence of local or distant metastasis, contralateral breast cancer, secondary carcinoma, or death from any cause) in the intention-to-treat population. This study is registered with EudraCT (number 2005-005275-15) and ClinicalTrials.gov (number NCT00556374), and is ongoing for long-term follow-up. FINDINGS: Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled and randomly assigned; 1711 to the denosumab group and 1709 to the placebo group (with five others withdrawing consent). After a median follow-up of 73 months (IQR 58-95), 240 (14·0%) patients in the denosumab and 287 (16·8%) in the placebo group had disease-free survival events. Disease-free survival was significantly improved in the denosumab group versus the placebo group (hazard ratio 0·82, 95% CI 0·69-0·98, Cox p=0·0260; descriptive analysis, without controlling for multiplicity). In the denosumab group, disease-free survival was 89·2% (95% CI 87·6-90·8) at 5 years and 80·6% (78·1-83·1) at 8 years of follow-up, compared with 87·3% (85·7-89·0) at 5 years and 77·5% (74·8-80·2) and 8 years in the placebo group. No independently adjudicated cases of osteonecrosis of the jaw or confirmed atypical femoral fractures were recorded. The total number of adverse events was similar in the denosumab group (1367 [including 521 serious] adverse events) and the placebo group (1339 [515 serious]). The most common serious adverse events were osteoarthritis (62 [3·6%] of 1709 in the denosumab group vs 58 [3·4%] of 1690 in the placebo group), meniscus injury (23 [1·3%] vs 24 [1·4%]), and cataract (16 [0·9%] vs 28 [1·7%]). One (<0·1%) treatment-related death (due to pneumonia, septic kidney failure, and cardiac decompensation) occurred in the denosumab group. INTERPRETATION: Denosumab constitutes an effective and safe adjuvant treatment for patients with postmenopausal hormone receptor-positive early breast cancer receiving aromatase inhibitor therapy. FUNDING: Amgen.

Buparlisib plus fulvestrant in postmenopausal women with hormone-receptor-positive, HER2-negative, advanced breast cancer progressing on or after mTOR inhibition (BELLE-3): a randomised, double-blind, placebo-controlled, phase 3 trial.

BACKGROUND: Activation of the PI3K/AKT/mTOR pathway occurs frequently in breast cancer that is resistant to endocrine therapy. Approved mTOR inhibitors effectively inhibit cell growth and proliferation but elicit AKT phosphorylation via a feedback activation pathway, potentially leading to resistance to mTOR inhibitors. We evaluated the efficacy and safety of buparlisib plus fulvestrant in patients with advanced breast cancer who were pretreated with endocrine therapy and mTOR inhibitors. METHODS: BELLE-3 was a randomised, double-blind, placebo-controlled, multicentre, phase 3 study. Postmenopausal women aged 18 years or older with histologically or cytologically confirmed hormone-receptor-positive, HER2-negative, locally advanced or metastatic breast cancer, who had relapsed on or after endocrine therapy and mTOR inhibitors, were recruited from 200 trial centres in 22 countries. Eligible patients were randomly assigned (2:1) via interactive response technology (block size of six) to receive oral buparlisib (100 mg per day) or matching placebo starting on day 1 of cycle 1, plus intramuscular fulvestrant (500 mg) on days 1 and 15 of cycle 1 and on day 1 of subsequent 28-day cycles. Randomisation was stratified by visceral disease status. The primary endpoint was progression-free survival by local investigator assessment as per the Response Evaluation Criteria In Solid Tumors (RECIST) version 1.1 in the full analysis population (all randomised patients, by intention-to-treat). Safety was analysed in all patients who received at least one dose of treatment and at least one post-baseline safety assessment. This study is registered with ClinicalTrials.gov, number NCT01633060, and is ongoing but no longer enrolling patients. FINDINGS: Between Jan 15, 2013, and March 31, 2016, 432 patients were randomly assigned to the buparlisib (n=289) or placebo (n=143) groups. Median progression-free survival was significantly longer in the buparlisib versus placebo group (3·9 months [95% CI 2·8-4·2] vs 1·8 months [1·5-2·8]; hazard ratio [HR] 0·67, 95% CI 0·53-0·84, one-sided p=0·00030). The most frequent grade 3-4 adverse events in the buparlisib versus placebo group were elevated alanine aminotransferase (63 [22%] of 288 patients vs four [3%] of 140), elevated aspartate aminotransferase (51 [18%] vs four [3%]), hyperglycaemia (35 [12%] vs none), hypertension (16 [6%] vs six [4%]), and fatigue (ten [3%] vs two [1%]). Serious adverse events were reported in 64 (22%) of 288 patients in the buparlisib group versus 23 (16%) of 140 in the placebo group; the most frequent serious adverse events (affecting ≥2% of patients) were elevated aspartate aminotransferase (six [2%] vs none), dyspnoea (six [2%] vs one [1%]), and pleural effusion (six [2%] vs none). On-treatment deaths occurred in ten (3%) of 288 patients in the buparlisib group and in six (4%) of 140 in the placebo group; most deaths were due to metastatic breast cancer, and two were considered treatment-related (cardiac failure [n=1] in the buparlisib group and unknown reason [n=1] in the placebo group). INTERPRETATION: The safety profile of buparlisib plus fulvestrant does not support its further development in this setting. Nonetheless, the efficacy of buparlisib supports the rationale for the use of PI3K inhibitors plus endocrine therapy in patients with PIK3CA mutations. FUNDING: Novartis Pharmaceuticals Corporation.

Ixazomib in combination with carboplatin in pretreated women with advanced triple-negative breast cancer, a phase I/II trial of the AGMT (AGMT MBC-10 trial).

BACKGROUND: Triple-negative breast cancer (TNBC) comprises a heterogeneous group of diseases which are generally associated with poor prognosis. Up to now, no targeted treatment beyond anti-VEGF therapy has been approved for TNBC and cytotoxic agents remain the mainstay of treatment. Ixazomib is a selective and reversible inhibitor of the proteasome, which has been mainly investigated in the treatment of multiple myeloma. In a preclinical study TNBC cells were treated with the first-generation proteasome inhibitor bortezomib in combination with cisplatin and synergistic efficacy was demonstrated. Clinical data are available for carboplatin plus bortezomib in metastatic ovarian and lung cancers showing remarkable antitumor activity and good tolerability (Mol Cancer 11:26 2012, J Thorac Oncol 4:87-92 2009, J Thorac Oncol 7:1032-1040, 2012). Based on this evidence, the phase I/II MBC-10 trial will evaluate the toxicity profile and efficacy of the second-generation proteasome inhibitor ixazomib in combination with carboplatin in patients with advanced TNBC. METHODS: Patients with metastatic TNBC pretreated with at least one prior line of chemotherapy for advanced disease with a confirmed disease progression and measurable disease according to RECIST criteria 1.1 are eligible for this study. Patients will receive ixazomib in combination with carboplatin on days 1, 8, and 15 in a 28-day cycle. The phase I part of this study utilizes an alternate dose escalation accelerated titration design. After establishing the maximum tolerated dose (MTD), the efficacy and safety of the combination will be further evaluated (phase II, including 41 evaluable patients). All patients will continue on study drugs until disease progression, unacceptable toxicity or discontinuation for any other reason. Primary endpoint of the phase II is overall response rate, secondary endpoints include progression-free survival, safety, and quality of life. This trial is open for patient enrollment since November 2016 in six Austrian cancer centers. Accrual is planned to be completed within 2 years. DISCUSSION: Based on preclinical and clinical findings an ixazomib and carboplatin combination is thought to be effective in metastatic TNBC patients. The MBC-10 trial is accompanied by a broad biomarker program investigating predictive biomarkers for treatment response and potential resistance mechanisms to the investigational drug combination. TRIAL REGISTRATION: EudraCT Number: 2016-001421-13 received on March 31, 2016, ClinicalTrials.gov Identifier: NCT02993094 first posted on December 15, 2016. This trial was registered prospectively.

Adjuvant denosumab in breast cancer (ABCSG-18): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: Adjuvant endocrine therapy compromises bone health in patients with breast cancer, causing osteopenia, osteoporosis, and fractures. Antiresorptive treatments such as bisphosphonates prevent and counteract these side-effects. In this trial, we aimed to investigate the effects of the anti-RANK ligand antibody denosumab in postmenopausal, aromatase inhibitor-treated patients with early-stage hormone receptor-positive breast cancer. METHODS: In this prospective, double-blind, placebo-controlled, phase 3 trial, postmenopausal patients with early hormone receptor-positive breast cancer receiving treatment with aromatase inhibitors were randomly assigned in a 1:1 ratio to receive either denosumab 60 mg or placebo administered subcutaneously every 6 months in 58 trial centres in Austria and Sweden. Patients were assigned by an interactive voice response system. The randomisation schedule used a randomly permuted block design with block sizes 2 and 4, stratified by type of hospital regarding Hologic device for DXA scans, previous aromatase inhibitor use, and baseline bone mineral density. Patients, treating physicians, investigators, data managers, and all study personnel were masked to treatment allocation. The primary endpoint was time from randomisation to first clinical fracture, analysed by intention to treat. As an additional sensitivity analysis, we also analysed the primary endpoint on the per-protocol population. Patients were treated until the prespecified number of 247 first clinical fractures was reached. This trial is ongoing (patients are in follow-up) and is registered with the European Clinical Trials Database, number 2005-005275-15, and with ClinicalTrials.gov, number NCT00556374. FINDINGS: Between Dec 18, 2006, and July 22, 2013, 3425 eligible patients were enrolled into the trial, of whom 3420 were randomly assigned to receive denosumab 60 mg (n=1711) or placebo (n=1709) subcutaneously every 6 months. Compared with the placebo group, patients in the denosumab group had a significantly delayed time to first clinical fracture (hazard ratio [HR] 0·50 [95% CI 0·39-0·65], p<0·0001). The overall lower number of fractures in the denosumab group (92) than in the placebo group (176) was similar in all patient subgroups, including in patients with a bone mineral density T-score of -1 or higher at baseline (n=1872, HR 0·44 [95% CI 0·31-0·64], p<0·0001) and in those with a bone mineral density T-score of less than -1 already at baseline (n=1548, HR 0·57 [95% CI 0·40-0·82], p=0·002). The patient incidence of adverse events in the safety analysis set (all patients who received at least one dose of study drug) did not differ between the denosumab group (1366 events, 80%) and the placebo group (1334 events, 79%), nor did the numbers of serious adverse events (521 vs 511 [30% in each group]). The main adverse events were arthralgia and other aromatase-inhibitor related symptoms; no additional toxicity from the study drug was reported. Despite proactive adjudication of every potential osteonecrosis of the jaw by an international expert panel, no cases of osteonecrosis of the jaw were reported. 93 patients (3% of the full analysis set) died during the study, of which one death (in the denosumab group) was thought to be related to the study drug. INTERPRETATION: Adjuvant denosumab 60 mg twice per year reduces the risk of clinical fractures in postmenopausal women with breast cancer receiving aromatase inhibitors, and can be administered without added toxicity. Since a main side-effect of adjuvant breast cancer treatment can be substantially reduced by the addition of denosumab, this treatment should be considered for clinical practice. FUNDING: Amgen.

Effect of Tailored Dose-Dense Chemotherapy vs Standard 3-Weekly Adjuvant Chemotherapy on Recurrence-Free Survival Among Women With High-Risk Early Breast Cancer: A Randomized Clinical Trial.

Importance: Standard dosing of chemotherapy based on body surface area results in marked interpatient variation in pharmacokinetics, toxic effects, and efficacy. Whether tailored dosing can improve outcomes is unknown, as is the role of dose-dense adjuvant chemotherapy. Objective: To determine whether tailored dose-dense adjuvant chemotherapy improves the outcomes of early breast cancer compared with a standard 3-weekly chemotherapy schedule. Design, Setting, and Participants: A randomized, open-label, phase 3 trial of women aged 65 years and younger who had surgery for nonmetastatic node-positive or high-risk node-negative breast cancer at 86 sites in Sweden, Germany, and Austria between February 20, 2007, and September 14, 2011. Interventions: Patients were randomized 1:1 either to 4 cycles of leukocyte nadir-based tailored and dose-dense adjuvant epirubicin and cyclophosphamide every 2 weeks followed by 4 cycles of tailored dose-dense docetaxel every 2 weeks, or to standard-interval chemotherapy with 3 cycles of fluorouracil and epirubicin-cyclophosphamide every 3 weeks followed by 3 cycles of docetaxel every 3 weeks. Main Outcomes and Measures: The primary end point was breast cancer recurrence-free survival (BCRFS). Secondary end points included 5-year event-free survival (EFS), distant disease-free survival (DDFS), overall survival (OS), and rates of grade 3 or 4 toxic effects. Results: Among 2017 randomized patients (1006 in the tailored dose-dense group and 1011 in the control group; median [IQR] age, 51 [45-58] years; 80% with hormone receptor-positive tumors; 97% with node-positive disease), 2000 received study treatment (≥1 cycle of chemotherapy; 1001 in the tailored dose-dense group and 999 in the control group). After a median follow-up of 5.3 years (IQR, 4.5-6.1 years), 269 BCRFS events were reported, 118 in the tailored dose-dense group and 151 in the control group (HR, 0.79; 95% CI, 0.61-1.01; log-rank P = .06; 5-year BCRFS, 88.7% vs 85.0%). The tailored dose-dense group had significantly better EFS than the control group (HR, 0.79; 95% CI, 0.63-0.99; P = .04; 5-year EFS, 86.7% vs 82.1%). The groups did not differ in OS (HR, 0.77; 95% CI, 0.57-1.05; P = .09; 5-year OS, 92.1% vs 90.2%) or DDFS (HR, 0.83; 95% CI, 0.64-1.08; P = .17; 5-year DDFS, 89.4% vs 86.7%). Grade 3 or 4 nonhematologic toxic effects occurred in 527 (52.6%) in the tailored dose-dense group and 366 (36.6%) in the control group. Conclusions and Relevance: Among women with high-risk early breast cancer, the use of tailored dose-dense chemotherapy compared with standard adjuvant chemotherapy did not result in a statistically significant improvement in breast cancer recurrence-free survival. Nonhematologic toxic effects were more frequent in the tailored dose-dense group. Trial Registration: clinicaltrials.gov Identifier: NCT00798070; isrctn.org Identifier: ISRCTN39017665.

Epigenetic stem cell signature in cancer.

Embryonic stem cells rely on Polycomb group proteins to reversibly repress genes required for differentiation. We report that stem cell Polycomb group targets are up to 12-fold more likely to have cancer-specific promoter DNA hypermethylation than non-targets, supporting a stem cell origin of cancer in which reversible gene repression is replaced by permanent silencing, locking the cell into a perpetual state of self-renewal and thereby predisposing to subsequent malignant transformation.

Perinatal mortality and advanced maternal age.

OBJECTIVE: To investigate the impact of advanced maternal age on the rate of perinatal mortality. DESIGN: Retrospective cohort study including all 56,517 singleton hospital deliveries between 1999 and 2008. METHODS: Data were analyzed according to maternal age at delivery in 3 groups of women, 25-34 years, 35-39 years and ≥ 40 years, using the youngest as the reference group. RESULTS: Odds ratios (ORs) for antenatal deaths were 0.98 (CI: 0.67-1.43) and 2.57 (CI: 1.57-4.22) for age groups 35-39 years and ≥ 40 years, respectively. Significant differences in neonatal mortality rates between the age groups were not found. Significant amendable risk factors were attendance of <4 health care visits (OR = 15.55, CI: 9.47-25.51 in age group 35-39 years; OR = 16.38, CI: 9.78-27.43 in the age group ≥ 40 years) and obesity (OR = 1.85, CI: 1.27-2.70 in age group 35-39 years; OR = 1.83, CI: 1.22-2.74 in the age group ≥ 40 years). In the multivariate regression analysis, the adjusted ORs for perinatal mortality were 1.03 (95% CI: 0.77-1.39) and 1.66 (95% CI: 1.03-2.66) for age groups 35-39 and ≥ 40, respectively. CONCLUSIONS: Women older than 40 years carry an increased risk for stillbirth. Important amendable risk factors are obesity and poor antenatal care.

Shear-Wave Elastography Gradient Analysis of Newly Diagnosed Breast Tumours: A Critical Analysis.

BACKGROUND: A better understanding of the peritumoral stroma changes due to tumour invasion using non-invasive diagnostic methods may improve the differentiation between benign and malignant breast lesions. This study aimed to assess the correlation between breast lesion differentiation and intra- and peritumoral shear-wave elastography (SWE) gradients. METHODS: A total of 135 patients with newly diagnosed breast lesions were included. Intratumoral, subsurface, and three consecutive peritumoral SWE value measurements (with three repetitions) were performed. Intratumoral, interface, and peritumoral gradients (Gradient 1 and Gradient 2) were calculated using averaged SWE values. Statistical analysis included descriptive statistics and an ordinary one-way ANOVA to compare overall and individual gradients among Breast Imaging-Reporting and Data System (BI-RADS) 2, 3, and 5 groups. RESULTS: Malignant tumours showed higher average SWE velocity values at the tumour centre (BI-RADS 2/3: 4.1 ± 1.8 m/s vs. BI-RADS 5: 4.9 ± 2.0 m/s, p = 0.04) and the first peritumoral area (BI-RADS 2/3: 3.4 ± 1.8 m/s vs. BI-RADS 5: 4.3 ± 1.8 m/s, p = 0.003). No significant difference was found between intratumoral gradients (0.03 ± 0.32 m/s vs. 0.0 ± 0.28 m/s; p > 0.999) or gradients across the tumour-tissue interface (-0.17 ± 0.18 m/s vs. -0.13 ± 0.35 m/s; p = 0.202). However, the first peritumoral gradient (-0.16 ± 0.24 m/s vs. -0.35 ± 0.31 m/s; p < 0.0001) and the second peritumoral gradient (-0.11 ± 0.18 m/s vs. -0.22 ± 0.28 m/s; p = 0.037) were significantly steeper in malignant tumours. The AUC was best for PTG1 (0.7358) and PTG2 (0.7039). A threshold value for peritumoral SWI PT1 above 3.76 m/s and for PTG1 below -0.238 m/s·mm-1 indicated malignancy in 90.6% of cases. CONCLUSIONS: Evaluating the peritumoral SWE gradient may improve the diagnostic pre-test probability, as malignant tumours showed a significantly steeper curve of the elasticity values in the peritumoral stroma compared to the linear regression with a relatively flat curve of benign lesions.