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Background Further research is still needed to fully understand the potential of prostate-specific membrane antigen (PSMA) in breast cancer (BC) and to develop and optimize targeted therapies and imaging modalities. The objective of this study was to present a comprehensive analysis of immunohistochemistry data on PSMA staining in BC and to discuss its potential value in a theranostic approach. Methods Fifty-eight male and female patients were randomly selected from a retrospective database of patients who underwent surgery for breast cancer between January 2012 and December 2017 and for whom a specimen is available in our tumour library. Immunodetection of PSMA and CD31 was performed on serial slides. The digitized slides were reviewed and analysed by an experienced pathologist. Additionally, the corresponding TIFF images were processed to calculate the percentage of positive neovessels. Results Eighteen patients (31.6%) had no expression, 29 (50.9%) had PSMA neovascular expression scored as “1”, and 10 (17.5%) had neovascular expression scored as “2”. Digital immunohistochemistry analysis for this last specific group of patients showed a median proportion of positive neovessels equal to 5% (range: 3–19). A multivariable logistic regression demonstrated that the odds of PSMA positivity were 4.55 times higher in non-luminal tumours and decreased by a factor of 0.12 in lobular subtypes. There was no association between sex or the presence of a germline BRCA1/2 mutation and PSMA expression in tumours. Conclusions Our study highlights generally low neovascular expression of PSMA in specific histopathological subtypes of breast cancer, which will likely hamper the development of an adequate theranostic strategy. Trial registration The procedure has been retrospectively registered to the French National Institute for Health Data (N° F20220615153900).

Background Endocrine therapy is recommended as a first-line treatment for hormone receptor-positive metastatic breast cancer (HR+MBC) patients. No biomarker has been validated to predict tumor progression in that setting. We aimed to prospectively compare the risk of early progression according to circulating ESR1 mutations, CA-15.3, and circulating cell-free DNA in MBC patients treated with a first-line aromatase inhibitor (AI). Methods Patients with MBC treated with a first-line AI were prospectively included. Circulating biomarker assessment was performed every 3 months. The primary objective was to determine the risk of progression or death at the next follow-up visit (after 3 months) in case of circulating ESR1 mutation detection among patients treated with a first-line AI for HR+MBC. Results Overall, 103 patients were included, and 70 (68%) had progressive disease (PD). Circulating ESR1 mutations were detected in 22/70 patients with PD and in 0/33 patients without progression ( p  < 0.001). Among the ESR1 -mutated patients, 18/22 had a detectable mutation prior to progression, with a median delay of 110 days from first detection to PD. The detection of circulating ESR1 mutations was associated with a 4.9-fold (95% CI 3.0–8.0) increase in the risk of PD at 3 months. Using a threshold value of 25% or 100%, a CA-15.3 increase was also correlated with progression ( p  < 0.001 and p  = 0.003, respectively). In contrast to ESR1 , the CA-15.3 increase occurred concomitantly with PD in most cases, in 27/47 (57%) with a 25% threshold and in 21/25 (84%) with a 100% threshold. Using a threshold value of either 25% or 100%, cfDNA increase was not correlated with progression. Conclusion The emergence of circulating ESR1 mutations is associated with a 4.9-fold increase in the risk of early PD during AI treatment in HR+MBC. Our results also highlighted that tracking circulating ESR1 mutations is more relevant than tracking CA-15.3 or cfDNA increase to predict progression in this setting. Trial registration ClinicalTrials . gov, NCT02473120 . Registered 16 June 2015—retrospectively registered after one inclusion (first inclusion 1 June 2015)

Background Non-metastatic breast cancer treatment is mainly based on surgery, with or without chemotherapy, radiotherapy and/or hormone therapy. To reduce the risk of hormone receptor positive (HR+) disease recurrence, hormone therapy is prescribed for at least 5 years. It may induce adverse drug reactions (ADRs) as joint pain, sexual dysfunction, weight increase, fatigue, mood disorders and vasomotor symptoms. Around 30–40% of patients withhold hormone therapy within 5 years after initiation. Based on encouraging results of mobile health in patient follow-up, we developed a web-application addressed for breast cancer patients initiating adjuvant hormonal therapy and aimed to assess its impact on hormone therapy adherence, ADRs management, and health-related quality of life. Methods The WEBAPPAC trial is a randomized, open-label, prospective, single-center phase 3 study aiming to assess the interest of a web-application support as compared to standard management among breast cancer patients initiating hormone therapy. The main endpoint is the proportion of patients with hormone therapy adherence failure within 18 months after treatment start, in each arm. Eligible patients will be 1:1 randomized between the WEBAPPAC web-application support (experimental arm,) or standard support (control arm), with stratification on type of hormone therapy (Aromatase inhibitor or Tamoxifen). We plan to enroll 438 patients overall. Failure to hormone therapy will be assessed using the Morisky 8-item self-questionnaire (MMSA8), patient adherence logbook, and medical consultations. Secondary outcomes include hormone therapy adherence at 6 months, pain (Visual Analogue Scale and Brief Pain Inventory), quality of life (EORTC QLQ-C30 and BR23 self-questionnaires), anxiety and depression (Hospital and Depression Scale), and return to work and/or daily activities. The user experience with the WEBAPPAC web-application will be assessed using the System Usability Scale (SUS) questionnaire. Discussion Hormone therapy discontinuation or adherence failure in breast cancer patients may be indirectly related to an increased risk of recurrence. A better control of medication adherence, through the detection of side effects and some proposed actions trying to reduce them, appears therefore essential to limit the risk of disease recurrence. The WEBAPPAC web-application thus aims better monitoring and allowing higher level of responsiveness in case of ADRs, thus improving treatment adherence. Trial registration NCT04554927, registered September 18, 2020. Protocol version Version 2.1 dated from December 21, 2021.

Abstract Rest-activity rhythm (RAR) disruptions are frequently associated with chemotherapy in breast cancer (BC), but they are less known in BC with endocrine therapy (ET). The aim of this ancillary study was to characterize the RAR and estimated sleep characteristics from actigraphy in BC patients either treated (ET+) or untreated with ET (ET−), compared to healthy controls (HC) and using a cross-sectional design. Eighteen ET+, 18 ET−, and 16 HC completed questionnaires and wore wrist actigraphs at home for 2 weeks. Parametric and nonparametric RAR, sleep parameters, and quality of life were compared between groups (p < .05). BC groups presented lower daytime activity than HC according to RAR analysis (mesor and M10 parameters). Compared to HC, ET− had lower inter-daily stability and ET+ had greater sleep complaints. Compared to ET−, ET+ had lower sleep efficiency, more time awake, and higher activity levels at night, as assessed with actigraphy. Our results suggest an effect of cancer independent of treatment on RAR in BC, highlighting the need for further investigation of this topic. In contrast, sleep as assessed with actigraphy seems modified only during ET which matches with patients’ sleep complaints. Further longitudinal studies would aid in confirming the latter hypothesis.

Background Exploring the value of baseline and early 18 F-FDG PET/CT evaluations in prediction PFS in ER+/HER2- metastatic breast cancer patients treated with a cyclin-dependent kinase inhibitor in combination with an endocrine therapy. Methods Sixty-six consecutive breast cancer patients who underwent a pre-therapeutic 18 F-FDG PET/CT and a second PET/CT within the first 6 months of treatment were retrospectively included. Metabolic tumour volume (MTV) and total lesion glycolysis (TLG) and D max , which represents tumour dissemination and is defined as the distance between the two most distant lesions, were computed. The variation in these parameters between baseline and early evaluation PET as well as therapeutic evaluation using PERCIST were assessed as prognosticators of PFS at 18 months. Results The median follow-up was equal to 22.5 months. Thirty progressions occurred (45.4%). The average time to event was 17.8 ± 10.4 months. At baseline, D max was the only predictive metabolic parameter. Patients with a baseline D max ≤ 18.10 cm had a significantly better 18 m-PFS survival than the others: 69.2% (7.7%) versus 36.7% (8.8%), p  = 0.017. There was no association between PERCIST evaluation and 18 m-PFS status ( p  = 0.149) and there was no difference in 18 m-PFS status between patients classified as complete, partial metabolic responders or having stable metabolic disease. Conclusion Disease spread at baseline PET, as assessed by D max , is predictive of an event occurring within 18 months. In the absence of early metabolic progression, which occurs in 15% of patients, treatment should be continued regardless of the quality of the initial response to treatment.

Cognitive complaints are common in breast cancer (BC). Previous studies have linked sleep-disordered breathing (SDB) to cognitive decline in the general population, highlighting hypoxia as a key factor in cognitive decline severity. This link is understudied in BC patients. We investigated the association between nocturnal hypoxia and cognitive performance in 35 BC patients compared to 21 healthy controls (HC; mean ages: 61.6 ± 5.3 and 62.6 ± 4.3, respectively) using in-home ambulatory polysomnography, including oximeter to record oxygen saturation. All participants completed questionnaires and cognitive tests. Non-parametric Wilcoxon tests were conducted to compare the two groups and multivariable models to measure the association between hypoxia and cognitive performance, adjusting for anxiety and depression. Our results showed more frequent nocturnal hypoxia and more cognitive complaints in BC patients compared to HCs ( p  < 0.05). However, cognitive tests did not show significant impairment in the BC group, and no significant association was found between nocturnal hypoxia and cognitive performance. Our patients were treated with radiotherapy and/or endocrine therapy, but without chemotherapy, which may explain their normal cognitive scores despite subjective cognitive complaints. Nocturnal hypoxia is more prevalent in BC patients than in HCs, but it may not be the primary factor influencing cognitive performance in this population. Trial registration: NCT03420105, registered: January 10, 2018.

Background HER2 expression has a prognostic and predictive impact in early-stage breast cancer (BC). HER2 positive BC (immunohistochemistry (IHC) score 3 + or 2 + with in situ hybridization (ISH) amplification) are treated with HER2 targeted therapies. The concept of HER2-low BC (IHC score 1 + or 2 + without ISH amplification) is drawing attention as anti-HER2 treatment has recently shown efficacy in this subgroup. We aimed to explore the response to neoadjuvant chemotherapy (NAC) in HER2-low early BC according to the HER2 score (1 + or 2 + without amplification). Methods We conducted a retrospective study in two French comprehensive cancer centers. All patients with HER2-low BC treated with NAC from January 2014 to December 2020 were included. The primary objective was to analyze the pathological complete response (pCR) rate to NAC using the Sataloff or RCB system, according to the HER2 score. Secondary objectives were to assess disease free survival (DFS), overall survival (OS) and to explore the immune environment through the Neutrophil-to-Lymphocyte Ratio (NLR), according to HER2 expression. Univariate and multivariate analyses were performed. Results We included 237 tumors for 229 patients. Of these, 160 (67.5%) tumors were HER2 1 + , 77 (32.5%) were HER2 2 + , and 152 (64.1%) were hormone receptor (HR) positive. The median age was 53.9 years. No differences in tumor characteristics were observed between HER2 1 + and HER2 2 + subgroups. pCR was achieved in 38 tumors (17%), without any difference between HER2 1 + and HER2 2 + subgroups ( p  = 0.77). DFS and OS were significantly different between HER2 1 + and HER2 2 + patients (HR = 0.41,CI95%[0.17;0.97] p  = 0.037 and HR = 0.31,CI95%[0.09;1.02] p  = 0.042, respectively). HER2 status was still associated with DFS and OS after adjustment for age, HR status and NLR, with better outcomes in favor of HER2 score 2 + (HR = 0.35 [0.15–0.84] and HR = 0.24 [0.07–0.81], respectively). NLR was not associated with worse DFS or OS. Conclusion In HER2-low early BC, no differences in pCR were observed between HER2 1 + and HER2 2 + tumors, however patients with HER2 2 + tumors had a better DFS and OS than those with HER2 1 + . Further investigations are needed to describe the intrinsic differences in the spectrum of HER2-low BC.

ImportanceERBB2-low (ie,ERBB2immunohistochemistry score of 1+ or 2+ in the absence ofERBB2gene amplification) breast cancer (BC) is a new entity, with emerging dedicated treatments. Little is known about its prognosis and response to conventional therapy compared withERBB2-zero breast tumors (ie, those with an immunohistochemistry score of 0).ObjectiveTo compare the outcomes for patients withERBB2-low metastatic BC (MBC) with those of patients withERBB2-zero MBC.Design, Setting, and ParticipantsThis cohort study was conducted from the Epidemiological Strategy and Medical Economics MBC platform and included patients with MBC treated between 2008 and 2016 in 18 French comprehensive cancer centers. The data analysis was conducted from July 16, 2020, to April 1, 2022.Main Outcomes and MeasuresThe main outcome was overall survival (OS), and the secondary outcome was progression-free survival under first-line treatments (PFS1).ResultsThe median (range) age was 60.0 (22.0-103.0) years. Among 15 054 patients with MBC, 4671 (31%) hadERBB2-low MBC and 10 383 (69%) hadERBB2-zero MBC. The proportion ofERBB2-low cancers was higher among patients with hormone receptor–positive MBC than those with hormone receptor–negative disease (4083 patients [33.0%] vs 588 patients [21.0%]). With a median follow-up of 49.5 months (95% CI, 48.6-50.4 months), the median OS of theERBB2-low group was 38.0 months (95% CI, 36.4-40.5 months) compared with 33.9 months (95% CI, 32.9-34.9 months) for theERBB2-zero group (P < .001). After adjustment for age, visceral metastases, number of metastatic sites, de novo disease, period of care, and hormone receptor status, patients withERBB2-low MBC had slightly better OS compared with patients withERBB2-zero MBC (adjusted hazard ratio, 0.95; 95% CI, 0.91-0.99;P = .02). In contrast, PFS1 did not differ byERBB2status (adjusted hazard ratio, 0.99; 95% CI, 0.95-1.02;P = .45). No significant differences in OS and PFS1 were observed in multivariate analyses by hormone receptor status and types of frontline treatment.Conclusions and RelevanceIn this large cohort study, patients withERBB2-low MBC had a slightly better OS than those with completelyERBB2-zero tumors, but identical PFS1, which could help guide treatment selection.

Abstract Background Although adjuvant cancer treatments increase cure rates, they may induce clonal selection and tumor resistance. Information still lacks as whether (neo)adjuvant anti-HER2 treatments impact the patterns of recurrence and outcomes of HER2-positive (HER2+) metastatic breast cancer (MBC). We aimed to assess this in the large multicenter ESME real-world database. Patients and Methods We examined the characteristics and outcomes (overall survival (OS) and progression-free survival under first-line treatment (PFS1)) of HER2+ patients with MBC from the French ESME program with recurrent disease, as a function of the previous receipt of adjuvant trastuzumab. Multivariable analyses used Cox models adjusted for baseline demographic, prognostic factors, adjuvant treatment received, and disease-free interval. Results Two thousand one hundred and forty-three patients who entered the ESME cohort between 2008 and 2017 had a recurrent HER2+ MBC. Among them, 56% had received (neo)adjuvant trastuzumab and 2.5% another anti-HER2 in this setting. Patients pre-exposed to trastuzumab were younger, had a lower disease-free interval, more HR-negative disease and more metastatic sites. While the crude median OS appeared inferior in patients exposed to adjuvant trastuzumab, as compared to those who did not (37.2 (95%CI 34.4-40.3) versus 53.5 months (95% CI: 47.6-60.1)), this difference disappeared in the multivariable model (HR = 1.05, 95%CI 0.91-1.22). The same figures were observed for PFS1. Conclusions Among patients with relapsed HER2+ MBC, the receipt of adjuvant trastuzumab did not independently predict for worse outcomes when adjusted to other prognostic factors. There is limited real-world information on the impact of adjuvant and neoadjuvant anti-HER2-targeted treatments on patterns of recurrence and outcomes of patients with HER2+ metastatic breast cancer. This article reports on how anti-HER2 targeted treatment in the early setting impacts overall and progression-free survival under first-line treatment of patients with metastatic HER2+ breast cancer.

Currently, there is no recommendation for the treatment of breast cancer (BC) with bone-marrow cell infiltration (BMI). We evaluated the efficacy and safety of weekly-paclitaxel in this population. This retrospective study included all BC patients with BMI receiving weekly-paclitaxel between January 2014 and May 2018. Overall-survival (OS) was the primary endpoint. Secondary endpoints were progression-free-survival (PFS) and safety. BMI was diagnosed in 26 patients. This infiltration was suggested by peripheral blood smear in 73% of cases. All patients had anemia, and 77% had thrombocytopenia. OS and PFS were 7.2 months [95% confidence interval (CI)=2.6-20.7] and 3.3 months (95%CI=1.6-7.2), respectively. Good performance-status, absence of thrombocytopenia and presence of less than 5% of circulating erythroblasts at BMI diagnosis, were associated with better survival. One patient presented grade 5 febrile neutropenia but no episodes of bleeding were reported. Weekly-paclitaxel is an effective therapeutic option with limited toxicity for BC with BMI.