A prospective study on tumour response assessment methods after neoadjuvant endocrine therapy in early oestrogen receptor-positive breast cancer.

BACKGROUND: Neoadjuvant endocrine therapy (NET) in oestrogen receptor-positive (ER+) /HER2-negative (HER2-) breast cancer allows real-time evaluation of drug efficacy as well as investigation of the biological and molecular changes that occur after estrogenic deprivation. Clinical and pathological evaluation after NET may be used to obtain prognostic and predictive information of tumour response to decide adjuvant treatment. In this setting, clinical scales developed to evaluate response after neoadjuvant chemotherapy are not useful and there are not validated biomarkers to assess response to NET beyond Ki67 levels and preoperative endocrine prognostic index score (mPEPI). METHODS: In this prospective study, we extensively analysed radiological (by ultrasound scan (USS) and magnetic resonance imaging (MRI)) and pathological tumour response of 104 postmenopausal patients with ER+ /HER2- resectable breast cancer, treated with NET for a mean of 7 months prior to surgery. We defined a new score, tumour cellularity size (TCS), calculated as the product of the residual tumour cellularity in the surgical specimen and the tumour pathological size. RESULTS: Our results show that radiological evaluation of response to NET by both USS and MRI underestimates pathological tumour size (path-TS). Tumour size [mean (range); mm] was: path-TS 20 (0-80); radiological-TS by USS 9 (0-31); by MRI: 12 (0-60). Nevertheless, they support the use of MRI over USS to clinically assess radiological tumour response (rad-TR) due to the statistically significant association of rad-TR by MRI, but not USS, with Ki67 decrease (p = 0.002 and p = 0.3, respectively) and mPEPI score (p = 0.002 and p = 0.6, respectively). In addition, we propose that TCS could become a new tool to standardize response assessment to NET given its simplicity, reproducibility and its good correlation with existing biomarkers (such as ΔKi67, p = 0.001) and potential added value. CONCLUSION: Our findings shed light on the dynamics of tumour response to NET, challenge the paradigm of the ability of NET to decrease surgical volume and point to the utility of the TCS to quantify the scattered tumour response usually produced by endocrine therapy. In the future, these results should be validated in independent cohorts with associated survival data.

A Phase 1/2A trial of idroxioleic acid: first-in-class sphingolipid regulator and glioma cell autophagy inducer with antitumor activity in refractory glioma.

BACKGROUND: The first-in-class brain-penetrating synthetic hydroxylated lipid idroxioleic acid (2-OHOA; sodium 2-hydroxyoleate), activates sphingomyelin synthase expression and regulates membrane-lipid composition and mitochondrial energy production, inducing cancer cell autophagy. We report the findings of a multicentric first-in-human Phase 1/2A trial (NCT01792310) of 2-OHOA, identifying the maximum tolerated dose (MTD) and assessing safety and preliminary efficacy. METHODS: We performed an open-label, non-randomised trial to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumour activity of daily oral treatment with 2-OHOA monotherapy (BID/TID) in 54 patients with glioma and other advanced solid tumours. A dose-escalation phase using a standard 3 + 3 design was performed to determine safety and tolerability. This was followed by two expansion cohorts at the MTD to determine the recommended Phase-2 dose (RP2D). RESULTS: In total, 32 recurrent patients were enrolled in the dose-escalation phase (500-16,000 mg/daily). 2-OHOA was rapidly absorbed with dose-proportional exposure. Treatment was well-tolerated overall, with reversible grade 1-2 nausea, vomiting, and diarrhoea as the most common treatment-related adverse events (AEs). Four patients had gastrointestinal dose-limiting toxicities (DLTs) of nausea, vomiting, diarrhoea (three patients at 16,000 mg and one patient at 12,000 mg), establishing an RP2D at 12,000 mg/daily. Potential activity was seen in patients with recurrent high-grade gliomas (HGG). Of the 21 patients with HGG treated across the dose escalation and expansion, 5 (24%) had the clinical benefit (RANO CR, PR and SD >6 cycles) with one exceptional response lasting >2.5 years. CONCLUSIONS: 2-OHOA demonstrated a good safety profile and encouraging activity in this difficult-to-treat malignant brain-tumour patient population, placing it as an ideal potential candidate for the treatment of glioma and other solid tumour malignancies. CLINICAL TRIAL REGISTRATION: EudraCT registration number: 2012-001527-13; Clinicaltrials.gov registration number: NCT01792310.

Evaluating the clinical effectiveness and safety of various HER2-targeted regimens after prior taxane/trastuzumab in patients with previously treated, unresectable, or metastatic HER2-positive breast cancer: a systematic review and network meta-analysis.

PURPOSE: In the absence of head-to-head trial data, network meta-analysis (NMA) was used to compare trastuzumab emtansine (T-DM1) with other approved treatments for previously treated patients with unresectable or metastatic HER2-positive breast cancer (BC). METHODS: Systematic reviews were conducted of published controlled trials of treatments for unresectable or metastatic HER2-positive BC with early relapse (≤ 6 months) following adjuvant therapy or progression after trastuzumab (Tras) + taxane published from January 1998 to January 2018. Random-effects NMA was conducted for overall survival (OS), progression-free survival (PFS), overall response rate (ORR), and safety endpoints. RESULTS: The NMA included regimens from seven randomized controlled trials: T-DM1 and combinations of Tras, capecitabine (Cap), lapatinib (Lap), neratinib, or pertuzumab (Per; unapproved). OS results favored T-DM1 over approved comparators: hazard ratio (HR) (95% credible interval [95% CrI]) vs Cap 0.68 (0.39, 1.10), LapCap 0.76 (0.51, 1.07), TrasCap 0.78 (0.44, 1.19). PFS trends favored T-DM1 over all other treatments: HR (95% CrI) vs Cap 0.38 (0.19, 0.74), LapCap 0.65 (0.40, 1.10), TrasCap 0.62 (0.34, 1.18); ORR with T-DM1 was more favorable than with all approved treatments. In surface under cumulative ranking curve (SUCRA) analysis T-DM1 ranked highest for all efficacy outcomes. Discontinuation due to adverse events was less likely with T-DM1 than with all comparators except neratinib. In general, gastrointestinal side effects were less likely and elevated liver transaminases and thrombocytopenia more likely with T-DM1 than with comparators. CONCLUSIONS: The efficacy and tolerability profiles of T-DM1 are generally favorable compared with other treatments for unresectable or metastatic HER2-positive BC.

Efficacy and safety of dasatinib with trastuzumab and paclitaxel in first line HER2-positive metastatic breast cancer: results from the phase II GEICAM/2010-04 study.

BACKGROUND: An important proportion of HER2-positive metastatic breast cancer patients do not respond to trastuzumab. The combination of dasatinib and trastuzumab has shown to be synergistic in preclinical models. METHODS: We conducted a phase II trial combining dasatinib 100 mg once daily with trastuzumab 2 mg/kg and paclitaxel 80 mg/m2 weekly. Primary objective was objective response rate (ORR) and secondary included safety, other efficacy parameters and pharmacodynamics in tumour tissue, blood samples and skin biopsies. RESULTS: From June 2013 to December 2015, 29 patients were included. Median number of cycles was 12 (1-49). Only 6 patients discontinued due to adverse events. ORR was 79.3% (95% CI 60.3-92), clinical benefit rate 82.8% (95% CI 64.2-94.2). Median time to progression 23.9 months (95% CI 14.9-not reached [NR]), median progression-free survival 23.9 months (95% CI 10.3-NR). No grade 4 toxicity was seen. Grade 3 toxicities included: ejection fraction decrease, neutropenia, hyponatremia, fatigue and sensory neuropathy and one left ventricular systolic dysfunction. Phosphorylated (p)-SRC was reduced in peripheral blood mononuclear cells. Phosphorylated SRC, ERK and AKT were also reduced in epidermal keratinocytes. CONCLUSIONS: Dasatinib can be safely combined with trastuzumab and paclitaxel. The combination is active with an ORR of almost 80%. TRIAL REGISTRATION: NCT01306942, EudraCT 2010-023304-27.

A phase Ib study of sonidegib (LDE225), an oral small molecule inhibitor of smoothened or Hedgehog pathway, in combination with docetaxel in triple negative advanced breast cancer patients: GEICAM/2012-12 (EDALINE) study.

Up-regulation of the Hedgehog (Hh) pathway is implicated in the genesis of a wide range of tumors including triple negative breast cancer (TNBC). Sonidegib is a potent and selective oral inhibitor of Smo, a key component of the Hh signaling pathway. We designed a phase I clinical study to explore the combination of sonidegib plus docetaxel (fixed dose at 75 mg/m2) in advanced TNBC patients. The primary objective was to ascertain the combination's maximum tolerated dose and the recommended phase II dose (RP2D), based on dose limiting toxicities (DLTs) in the first 2 cycles. A standard "3 + 3" design was followed including three dose levels (DL) of sonidegib: 400 mg (DL1), 600 mg (DL2), and 800 mg (DL3). Twelve patients were included. Sonidegib 800 mg orally q.d. plus docetaxel 75 mg/m2 given intravenously on day 1 of 21-day cycles was established as the RP2D. No DLTs were observed at any DL. The median number of administered cycles at DL3 was 8 (range: 6 to 9). Grade 3 adverse events (AEs) at DL3 were neutropenia (66.7%), CPK increase (33.3%), leukopenia (33.3%), and paresthesia (33.3%), grade 4 AEs were not reported at this DL. At the RP2D, the combination showed antitumor activity in three out of 10 patients with measurable disease. Median time to progression for the overall study was 42.5 days (95% Confidence Interval: 29-155), and 188 days at DL3. No drug-to-drug interactions between sonidegib and docetaxel were found in the PK assessment. Trial Registration: EudraCT study number: 2013-001750-96. Study GEICAM/2012-12. TRIAL REGISTRATION: EudraCT study number: 2013-001750-96. Study GEICAM/2012-12. ClinicalTrials.gov: NCT02027376.

Assessing taste and smell alterations in cancer patients undergoing chemotherapy according to treatment.

PURPOSE: Taste and smell changes are common side effects in cancer patients undergoing chemotherapy treatments (CT). This can lead to a reduced food enjoyment and an inadequate nutrient intake with a high impact on nutritional status and quality of life. The aim of this study was to evaluate the self-reported chemosensory alterations of patients undergoing chemotherapy according to CT type. METHODS: An observational study was conducted with 151 patients undergoing CT at Oncology Outpatient Unit from Onkologikoa Foundation. An interviewer-assisted questionnaire was designed to investigate chemosensory changes in patients undergoing CT. RESULTS: Seventy-six percent patients reported taste disorders and 45% smell changes. Xerostomia is the most frequent symptom reported by patients receiving chemotherapy in our study (63.6%), and it is strongly associated to bad taste in mouth (OR = 5.96; CI = 2.37-14.94; p value = 0.000) and taste loss (OR = 5.96; CI = 2.37-14.94; p value = 0.000). Anthracyclines, paclitaxel, carboplatin, and docetaxel were the CT agents producing the highest taste disturbance rates. Cisplatin and 5-Fluorouracil are the CT resulting in the lowest complaints. Logistic regression revealed statistically significant associations between taste loss and carboplatin and docetaxel (OR = 3.50; CI = 1.12-10.90; p value = 0.031) and cold hypersensitivity and oxaliplatin (OR = 12.14; CI = 4.18-35.25; p value = 0.000). Not only platin-based CT such as carboplatin produced dysgeusia, but also anthracyclines and paclitaxel treatments. CONCLUSIONS: The better knowledge of taste and smell alterations according to CT type may provide valuable information for the design of new strategies to tackle CT side effects. It is important to take into account taste and smell dysfunctions and other alterations such as xerostomia together.

VAV3 mediates resistance to breast cancer endocrine therapy.

INTRODUCTION: Endocrine therapies targeting cell proliferation and survival mediated by estrogen receptor α (ERα) are among the most effective systemic treatments for ERα-positive breast cancer. However, most tumors initially responsive to these therapies acquire resistance through mechanisms that involve ERα transcriptional regulatory plasticity. Herein we identify VAV3 as a critical component in this process. METHODS: A cell-based chemical compound screen was carried out to identify therapeutic strategies against resistance to endocrine therapy. Binding to ERα was evaluated by molecular docking analyses, an agonist fluoligand assay and short hairpin (sh)RNA-mediated protein depletion. Microarray analyses were performed to identify altered gene expression. Western blot analysis of signaling and proliferation markers, and shRNA-mediated protein depletion in viability and clonogenic assays, were performed to delineate the role of VAV3. Genetic variation in VAV3 was assessed for association with the response to tamoxifen. Immunohistochemical analyses of VAV3 were carried out to determine its association with therapeutic response and different tumor markers. An analysis of gene expression association with drug sensitivity was carried out to identify a potential therapeutic approach based on differential VAV3 expression. RESULTS: The compound YC-1 was found to comparatively reduce the viability of cell models of acquired resistance. This effect was probably not due to activation of its canonical target (soluble guanylyl cyclase), but instead was likely a result of binding to ERα. VAV3 was selectively reduced upon exposure to YC-1 or ERα depletion, and, accordingly, VAV3 depletion comparatively reduced the viability of cell models of acquired resistance. In the clinical scenario, germline variation in VAV3 was associated with the response to tamoxifen in Japanese breast cancer patients (rs10494071 combined P value = 8.4 × 10-4). The allele association combined with gene expression analyses indicated that low VAV3 expression predicts better clinical outcome. Conversely, high nuclear VAV3 expression in tumor cells was associated with poorer endocrine therapy response. Based on VAV3 expression levels and the response to erlotinib in cancer cell lines, targeting EGFR signaling may be a promising therapeutic strategy. CONCLUSIONS: This study proposes VAV3 as a biomarker and a rationale for its use as a signaling target to prevent and/or overcome resistance to endocrine therapy in breast cancer.

A randomized controlled trial of the effectiveness of a one-to-one peer support intervention on resilience, social support, and salivary cortisol in recently diagnosed women with breast cancer.

PURPOSE: Peer support has been suggested as a way to help women diagnosed with breast cancer to better cope with their situation, but studies on its effectiveness have conflicting results. This randomized controlled trial aimed to study the effectiveness of a one-to-one peer support intervention on psychological resilience, social support, and salivary cortisol among breast cancer patients. METHODS: The sample consisted of 121 newly diagnosed women at Onkologikoa Hospital. Patients who were prescribed chemotherapy were randomly assigned to Intervention Group 1 (IG1) or Control Group 1 (CG1). Similarly, those prescribed adjuvant radiotherapy were assigned to IG2 or CG2. Women in IG1 received 8 biweekly social support sessions from volunteer survivors who had successfully overcome breast cancer, while IG2 received 6 biweekly sessions. CG1 and CG2 only received standard care. Resilience, social support, and salivary cortisol were assessed at baseline (T1) and at the end of the intervention (T2). RESULTS: We found a non-significant, yet a small to moderate size increase in resilience from T1 to T2 in IG1 (p = 0.246; dDc = 0.47). Upon regression analysis, we observed that this increase was determined by changes in cortisol (ß = -0.658, p = 00.010), affective support (ß = -0.997, p = 00.014), and emotional support (ß = 0.935, p = 00.008). We also found a significant decrease in resilience levels in CG2 from T1 to T2 (p = 0.003; dDc = 0.88). CONCLUSION: The present study suggests that peer support can exert a protective psychological influence on women diagnosed with breast cancer, and further indicates an exciting avenue for future intervention development in the breast cancer care continuum. TRIAL REGISTRATION: ClinicalTrials.gov NCT05077371.

Acetyl-CoA carboxylase 1 controls a lipid droplet-peroxisome axis and is a vulnerability of endocrine-resistant ER+ breast cancer.

Targeting aromatase deprives ER+ breast cancers of estrogens and is an effective therapeutic approach for these tumors. However, drug resistance is an unmet clinical need. Lipidomic analysis of long-term estrogen-deprived (LTED) ER+ breast cancer cells, a model of aromatase inhibitor resistance, revealed enhanced intracellular lipid storage. Functional metabolic analysis showed that lipid droplets together with peroxisomes, which we showed to be enriched and active in the LTED cells, controlled redox homeostasis and conferred metabolic adaptability to the resistant tumors. This reprogramming was controlled by acetyl-CoA-carboxylase-1 (ACC1), whose targeting selectively impaired LTED survival. However, the addition of branched- and very long-chain fatty acids reverted ACC1 inhibition, a process that was mediated by peroxisome function and redox homeostasis. The therapeutic relevance of these findings was validated in aromatase inhibitor-treated patient-derived samples. Last, targeting ACC1 reduced tumor growth of resistant patient-derived xenografts, thus identifying a targetable hub to combat the acquisition of estrogen independence in ER+ breast cancers.

Preventing alpelisib-related hyperglycaemia in HR+/HER2-/PIK3CA-mutated advanced breast cancer using metformin (METALLICA): a multicentre, open-label, single-arm, phase 2 trial.

Background: Hyperglycaemia is an early and frequent adverse event during alpelisib treatment. METALLICA aimed to evaluate prophylactic metformin to prevent or reduce hyperglycaemia occurrence in patients with HR+/HER2-/PIK3CA-mutated advanced breast cancer (ABC). Methods: Between August 13th, 2020 and March 23rd, 2022, this 2-cohort, phase 2, multicentre, single-arm trial (NCT04300790) enrolled patients with HR+/HER2-/PIK3CA-mutated ABC: cohort A, normal glycaemia (fasting plasma glucose <100 mg/dL [<5.6 mmol/L] and HbA1c <5.7%), and cohort B, prediabetes (fasting plasma glucose 100-140 mg/dL [5.6-7.8 mmol/L] and/or haemoglobin A1C [HbA1c] 5.7-6.4%). Participants were at least 18 years old, with Eastern Cooperative Oncology Group performance status of 0-1, and up to two prior lines of endocrine therapy (ET) for ABC. Alpelisib plus ET were administered in 28-day cycles after initiation of prophylactic metformin plus ET. Primary endpoint was the incidence of grade 3-4 hyperglycaemia over the first 8 weeks. Secondary endpoints included safety, progression-free survival (PFS), objective response rate (ORR), and clinical benefit rate (CBR). The primary objective for cohort A and B is met with ≤7 (14.6%) and ≤4 (20%) patients with grade 3-4 hyperglycaemia over the first 8 weeks, respectively. Findings: 233 patients were screened, and 68 (20.2%) patients were enrolled in cohorts A (n = 48) and B (n = 20). Median follow-up was 7.8 months (IQR 1.4-19.6). Over the first 8 weeks, one (2.1%) of 48 patients in cohort A (95% CI: 0.5-11.1; P < 0.0001), and three (15.0%) of 20 patients in cohort B (95% CI: 5.6-37.8; P = 0.016) had grade 3-4 hyperglycaemia. Serious treatment-related adverse events occurred in seven patients (10.3%). The most common were rash (two [2.9%]), vomiting (two [2.9%]), and diarrhoea (two [2.9%]). Discontinuation of alpelisib caused by AEs was reported in nine patients (13.2%), none caused by hyperglycaemia. At data cutoff (15 June, 2022), no treatment-related deaths were observed. In the full analysis set, median PFS was 7.3 months (95% CI: 5.9-not reached), ORR was 20.6% (95% CI: 11.7-32.1%), and CBR was 52.9% (95% CI: 40.4-65.2). Interpretation: In HR+/HER2-/PIK3CA-mutated ABC, prophylactic metformin before alpelisib plus endocrine treatment has low incidence and severity of alpelicib-induced hyperglycaemia. Funding: Novartis Pharmaceuticals.

Early Detection of Brain Metastases in a Supervised Exercise Program for Patients with Advanced Breast Cancer: A Case Report.

INTRODUCTION: Around 25% of metastatic breast cancer (mBC) patients develop brain metastases, which vastly affects their overall survival and quality of life. According to the current clinical guidelines, regular magnetic resonance imaging screening is not recommended unless patients have recognized central nervous system-related symptoms. PATIENT PRESENTATION: The patient participated in the EFFECT study, a randomized controlled trial aimed to assess the effects of a 9-month structured, individualized and supervised exercise intervention on quality of life, fatigue and other cancer and treatment-related side effects in patients with mBC. She attended the training sessions regularly and was supervised by the same trainer throughout the exercise program. In month 7 of participation, her exercise trainer detected subtle symptoms (e.g., changes in movement pattern, eye movement or balance), which had not been noticed or reported by the patient herself or her family, and which were unlikely to have been detected by the oncologist or other health care providers at that point since symptoms were exercise related. When suspicion of brain metastases was brought to the attention of the oncologist by the exercise trainer, the response was immediate, and led to early detection and treatment of brain metastases. CONCLUSION AND CLINICAL IMPLICATIONS: The brain metastases of this patient were detected earlier due to the recognition of subtle symptoms detected by her exercise trainer and the trust and rapid action by the clinician. The implementation of physical exercise programs for cancer patients requires well-trained professionals who know how to recognize possible alterations in patients and also, good communication between trainers and the medical team to enable the necessary actions to be taken.

Functional Engagement of the PD-1/PD-L1 Complex But Not PD-L1 Expression Is Highly Predictive of Patient Response to Immunotherapy in Non-Small-Cell Lung Cancer.

PURPOSE: In many cancers, the expression of immunomodulatory ligands leads to immunoevasion, as exemplified by the interaction of PD-L1 with PD-1 on tumor-infiltrating lymphocytes. Profound advances in cancer treatments have come with the advent of immunotherapies directed at blocking these immuno-suppressive ligand-receptor interactions. However, although there has been success in the use of these immune checkpoint interventions, correct patient stratification for these therapies has been challenging. MATERIALS AND METHODS: To address this issue of patient stratification, we have quantified the intercellular PD-1/PD-L1 interaction in formalin-fixed paraffin-embedded tumor samples from patients with non-small cell lung carcinoma, using a high-throughput automated quantitative imaging platform (quantitative functional proteomics [QF-Pro]). RESULTS: The multisite blinded analysis across a cohort of 188 immune checkpoint inhibitor-treated patients demonstrated the intra- and intertumoral heterogeneity of PD-1/PD-L1 immune checkpoint engagement and notably showed no correlation between the extent of PD-1/PD-L1 interaction and PD-L1 expression. Importantly, PD-L1 expression scores used clinically to stratify patients correlated poorly with overall survival; by contrast, patients showing a high PD-1/PD-L1 interaction had significantly better responses to anti-PD-1/PD-L1 treatments, as evidenced by increased overall survival. This relationship was particularly strong in the setting of first-line treatments. CONCLUSION: The functional readout of PD-1/PD-L1 interaction as a predictive biomarker for the stratification of patients with non-small-cell lung carcinoma, combined with PD-L1 expression, should significantly improve the response rates to immunotherapy. This would both capture patients excluded from checkpoint immunotherapy (high PD-1/PD-L1 interaction but low PD-L1 expression, 24% of patients) and additionally avoid treating patients who despite their high PD-L1 expression do not respond and suffer from side effects.

Efficacy and safety of concurrent trastuzumab plus weekly paclitaxel-FEC as primary therapy for HER2-positive breast cancer in everyday clinical practice.

One of the most efficacious primary therapies in HER2-positive breast cancer was published by the M.D. Anderson group in 2005. This randomized trial evaluated the addition of trastuzumab to a taxane-anthracycline based chemotherapy. Despite largely significant differences in pathological complete response (pCR) in the trastuzumab group (65 vs. 26 %) this regimen did not become a common standard due to toxicity concerns and its premature closure with a small sample size. In order to evaluate the efficacy and safety of this regimen in an off-trial setting we conducted a prospectively monitorized series of consecutive patients with early or locally advanced Her-2 positive breast cancer following the same treatment strategy. Stage II-IIIC HER2-positive breast cancer patients, including inflammatory disease, were treated with weekly-trastuzumab for 24 weeks administered concurrently with all primary chemotherapy containing paclitaxel (80 mg/m(2)) for 12 weeks and 4 cycles of FEC-75 (fluorouracil 500 mg/m(2), epirubicine 75 mg/m(2), and cyclophosphamide 500 mg/m(2)) followed by surgery. The objectives were efficacy, in terms of pCR in both the breast and lymph nodes, and safety, with close cardiac monitoring during and after treatment. From August 2004 to February 2009, 83 patients were included. Most patients (73.5 %) had node involvement and 13.2 % had inflammatory disease. Fifty-one patients (61.4 %) achieved a pCR in breast and axilla (95 % CI 50-72 %). HR-negative tumors were associated with higher pCR rate than HR-positive tumors (77 vs. 48 %, P = 0.006). At a median follow-up of 50.2 months no patient developed symptomatic cardiac failure, and 9 patients (10.8 %) presented a transient asymptomatic decrease in left ventricular ejection fraction. Primary therapy with concurrent trastuzumab plus paclitaxel-FEC for HER2-positive breast cancer in everyday practice is highly effective and safe confirming the results observed in a randomized trial stopped prematurely.

Design of a multinational randomized controlled trial to assess the effects of structured and individualized exercise in patients with metastatic breast cancer on fatigue and quality of life: the EFFECT study.

BACKGROUND: Many patients with metastatic breast cancer experience cancer- and treatment-related side effects that impair activities of daily living and negatively affect the quality of life. There is a need for interventions that improve quality of life by alleviating fatigue and other side effects during palliative cancer treatment. Beneficial effects of exercise have been observed in the curative setting, but, to date, comparable evidence in patients with metastatic breast cancer is lacking. The aim of this study is to assess the effects of a structured and individualized 9-month exercise intervention in patients with metastatic breast cancer on quality of life, fatigue, and other cancer- and treatment-related side effects. METHODS: The EFFECT study is a multinational, randomized controlled trial including 350 patients with metastatic breast cancer. Participants are randomly allocated (1:1) to an exercise or control group. The exercise group participates in a 9-month multimodal exercise program, starting with a 6-month period where participants exercise twice a week under the supervision of an exercise professional. After completing this 6-month period, one supervised session is replaced by one unsupervised session for 3 months. In addition, participants are instructed to be physically active for ≥30 min/day on all remaining days of the week, while being supported by an activity tracker and exercise app. Participants allocated to the control group receive standard medical care, general written physical activity advice, and an activity tracker, but no structured exercise program. The primary outcomes are quality of life (EORTC QLQ-C30, summary score) and fatigue (EORTC QLQ-FA12), assessed at baseline, 3, 6 (primary endpoint), and 9 months post-baseline. Secondary outcomes include physical fitness, physical performance, physical activity, anxiety, depression, pain, sleep problems, anthropometric data, body composition, and blood markers. Exploratory outcomes include quality of working life, muscle thickness, urinary incontinence, disease progression, and survival. Additionally, the cost-effectiveness of the exercise program is assessed. Adherence and safety are monitored throughout the intervention period. DISCUSSION: This large randomized controlled trial will provide evidence regarding the (cost-) effectiveness of exercise during treatment of metastatic breast cancer. If proven (cost-)effective, exercise should be offered to patients with metastatic breast cancer as part of standard care. TRIAL REGISTRATION: ClinicalTrials.gov NCT04120298 . Registered on October 9, 2019.

Stromal oncostatin M cytokine promotes breast cancer progression by reprogramming the tumor microenvironment.

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.

A novel inhibitor of fatty acid synthase shows activity against HER2+ breast cancer xenografts and is active in anti-HER2 drug-resistant cell lines.

INTRODUCTION: Inhibiting the enzyme Fatty Acid Synthase (FASN) leads to apoptosis of breast carcinoma cells, and this is linked to human epidermal growth factor receptor 2 (HER2) signaling pathways in models of simultaneous expression of FASN and HER2. METHODS: In a xenograft model of breast carcinoma cells that are FASN+ and HER2+, we have characterised the anticancer activity and the toxicity profile of G28UCM, the lead compound of a novel family of synthetic FASN inhibitors. In vitro, we analysed the cellular and molecular interactions of combining G28UCM with anti-HER drugs. Finally, we tested the cytotoxic ability of G28UCM on breast cancer cells resistant to trastuzumab or lapatinib, that we developed in our laboratory. RESULTS: In vivo, G28UCM reduced the size of 5 out of 14 established xenografts. In the responding tumours, we observed inhibition of FASN activity, cleavage of poly-ADPribose polymerase (PARP) and a decrease of p-HER2, p- protein kinase B (AKT) and p-ERK1/2, which were not observed in the nonresponding tumours. In the G28UCM-treated animals, no significant toxicities occurred, and weight loss was not observed. In vitro, G28UCM showed marked synergistic interactions with trastuzumab, lapatinib, erlotinib or gefitinib (but not with cetuximab), which correlated with increases in apoptosis and with decreases in the activation of HER2, extracellular signal-regulated kinase (ERK)1/2 and AKT. In trastuzumab-resistant and in lapatinib-resistant breast cancer cells, in which trastuzumab and lapatinib were not effective, G28UCM retained the anticancer activity observed in the parental cells. CONCLUSIONS: G28UCM inhibits fatty acid synthase (FASN) activity and the growth of breast carcinoma xenografts in vivo, and is active in cells with acquired resistance to anti-HER2 drugs, which make it a candidate for further pre-clinical development.

Evidence for a link between TNFRSF11A and risk of breast cancer.

Intracellular signaling mediated by the receptor activator of nuclear factor-κB [Rank, encoded by the tumor necrosis factor receptor superfamily, member 11a (Tnfrsf11a) gene] is fundamental for mammary gland development in mice, regulating the expansion of stem and progenitor cell compartments. Conversely, Rank overexpression in mice promotes abnormal proliferation and impairs differentiation, leading to an increased incidence of tumorigenesis. Here, we show that a common genetic variant near the 5'-end of TNFRSF11A, rs7226991, is associated with breast cancer risk in the general population and among carriers of mutations in the breast cancer 2, early onset (BRCA2) gene. Akin to the results of the Cancer and Genetics Markers of Susceptibility initiative, combined analysis of rs7226991 in two Spanish case-control studies (1,365 controls and 1,323 cases in total) revealed a significant association with risk: odds ratio (OR) = 0.88, 95% confidence interval (CI) 0.78-0.98, P (trend) = 0.025. Subsequent examination of BRCA1 (n = 1,017) and BRCA2 (n = 885) mutation carriers revealed a consistent association in the latter group: weighted hazard ratio ((w)HR) = 0.70; 95% CI 0.55-0.88; and P (trend) = 0.003; compared to BRCA1 mutation carriers, (w)HR = 0.91; 95% CI 0.76-1.10; and P (trend) = 0.33. The results of this study need to be replicated in other populations and with larger numbers of BRCA1/2 mutation carriers.

Discovery and Proof-of-Concept Study of Nuclease Activity as a Novel Biomarker for Breast Cancer Tumors.

Breast cancer is one of the most common pathologies diagnosed in the clinical practice. Despite major advancements in diagnostic approaches, there is no widely accepted biomarker in the clinical practice that can diagnose breast malignancy. Confirmatory diagnosis still relies on the pathological assessment of tissue biopsies by expert pathologists. Thus, there is an unmet need for new types of biomarkers and novel platform technologies that can be easily and robustly integrated into the clinic and that can assist pathologists. Herein, we show that nuclease activity associated to malignant tumors can be used as a novel biomarker in breast cancer, which can be detected via specific degradation of nucleic acid probes. In this study we have identified a set of three chemically modified nucleic acid probes that can diagnose malignancy in biopsy samples with high accuracy (89%), sensitivity (82%) and specificity (94%). This work represents a breakthrough for the potential clinical use of nuclease activity as biomarker, which can be detected via nucleic acids probes, for the clinical diagnosis of malignancy in breast tissue biopsies. This platform technology could be readily implemented into the clinic as adjunct to histopathological diagnostic.

Avoiding axillary treatment in sentinel lymph node micrometastases of breast cancer: a prospective analysis of axillary or distant recurrence.

BACKGROUND: The need for axillary lymph node dissection (ALND) in breast cancer patients with sentinel lymph node (SLN) micrometastases remains controversial. The aims of the study were to evaluate the locoregional failure and outcome of breast cancer patients with sentinel node micrometastases who did not undergo completion ALND. METHODS: Between November 2000 and December 2006, SLN biopsy was successfully performed in 1178 patients with invasive breast carcinoma. Only patients with macrometastasis (>2 mm) underwent ALND, while patients with negative SLN or micrometastases did not undergo further treatment of the axilla, by either surgery or radiotherapy. Regarding adjuvant therapy decision, patients with SLN-micrometastases (pN1(mi)) were considered as node-positive patients. RESULTS: Of 1,178 patients, 59 (5%) had micrometastases. Of those with micrometastases, 14 (24%) underwent ALND because the intraoperative study of the SLN yielded a positive result. With a median follow-up of 60 (range, 8-94) months, none of the patients with SLN micrometastases in whom ALND was omitted developed an axillary recurrence, while one patient in whom ALND was performed developed infraclavicular lymph node recurrence. One patient, who declined postoperative breast irradiation, developed breast recurrence and distant metastasis. CONCLUSIONS: Breast cancer patients with SLN micrometastases in whom ALND was omitted had a very low locoregional failure rate. This study supports the theory that ALND might be avoided in these patients, providing that adjuvant systemic treatment equal to treatment provided to treat node-positive disease is administered. However, longer follow-up and results of additional prospective studies are needed.

Altered Levels of Desaturation and ω-6 Fatty Acids in Breast Cancer Patients' Red Blood Cell Membranes.

Red blood cell (RBC) membrane can reflect fatty acid (FA) contribution from diet and biosynthesis. In cancer, membrane FAs are involved in tumorigenesis and invasiveness, and are indicated as biomarkers to monitor the disease evolution as well as potential targets for therapies and nutritional strategies. The present study provides RBC membrane FA profiles in recently diagnosed breast cancer patients before starting chemotherapy treatment. Patients and controls were recruited, and their dietary habits were collected. FA lipidomic analysis of mature erythrocyte membrane phospholipids in blood samples was performed. Data were adjusted to correct for the effects of diet, body mass index (BMI), and age, revealing that patients showed lower levels of saturated fatty acids (SFA) and higher levels of monounsaturated fatty acid, cis-vaccenic (25%) than controls, with consequent differences in desaturase enzymatic index (∆9 desaturase, -13.1%). In the case of polyunsaturated fatty acids (PUFA), patients had higher values of ω-6 FA (C18:2 (+11.1%); C20:4 (+7.4%)). RBC membrane lipidomic analysis in breast cancer revealed that ω-6 pathways are favored. These results suggest new potential targets for treatments and better nutritional guidelines.