ABSTRACT
The metastatic cascade includes a blood circulation step for cells detached from the primary tumor. This stage involves significant shear stress as well as large and fast deformation as the cells circulate through the microvasculature. These mechanical stimuli are well reproduced in microfluidic devices. However, the recovery dynamics after deformation is also pivotal to understand how a cell can pass through the multiple capillary constrictions encountered during a single hemodynamic cycle. The microfluidic system developed in this work allows single cell recovery to be studied under flow-free conditions following pressure-actuated cell deformation inside constricted microchannels. We used three breast cancer cell lines - namely MCF-7, SK-BR3 and MDA-MB231 - as cellular models representative of different cancer phenotypes. Changing the size of the constriction allows exploration of moderate to strong deformation regimes, the latter being associated with the formation of plasma membrane blebs. In the regime of moderate deformation, all cell types display a fast elastic recovery behavior followed by a slower viscoelastic regime, well described by a double exponential decay. Among the three cell types, cells of the mesenchymal phenotype, i.e. the MDA-MB231 cells, are softer and the most fluid-like, in agreement with previous studies. Our main finding here is that the fast elastic recovery regime revealed by our novel microfluidic system is under the control of cell contractility ensured by the integrity of the cell cortex. Our results suggest that the cell cortex plays a major role in the transit of circulating tumor cells by allowing their fast morphological recovery after deformation in blood capillaries.
Subject(s)
Microfluidic Analytical Techniques , Humans , Cell Line, Tumor , Microfluidic Analytical Techniques/instrumentation , Breast Neoplasms/pathology , Breast Neoplasms/physiopathology , MCF-7 CellsABSTRACT
OBJECTIVES: Recent DESTINY-Breast trials have demonstrated trastuzumab deruxtecan's effectiveness in HER2-positive and HER2-low metastatic breast cancer. However, safety concerns remain regarding its combination with radiation therapy (RT). The purpose of this work is to assess the toxicity profile of combining trastuzumab deruxtecan and RT in patients with HER2-positive and HER2-low metastatic breast cancer to address these concerns. METHODS: We conducted a retrospective study which included patients treated at Institut Curie Paris between November 2020 and January 2024. Patients with HER2-positive and HER2-low metastatic breast cancer who received concurrent trastuzumab deruxtecan and RT were identified. Data on patient demographics, treatment regimens, radiation doses, toxicity profiles, and treatment discontinuations were collected. Follow-up was conducted from the last day of radiotherapy until death or the last examination and toxicities were graded using the CTCAE V5.0. RESULTS: The studied population includes all 33 patients with HER2-positive and HER2-low metastatic breast cancer who underwent concurrent treatment with trastuzumab deruxtecan and radiotherapy. The median follow-up was 11 months. The most common acute grade 1 toxicity was nausea. Grade 2 toxicities affected 21.2% of patients, including asthenia, mucositis, cardiac decompensation, and diarrhea. Trastuzumab deruxtecan discontinuation occurred in 5 patients due to systemic treatment-related toxicities, including nausea, thrombocytopenia, neutropenia, and cardiac decompensation. There were 21.2% reported with late toxicities, with nausea being the most prevalent. CONCLUSIONS: Our series of patients who received concurrent treatment of radiotherapy and trastuzumab deruxtecan are showing acceptable toxicity. Larger prospective studies are needed to evaluate the toxicity and efficacy of this combination.
ABSTRACT
BACKGROUND: Malnutrition and sarcopenia are challenges for patients with metastatic breast cancer and have been proposed as independent prognostic factors. Very few studies have addressed the temporal evolution of these parameters and, notably, the separate and combined analysis of sarcopenia and malnutrition. This study aimed to i) determine the prevalence of malnutrition and sarcopenia, individually and combined, and their evolution over time, ii) identify risk factors for each condition, and iii) explore their impact on overall survival (OS). METHODS: This retrospective study was conducted on 111 patients treated for at least a third-line metastatic breast cancer at the Institut Curie between January 1st and March 31st, 2018. Solitary malnutrition was defined from weight loss and body mass index values while solitary sarcopenia was defined solely based on low muscle mass. We analyzed solitary malnutrition, solitary sarcopenia, and then malnutrition with or without sarcopenia, at three key stages (T1: diagnosis of metastasis, T2: initiation of third-line treatment, and T3: 3-month re-evaluation). Univariate and multivariate logistic regression analyses were conducted to investigate the risk factors. We performed Cox proportional hazards analyses for each variable. RESULTS: At T1, the prevalence of solitary malnutrition, solitary sarcopenia and malnutrition with or without sarcopenia was 18.6%, 36.1% and 48.9% respectively, increasing to 27.7%, 45.5% and 56.6% at T2. At T2, in multivariate logistic regression analyses, patients aged over 60 years were at an elevated risk of experiencing solitary malnutrition as well as malnutrition with or without sarcopenia, but not solitary sarcopenia. In multivariate analyses, solitary malnutrition was significantly associated with poorer OS (HR 2.2 [95% CI 1.1-4.1], p = 0.02), while solitary sarcopenia and malnutrition with or without sarcopenia showed no association. CONCLUSION: Solitary malnutrition and sarcopenia were highly prevalent in patients with metastatic breast cancer, affecting around a quarter and half of patients respectively at third-line treatment initiation. Notably, solitary malnutrition emerged as a prognostic factor for overall survival, whereas no significant association was observed for solitary sarcopenia or malnutrition with or without sarcopenia. This highlights the critical need for early identification of patients at risk of malnutrition and the importance of timely intervention.
Subject(s)
Breast Neoplasms , Malnutrition , Sarcopenia , Humans , Sarcopenia/epidemiology , Sarcopenia/mortality , Female , Malnutrition/epidemiology , Malnutrition/mortality , Breast Neoplasms/mortality , Breast Neoplasms/complications , Breast Neoplasms/pathology , Prevalence , Retrospective Studies , Middle Aged , Aged , Risk Factors , Longitudinal Studies , Neoplasm Metastasis , Adult , Prognosis , Body Mass IndexABSTRACT
BACKGROUND: Early access program (formerly cohort Temporary Authorization for Use) was granted for trastuzumab deruxtecan (T-DXd) in France based on DESTINY-Breast01 trial which demonstrated its efficacy and safety in HER2-positive metastatic/unresectable breast cancer after ≥2 anti-HER2-based regimens received at metastatic stage. METHODS: This multicenter real-world early access program included HER2-positive metastatic/unresectable breast patients pretreated with at least two lines of anti-HER2 regimens who received T-DXd 5.4 mg/kg intravenously in monotherapy every 3 weeks. RESULTS: Four hundred and fifty-nine patients (median age, 58 years; hormone receptor-positive, 67%; brain metastases, 28.1%) received T-DXd. Before inclusion, 81.7% of patients had radiation therapy and 76.5% had undergone surgery. Median number of prior metastatic treatment lines was four (range, 2-22); 99.8% patients had received trastuzumab, 94.8% trastuzumab emtansine and 79.3% pertuzumab. Follow-up was performed from September 30, 2020 to March 30, 2021; when the early access program stopped, the median duration of T-DXd treatment was 3.4 (range, 0-7.8) months. In 160 patients with available tumor assessment, objective response rate was 56.7% and 12.1% had progression. In 57 patients with available brain tumor assessment, complete or partial intracranial response was reported for 35.7% patients and 5.4% had progression. A total of 17 (3.7%) patients with interstitial lung disease (ILD) was reported with no cases of ILD-related death. CONCLUSIONS: In this early access program in patients with heavily pretreated HER2-positive metastatic/unresectable breast cancer, T-DXd had antitumor activity with a similar response to that reported in previous clinical studies. T-DXd was well tolerated and no new safety signals were observed.
Subject(s)
Breast Neoplasms , Receptor, ErbB-2 , Trastuzumab , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Breast Neoplasms/metabolism , Trastuzumab/therapeutic use , Middle Aged , France , Receptor, ErbB-2/metabolism , Aged , Adult , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Immunoconjugates/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Aged, 80 and over , Treatment OutcomeABSTRACT
Between 30% and 70% of patients with breast cancer have pre-existing chronic conditions, and more than half are on long-term non-cancer medication at the time of diagnosis. Preliminary epidemiological evidence suggests that some non-cancer medications may affect breast cancer risk, recurrence, and survival. In this nationwide cohort study, we assessed the association between medication use at breast cancer diagnosis and survival. We included 235,368 French women with newly diagnosed non-metastatic breast cancer. In analyzes of 288 medications, we identified eight medications positively associated with either overall survival or disease-free survival: rabeprazole, alverine, atenolol, simvastatin, rosuvastatin, estriol (vaginal or transmucosal), nomegestrol, and hypromellose; and eight medications negatively associated with overall survival or disease-free survival: ferrous fumarate, prednisolone, carbimazole, pristinamycin, oxazepam, alprazolam, hydroxyzine, and mianserin. Full results are available online from an interactive platform ( https://adrenaline.curie.fr ). This resource provides hypotheses for drugs that may naturally influence breast cancer evolution.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/epidemiology , Breast Neoplasms/pathology , Cohort Studies , Comorbidity , SimvastatinABSTRACT
Importance: Little is known regarding the outcomes associated with tucatinib combined with trastuzumab and capecitabine (TTC) after trastuzumab-deruxtecan exposure among patients with ERBB2 (previously HER2)-positive metastatic breast cancer (MBC). Objective: To investigate outcomes following TTC treatment in patients with ERBB2-positive MBC who had previously received trastuzumab-deruxtecan. Design, Setting, and Participants: This cohort study included all patients with MBC who were treated in 12 French comprehensive cancer centers between August 1, 2020, and December 31, 2022. Exposure: Tucatinib combined with trastuzumab and capecitabine administered at the recommended dose. Main Outcomes and Measures: Clinical end points included progression-free survival (PFS), time to next treatment (TTNT), overall survival (OS), and overall response rate (ORR). Results: A total of 101 patients with MBC were included (median age, 56 [range, 31-85] years). The median number of prior treatment lines for metastatic disease at TTC treatment initiation was 4 (range, 2-15), including 82 patients (81.2%) with previous trastuzumab and/or pertuzumab and 94 (93.1%) with previous ado-trastuzumab-emtansine) exposure. The median duration of trastuzumab-deruxtecan treatment was 8.9 (range, 1.4-25.8) months, and 82 patients (81.2%) had disease progression during trastuzumab-deruxtecan treatment, whereas 18 (17.8%) had stopped trastuzumab-deruxtecan for toxic effects and 1 (1.0%) for other reasons. Tucatinib combined with trastuzumab and capecitabine was provided as a third- or fourth-line treatment in 37 patients (36.6%) and was the immediate treatment after trastuzumab-deruxtecan in 86 (85.1%). With a median follow-up of 11.6 (95% CI, 10.5-13.4) months, 76 of 101 patients (75.2%) stopped TTC treatment due to disease progression. The median PFS was 4.7 (95% CI, 3.9-5.6) months; median TTNT, 5.2 (95% CI, 4.5-7.0) months; and median OS, 13.4 (95% CI, 11.1 to not reached [NR]) months. Patients who received TTC immediately after trastuzumab-deruxtecan had a median PFS of 5.0 (95% CI, 4.2-6.0) months; median TTNT of 5.5 (95% CI, 4.8-7.2) months, and median OS of 13.4 (95% CI, 11.9-NR) months. Those who received TTC due to trastuzumab-deruxtecan toxicity-related discontinuation had a median PFS of 7.3 (95% CI, 3.0-NR) months. Best ORR was 29 of 89 patients (32.6%). Sixteen patients with active brain metastasis had a median PFS of 4.7 (95% CI, 3.0-7.3) months, median TTNT of 5.6 (95% CI, 4.4 to NR), and median OS of 12.4 (95% CI, 8.3-NR) months. Conclusions and Relevance: In this study, TTC therapy was associated with clinically meaningful outcomes in patients with ERBB2-positive MBC after previous trastuzumab-deruxtecan treatment, including those with brain metastases. Prospective data on optimal drug sequencing in this rapidly changing therapeutic landscape are needed.
Subject(s)
Brain Neoplasms , Breast Neoplasms , Oxazoles , Pyridines , Quinazolines , Humans , Middle Aged , Female , Breast Neoplasms/drug therapy , Capecitabine/therapeutic use , Cohort Studies , Prospective Studies , Trastuzumab/therapeutic use , Disease Progression , Receptor, ErbB-2ABSTRACT
BACKGROUND: Sacituzumab govitecan (SG) has been approved by FDA in April 2021 for pre-treated metastatic triple-negative breast cancer (mTNBC), following the ASCENT trial results. METHODS: We set up an ambispective bicentric cohort study to assess the real-world effectiveness and safety of SG in patients with mTNBC treated at Institut Curie Hospitals, with a focus on patients with brain metastases. RESULTS: This study included 99 patients treated through the French Early Access Program to SG from May 2021 to January 2023. Median age was 55 years [26-89], N = 8 patients (8%) had BRCA1/2 mutation, N = 12 (12%) de novo stage IV disease and N = 31 (31%) brain metastases. Patients had previously received a median of two [1-10] lines of treatment in advanced setting. After a median follow-up of 9.7 months, the median progression-free survival (PFS) and overall survival (OS) were 3.9 months (95%CI[3.4-5.0]) and 8.6 months (95%CI[7.1-11.9]), respectively, while objective response rate was 29% (95%CI[21-39]). Among patients with brain metastases, median PFS and OS were 3.7 months (95%CI[2.6-6.2]) and 6.7 months (95%CI[6.3-NR]), respectively, with intracranial tumor responses. Dose reductions were required in N = 17 patients (17%) within a median of three [2-11] cycles, due to gastrointestinal toxicity (N = 6; 6%), hematological toxicity (N = 9; 9%) including febrile neutropenia (N = 2; 2%), liver enzyme elevation (N = 1; 1%), and physical deterioration (N = 1; 1%). There was no related death to SG. CONCLUSIONS: The observed response rate and safety of SG are consistent with the results of the ASCENT trial, with efficacy observed in patients with brain metastases, but observed PFS and OS are numerically shorter.
Subject(s)
Antibodies, Monoclonal, Humanized , Brain Neoplasms , Camptothecin , Triple Negative Breast Neoplasms , Humans , Middle Aged , Female , Adult , Aged , Brain Neoplasms/secondary , Brain Neoplasms/drug therapy , Antibodies, Monoclonal, Humanized/therapeutic use , Antibodies, Monoclonal, Humanized/adverse effects , Triple Negative Breast Neoplasms/drug therapy , Triple Negative Breast Neoplasms/pathology , Aged, 80 and over , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Camptothecin/adverse effects , Camptothecin/administration & dosage , France , Progression-Free Survival , Retrospective Studies , ImmunoconjugatesABSTRACT
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).
Subject(s)
Breast Neoplasms , Receptor, ErbB-2 , Trastuzumab , Humans , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Female , Receptor, ErbB-2/metabolism , Receptor, ErbB-2/antagonists & inhibitors , Trastuzumab/therapeutic use , Europe , Prospective Studies , Immunoconjugates/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Treatment Outcome , Research Design , Neoplasm Staging , Camptothecin/analogs & derivativesABSTRACT
Purpose: The current standard-of-care management of locally advanced triple negative breast cancer (TNBC) is based on neoadjuvant chemo-immunotherapy with pembrolizumab, surgery, radiation therapy (RT), and adjuvant pembrolizumab. However, the safety of combining pembrolizumab with adjuvant breast RT has never been evaluated. This study evaluated the tolerance profile of concurrent pembrolizumab with adjuvant RT in patients with locally advanced TNBC. Methods and Materials: This bicentric ambispective study included all the patients with early and locally advanced TNBC who received neoadjuvant chemo-immunotherapy with pembrolizumab and adjuvant RT as part of their treatment. The tolerance profile of adjuvant RT was evaluated and compared in patients who received concurrent pembrolizumab and in patients for whom pembrolizumab was withheld. Results: Fifty-five patients were included between July 2021 and March 2023. Twenty-eight patients received adjuvant RT with concurrent pembrolizumab (RT+P group), and 27 patients had pembrolizumab withheld while receiving adjuvant RT (RT-only group). Two patients developed grade ≥3 toxicity (1 grade 3 pain in the RT+P group and 1 grade 3 radiodermatitis in the RT-only group), and there were no differences in terms of toxicity between the RT-only and the RT+P groups. No cardiac or pulmonary adverse event was reported during RT. With a median follow-up of 12 months (10-26), no patient relapsed. Conclusions: In this study of limited size, the authors did not find a difference between the RT-only and RT+P groups in terms of toxicity. More studies and longer follow-up may add to the strength of this evidence.
ABSTRACT
In a prospective study (NCT02866149), we assessed the efficacy of fulvestrant and everolimus in CDK4/6i pre-treated mBC patients and circulating tumor DNA (ctDNA) changes throughout therapy. Patients treated with fulvestrant and everolimus had their ctDNA assessed at baseline, after 3-5 weeks and at disease progression. Somatic mutations were identified in archived tumor tissues by targeted NGS and tracked in cell-free DNA by droplet digital PCR. ctDNA detection was then associated with clinicopathological characteristics and patients' progression-free survival (PFS), overall survival (OS) and best overall response (BOR). In the 57 included patients, median PFS and OS were 6.8 (95%CI [5.03-11.5]) and 38.2 (95%CI [30.0-not reached]) months, respectively. In 47 response-evaluable patients, BOR was a partial response or stable disease in 15 (31.9%) and 11 (23.4%) patients, respectively. Among patients with trackable somatic mutation and available plasma sample, N = 33/47 (70.2%) and N = 19/36 (52.8%) had ctDNA detected at baseline and at 3 weeks, respectively. ctDNA detection at baseline and PIK3CA mutation had an adverse prognostic impact on PFS and OS in multivariate analysis. This prospective cohort study documents the efficacy of fulvestrant and everolimus in CDK4/6i-pretreated ER + /HER2- mBC and highlights the clinical validity of early ctDNA changes as pharmacodynamic biomarker.
Subject(s)
Circulating Tumor DNA , Humans , Fulvestrant/therapeutic use , Circulating Tumor DNA/genetics , Prospective Studies , Everolimus/therapeutic use , Biomarkers, Tumor/genetics , Mutation , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Receptor, ErbB-2/genetics , Cyclin-Dependent Kinase 4/geneticsABSTRACT
The National College of Cancerology Teachers (CNEC) was created in September 1986. Its missions are to develop the teaching of oncology, to promote educational actions in the discipline, to participate in the development of teaching content and the definition of curricula and the control of knowledge for the training of medical students and specialists, to develop and validate educational documents relating to the above teaching, to ensure the representation of oncology teaching to of the National University Council (CNU) and administrative authorities, to ensure and coordinate relations with other university disciplines, scientific societies, national, European, and international professional groups, and to contribute to the development of research in the discipline. The current office was elected in September 2022 for three years.
Subject(s)
Educational Personnel , Students, Medical , Humans , Universities , CurriculumABSTRACT
INTRODUCTION: The MonarchE trial explored the use of abemaciclib, a CDK4/6 inhibitor, as an adjuvant treatment in high-risk early-stage luminal-like breast cancer. The study's inclusion criteria, especially the N2 status, may require revisiting surgical interventions, including invasive axillary lymph node dissection (ALND)-a procedure that current guidelines generally do not recommend. METHODS: We conducted a single-centre, retrospective, observational cohort study on non-metastatic breast cancer patients managed from 2002 to 2011, at the Institut Curie. Data collection involved clinical and histological characteristics plus treatment follow-up. RESULTS: Out of 8715 treated patients, 721 met the inclusion criteria. Overall, 12% (87) were classified as N2 ( ≥ 4 positive lymph nodes), thus eligible for abemaciclib per "node criterion." Tumour size, positive sentinel lymph nodes, and lobular histology showed a significant correlation with N2 status. Approximately 1000 ALNDs would be required to identify 120 N2 cases and prevent four recurrences. CONCLUSION: The MonarchE trial may significantly affect surgical practices due to the need for invasive procedures to identify high-risk patients for adjuvant abemaciclib treatment. The prospect of unnecessary morbidity demands less invasive N2 status determination methods. Surgical decisions must consider patient health and potential treatment benefits.
Subject(s)
Aminopyridines , Benzimidazoles , Breast Neoplasms , Humans , Female , Breast Neoplasms/drug therapy , Breast Neoplasms/surgery , Breast Neoplasms/pathology , Sentinel Lymph Node Biopsy , Retrospective Studies , Reoperation , Lymphatic Metastasis/pathology , Lymph Node Excision/adverse effects , Axilla/pathology , Lymph Nodes/pathologyABSTRACT
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.In patients with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer, the STIC CTC trial established that, for choosing between endocrine therapy (ET) or chemotherapy, the use of circulating tumor cell (CTC) count is noninferior to the investigator's choice in terms of progression-free survival. Here, we report overall survival (OS) results, a secondary end point. Patients were randomly assigned in a 1:1 ratio to have their first-line treatment (ET or chemotherapy) determined by investigators or CTC count (chemotherapy if ≥ 5 CTCs/7.5 mL; ET if low CTC count; CellSearch). OS was assessed at the discontinuation of follow-up. After a median follow-up of 4.7 years, 382 deaths (50.6%) had occurred among 755 patients. Median OS was 51.3 months (95% CI, 46.8 to 55.1) in the CTC arm and 45.5 months (95% CI, 40.9 to 51.1) in the standard arm (hazard ratio [HR] for death, 0.85; 95% CI, 0.69 to 1.03; P = .11). Among 189 patients (25.0%) with ET recommended by clinicians and high CTC count, chemotherapy was superior to ET (HR for death, 0.53; 95% CI, 0.36 to 0.78; P = .001). In case of a discordant estimate, OS data demonstrate the clinical utility of CTC count.
Subject(s)
Breast Neoplasms , Neoplastic Cells, Circulating , Humans , Female , Breast Neoplasms/pathology , Neoplastic Cells, Circulating/metabolism , Prognosis , Progression-Free Survival , Proportional Hazards Models , Antineoplastic Combined Chemotherapy Protocols/adverse effectsABSTRACT
With more than 60,000 new cases of breast cancer in mainland France in 2023 and 8% of all cancer deaths, breast cancer is the leading cancer in women in terms of incidence and mortality. While the number of new cases has almost doubled in 30 years, the percentage of patients at all stages alive at 5 years (87%) and 10 years (76%) testifies to the major progress made in terms of screening, characterisation and treatment. However, this progress, rapid as it is, needs to be evaluated and integrated into an overall strategy, taking into account the characteristics of the disease (stage and biology), as well as those of the patients being treated. These are the objectives of the St Paul-de-Vence recommendations for clinical practice. We report here the summary of the votes, discussions and conclusions of the Saint-Paul-de-Vence 2022-2023 RPCs.
Subject(s)
Breast Neoplasms , Humans , Female , France/epidemiologyABSTRACT
Importance: Targeted therapies directed against ERBB2 are the cornerstone of medical treatment for ERBB2-positive breast cancers but are contraindicated during pregnancy. Objectives: To describe the association of exposure to anti-ERBB2 agents during pregnancy with pregnancy and fetal or newborn outcomes, and to compare the risk and types of adverse outcomes reported more frequently in this context than after exposure to other anticancer agents. Design, Setting, and Participants: For this case-control study, All reports with a pregnancy-related condition and an antineoplastic agent (Anatomical Therapeutic Chemical classification group L01) registered in the World Health Organization international pharmacovigilance database VigiBase up to June 26, 2022, were extracted. All reports with a pregnancy, an antineoplastic treatment during pregnancy, and a cancer were retained. Reports with anticancer agents prescribed for nononcologic purposes were not included. Exposure: The exposure group was defined as reports that mention anti-ERBB2 agents compared with exposure to other anticancer agents. Main Outcome and Measures: The main outcome was the reporting odds ratio (ROR) for maternofetal complications in the group exposed to anti-ERBB2 agents compared with other anticancer agents, as determined using a disproportionality analysis. Results: A total of 3558 reports (anti-ERBB2 agents, 328; other anticancer agents, 3230) were included in the analysis. In the group exposed to anti-ERBB2 agents, most reports were from the US (159 [48.5%]), the mean (SD) age of participants was 30.8 (10.4) years, and 209 patients (97.7%) were treated for breast cancers. The molecules most frequently involved in cases with anti-ERBB2 agents were trastuzumab (n = 302), pertuzumab (n = 55), trastuzumab-emtansine (n = 20), and lapatinib (n = 18). The outcomes overreported in these cases included oligohydramnios (ROR, 17.68 [95% CI, 12.26-25.52]; P < .001), congenital respiratory tract disorders (ROR, 9.98 [95% CI, 2.88-34.67]; P < .001), and neonatal kidney failure (ROR, 9.15 [95% CI, 4.62-18.12]; P < .001). Sensitivity and multivariable analyses found similar results. Toxic effects were also significantly overreported for trastuzumab-emtansine (cardiovascular malformation: ROR, 4.46 [95% CI, 1.02-19.52]) and lapatinib (intrauterine growth restriction: ROR, 7.68 [95% CI, 3.01-19.59]). Conclusions and Relevance: In this case-control study of 328 individuals exposed to anti-ERBB2 agents during pregnancy, exposure was associated with a severe specific adverse pregnancy and fetal or newborn outcomes compared with exposure to other anticancer treatments.
Subject(s)
Antineoplastic Agents , Breast Neoplasms , Infant, Newborn , Female , Pregnancy , Humans , Adult , Lapatinib , Case-Control Studies , Trastuzumab/adverse effects , Ado-Trastuzumab Emtansine , Breast Neoplasms/drug therapy , Antineoplastic Agents/adverse effects , Receptor, ErbB-2ABSTRACT
Following the results of the IMpassion130 trial, an early access program (EAP) was opened in France, allowing patients with PD-L1-positive advanced triple negative breast cancer (aTNBC) to receive a combination of paclitaxel and atezolizumab as first line therapy. This EAP was later discontinued when the IMpassion131 trial read out with negative results. We performed a retrospective multicentric analysis in patients who were prospectively enrolled in the French EAP. Efficacy and toxicity data were obtained on 64 patients treated from August 2019 to August 2020 in 10 French cancer centers. Median progression-free survival (PFS) and overall survival (OS) were 4.1 months (95% CI [3.0-5.8]) and 17.9 months (95% CI [12.4-NR]), respectively. The 6-months PFS rate was 28% (95% CI [16-40%]) (N = 18/64), while N = 33/64 patients (52%, 95% CI [38-63%]) experienced a tumor response. Exploratory subgroup analyses retrieved that corticosteroid use at inclusion in the EAP, before treatment initiation, was the only independent unfavorable prognostic factor for PFS (HR 2.7, 95% CI [1.3-5.6]). No new safety signal was observed. This real-life study, unique by its setting (EAP granted by anticipation and later withdrawn), suggests atezolizumab and paclitaxel has a limited efficacy in PD-L1-positive aTNBC, especially in patients receiving corticosteroids as comedication before treatment start.
Subject(s)
Paclitaxel , Triple Negative Breast Neoplasms , Humans , Paclitaxel/therapeutic use , Triple Negative Breast Neoplasms/drug therapy , B7-H1 Antigen , Retrospective StudiesABSTRACT
Interstitial lung disease (ILD) has been reported with many cancer drugs including some recent antibody-drug conjugates (ADCs). The mechanisms of ILD induced by many chemotherapy drugs, other drug classes and ADCs used in cancer, including breast cancer, are not clearly elucidated. In the absence of specific clinical or radiological signs, the diagnosis of drug-induced ILD is often a diagnosis of exclusion. When present, the most frequent symptoms are respiratory signs (cough, dyspnea, chest pain) and general signs (fatigue, fever). Any suspicion of ILD should be evaluated by imaging and, if in doubt, the CT scan should be evaluated by a pulmonologist and a radiologist. A network of multidisciplinary experts for proactive early management of ILD is important, including oncologist, radiologist, pulmonologist, infectious disease specialist and nurses. Patient education is essential to report new or exacerbated lung symptoms and prevent high-grade ILD. Study drug is discontinued temporarily or permanently according to ILD severity and type of ADC. For asymptomatic cases (Grade 1), the efficacy of corticosteroids is not clearly established; for higher grades, the benefit/risk balance of long-term corticosteroid therapy should be considered for the dose and treatment duration. Hospitalization and oxygen supplementation are required for severe cases (Grades 3-4). For patient follow-up, the expertise of a pulmonologist is necessary with repeated chest scans, spirometry and DLCO. Preventing ADC-induced ILDs and evolution to high grade rests on a network of multidisciplinary experts for assessment of individual risk factors, early management, close follow-up and patient education.
ABSTRACT
OBJECTIVES: To evaluate the association between pretreatment MRI descriptors and breast cancer (BC) pathological complete response (pCR) to neoadjuvant chemotherapy (NAC). MATERIALS AND METHODS: Patients with BC treated by NAC with a breast MRI between 2016 and 2020 were included in this retrospective observational single-center study. MR studies were described using the standardized BI-RADS and breast edema score on T2-weighted MRI. Univariable and multivariable logistic regression analyses were performed to assess variables association with pCR according to residual cancer burden. Random forest classifiers were trained to predict pCR on a random split including 70% of the database and were validated on the remaining cases. RESULTS: Among 129 BC, 59 (46%) achieved pCR after NAC (luminal (n = 7/37, 19%), triple negative (n = 30/55, 55%), HER2 + (n = 22/37, 59%)). Clinical and biological items associated with pCR were BC subtype (p < 0.001), T stage 0/I/II (p = 0.008), higher Ki67 (p = 0.005), and higher tumor-infiltrating lymphocytes levels (p = 0.016). Univariate analysis showed that the following MRI features, oval or round shape (p = 0.047), unifocality (p = 0.026), non-spiculated margins (p = 0.018), no associated non-mass enhancement (p = 0.024), and a lower MRI size (p = 0.031), were significantly associated with pCR. Unifocality and non-spiculated margins remained independently associated with pCR at multivariable analysis. Adding significant MRI features to clinicobiological variables in random forest classifiers significantly increased sensitivity (0.67 versus 0.62), specificity (0.69 versus 0.67), and precision (0.71 versus 0.67) for pCR prediction. CONCLUSION: Non-spiculated margins and unifocality are independently associated with pCR and can increase models performance to predict BC response to NAC. CLINICAL RELEVANCE STATEMENT: A multimodal approach integrating pretreatment MRI features with clinicobiological predictors, including tumor-infiltrating lymphocytes, could be employed to develop machine learning models for identifying patients at risk of non-response. This may enable consideration of alternative therapeutic strategies to optimize treatment outcomes. KEY POINTS: ⢠Unifocality and non-spiculated margins are independently associated with pCR at multivariable logistic regression analysis. ⢠Breast edema score is associated with MR tumor size and TIL expression, not only in TN BC as previously reported, but also in luminal BC. ⢠Adding significant MRI features to clinicobiological variables in machine learning classifiers significantly increased sensitivity, specificity, and precision for pCR prediction.
Subject(s)
Breast Neoplasms , Humans , Female , Breast Neoplasms/diagnostic imaging , Breast Neoplasms/drug therapy , Breast Neoplasms/pathology , Neoadjuvant Therapy , Retrospective Studies , Magnetic Resonance Imaging , Treatment Outcome , Edema/etiologyABSTRACT
Synchronous bilateral breast cancer (sBBC) occurs after both breasts have been affected by the same germline genetics and environmental exposures. Little evidence exists regarding immune infiltration and response to treatment in sBBCs. Here we show that the impact of the subtype of breast cancer on levels of tumor infiltrating lymphocytes (TILs, n = 277) and on pathologic complete response (pCR) rates (n = 140) differed according to the concordant or discordant subtype of breast cancer of the contralateral tumor: luminal breast tumors with a discordant contralateral tumor had higher TIL levels and higher pCR rates than those with a concordant contralateral tumor. Tumor sequencing revealed that left and right tumors (n = 20) were independent regarding somatic mutations, copy number alterations and clonal phylogeny, whereas primary tumor and residual disease were closely related both from the somatic mutation and from the transcriptomic point of view. Our study indicates that tumor-intrinsic characteristics may have a role in the association of tumor immunity and pCR and demonstrates that the characteristics of the contralateral tumor are also associated with immune infiltration and response to treatment.
Subject(s)
Breast Neoplasms , Female , Humans , Breast Neoplasms/pathology , Breast/pathology , Lymphocytes, Tumor-Infiltrating , Neoadjuvant Therapy , Gene Expression ProfilingABSTRACT
INTRODUCTION: Chemorefractory nonmetastatic inflammatory breast cancer (IBC) which progresses under neoadjuvant chemotherapy poses specific therapeutic challenges: either pursuing a curative-intent treatment with a salvage combination of radiotherapy and surgery or switching to second-line systemic treatments despite the absence of metastasis. Due to the rarity of this situation, no specific management guidelines exist and the outcomes of these patients remain uncertain. In this retrospective observational study, we aimed to report the clinical outcomes of patients treated in a curative intent for chemorefractory nonmetastatic IBC, with a multimodal salvage treatment combining radiotherapy and surgery. MATERIALS AND METHODS: This single-center retrospective observational study included all chemorefractory nonmetastatic IBC treated at the Institut Curie (Paris, France). Overall survival (OS), disease-free survival (DFS), and locoregional relapse-free survival (LRRFS) were calculated from the time of diagnosis and from the time of neoadjuvant chemotherapy interruption. RESULTS: Between January 2010 and January 2018, 7 patients presented with chemorefractory nonmetastatic IBC with a progressive disease during neoadjuvant chemotherapy. Overall, chemorefractory IBC patients were young (median age of 50 years), had a good performance status, and usually presented with node-positive tumors characterized by a combination of adverse histological factors such as triple-negative breast cancer (TNBC), grade III, and high proliferation index. From the date of pathological diagnosis, 1year OS, DFS, and LRRFS were 64.3%, 53.6%, and 71.4%, respectively. From the date of neoadjuvant chemotherapy interruption, 1year OS, DFS, and LRRFS were 47.6%, 19.0%, and 45.7%, respectively, and median OS, DFS, and LRRFS were 8.3, 5.0, and 5.0 months, respectively. CONCLUSION: The prognosis of chemorefractory nonmetastatic IBC treated with a multimodal approach combining surgery and radiotherapy is particularly reserved, despite the curative intent of the salvage treatment and the lack of distant metastasis at the time of treatment. Optimal treatment modalities are still to be defined in this rare but critical presentation of IBC.