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BACKGROUND: The main objective of this study was to undertake an exhaustive investigation of sex-related differences in cancer surgery. METHODS: This observational study used data from the French national health insurance system database covering 98.8% of the population. Patients diagnosed with non-sex-specific solid invasive cancers between January 2018 and December 2019 were included. The main outcomes were likelihood of undergoing cancer surgery, type of oncological surgery performed, and associated 30-, 60-, and 90-day postoperative reoperation and mortality rates, by sex. RESULTS: For the 367 887 patients included, women were 44% more likely than men to undergo cancer surgery (OR 1.44, 95% c.i. 1.31 to 1.59; P < 0.001). However, the likelihood of surgery decreased with advancing age (OR 0.98, 0.98 to 0.98; P < 0.001), and with increasing number of co-morbid conditions (OR 0.95, 0.95 to 0.96; P < 0.001), especially in women. Men had higher 90-day reoperation (21.2 versus 18.8%; P < 0.001) and mortality (1.2 versus 0.9%; P < 0.001) rates than women, overall, and for most cancer types, with the exception of bladder cancer, for which the 90-day mortality rate was higher among women (1.8 versus 1.4%; P < 0.001). After adjustment for age, number of co-morbid conditions, and surgical procedure, 90-day mortality remained higher in men (OR 1.16, 1.07 to 1.26; P < 0.001), and men were 21% more likely than women to undergo reoperation within 90 days (OR 1.21, 1.18 to 1.23; P < 0.001). CONCLUSION: Women were much more likely than men to undergo cancer surgery than men, but the likelihood of surgery decreased with advancing age and with increasing number of co-morbid conditions, especially in women. These findings highlight a need for both increased awareness and strategies to ensure gender equality in access to oncological surgical treatment and improved outcomes.
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Neoplasias , Humanos , Feminino , França/epidemiologia , Masculino , Pessoa de Meia-Idade , Idoso , Neoplasias/cirurgia , Neoplasias/mortalidade , Neoplasias/epidemiologia , Fatores Sexuais , Adulto , Reoperação/estatística & dados numéricos , Complicações Pós-Operatórias/epidemiologia , Complicações Pós-Operatórias/etiologia , Idoso de 80 Anos ou maisRESUMO
BACKGROUND: The effect of primary cytoreductive surgery versus interval cytoreductive surgery on FIGO IV ovarian cancer outcomes remains uncertain, and may vary depending on the stage and the extraperitoneal metastasis location. Emulating target trials through causal assessment combined with propensity score adjustment has become a leading method for evaluating interventions using observational data. OBJECTIVE: To assess the effect of primary versus interval cytoreductive surgery on progression-free and overall survival in patients with FIGO IV ovarian cancer using target trial emulation. STUDY DESIGN: Utilizing the comprehensive French national health insurance database, we emulated a target trial to explore primary versus interval cytoreductive surgery causal impacts on FIGO IV ovarian cancer prognosis (Surgery for Ovarian cancer FIGO 4: SOFI-4). The clone method with inverse probability of censoring weighting was used to adjust for informative censoring and balance baseline characteristics between the groups. Subgroup analyses were conducted based on FIGO stages and extraperitoneal metastasis locations. The study included patients under 75 years of age, in good health condition, diagnosed with FIGO IV ovarian cancer between January 1, 2014, and December 31, 2022. The primary and secondary outcomes were respectively five-year progression-free survival and seven-year overall survival. RESULTS: Among the 2,772 patients included in the study, 948 (34.2%) were classified as FIGO IVA and 1,824 (65.8%) as FIGO IVB at inclusion. Primary cytoreductive surgery was performed on 1,182 patients (42.6%), while interval cytoreductive surgery was conducted on 1,590 patients (57.4%). The median progression survival for primary cytoreductive surgery was 19.7 months (interquartile range [IQR]: 19.3-20.1), compared to 15.7 months (IQR: 15.7-16.1) for those who underwent interval cytoreductive surgery. The median overall survival was 63.1 months [IQR: 61.7-65.4] for primary cytoreductive surgery, in comparison to 55.6 months [IQR: 53.8-56.3] for interval cytoreductive surgery. The findings of our study indicate that primary cytoreductive surgery is associated with a 5.0-month increase in five-year progression-free survival (95% Confidence Intervals [CI]: 3.8-6.2) and a 3.9-month increase in seven-year overall survival (95% CI: 1.9-6.2). These survival benefits of primary over interval cytoreductive surgery were observed in both the FIGO IVA and IVB subgroups. Primary cytoreductive surgery demonstrated improved progression-free survival and overall survival in patients with pleural, supra-diaphragmatic, or extra-abdominal lymph node metastasis. CONCLUSIONS: SOFI-4 advocates for the benefits of primary cytoreductive surgery over interval cytoreductive surgery for patients with FIGO IV ovarian cancer, suggesting extraperitoneal metastases like supra-diaphragmatic or extra-abdominal lymph nodes should not automatically preclude primary cytoreductive surgery consideration in suitable patients.
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Importance: Young women with breast cancer who have germline pathogenic variants in BRCA1 or BRCA2 face unique challenges regarding fertility. Previous studies demonstrating the feasibility and safety of pregnancy in breast cancer survivors included limited data regarding BRCA carriers. Objective: To investigate cumulative incidence of pregnancy and disease-free survival in young women who are BRCA carriers. Design, Setting, and Participants: International, multicenter, hospital-based, retrospective cohort study conducted at 78 participating centers worldwide. The study included female participants diagnosed with invasive breast cancer at age 40 years or younger between January 2000 and December 2020 carrying germline pathogenic variants in BRCA1 and/or BRCA2. Last delivery was October 7, 2022; last follow-up was February 20, 2023. Exposure: Pregnancy after breast cancer. Main Outcomes and Measures: Primary end points were cumulative incidence of pregnancy after breast cancer and disease-free survival. Secondary end points were breast cancer-specific survival, overall survival, pregnancy, and fetal and obstetric outcomes. Results: Of 4732 BRCA carriers included, 659 had at least 1 pregnancy after breast cancer and 4073 did not. Median age at diagnosis in the overall cohort was 35 years (IQR, 31-38 years). Cumulative incidence of pregnancy at 10 years was 22% (95% CI, 21%-24%), with a median time from breast cancer diagnosis to conception of 3.5 years (IQR, 2.2-5.3 years). Among the 659 patients who had a pregnancy, 45 (6.9%) and 63 (9.7%) had an induced abortion or a miscarriage, respectively. Of the 517 patients (79.7%) with a completed pregnancy, 406 (91.0%) delivered at term (≥37 weeks) and 54 (10.4%) had twins. Among the 470 infants born with known information on pregnancy complications, 4 (0.9%) had documented congenital anomalies. Median follow-up was 7.8 years (IQR, 4.5-12.6 years). No significant difference in disease-free survival was observed between patients with or without a pregnancy after breast cancer (adjusted hazard ratio, 0.99; 95% CI, 0.81-1.20). Patients who had a pregnancy had significantly better breast cancer-specific survival and overall survival. Conclusions and Relevance: In this global study, 1 in 5 young BRCA carriers conceived within 10 years after breast cancer diagnosis. Pregnancy following breast cancer in BRCA carriers was not associated with decreased disease-free survival. Trial Registration: ClinicalTrials.gov Identifier: NCT03673306.
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Neoplasias da Mama , Genes BRCA1 , Genes BRCA2 , Complicações Neoplásicas na Gravidez , Resultado da Gravidez , Adulto , Feminino , Humanos , Gravidez , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Intervalo Livre de Doença , Mutação em Linhagem Germinativa , Estudos Retrospectivos , Complicações Neoplásicas na Gravidez/genética , Complicações Neoplásicas na Gravidez/mortalidade , InternacionalidadeRESUMO
BACKGROUND: Previous studies have independently validated the prognostic relevance of residual cancer burden (RCB) after neoadjuvant chemotherapy. We used results from several independent cohorts in a pooled patient-level analysis to evaluate the relationship of RCB with long-term prognosis across different phenotypic subtypes of breast cancer, to assess generalisability in a broad range of practice settings. METHODS: In this pooled analysis, 12 institutes and trials in Europe and the USA were identified by personal communications with site investigators. We obtained participant-level RCB results, and data on clinical and pathological stage, tumour subtype and grade, and treatment and follow-up in November, 2019, from patients (aged ≥18 years) with primary stage I-III breast cancer treated with neoadjuvant chemotherapy followed by surgery. We assessed the association between the continuous RCB score and the primary study outcome, event-free survival, using mixed-effects Cox models with the incorporation of random RCB and cohort effects to account for between-study heterogeneity, and stratification to account for differences in baseline hazard across cancer subtypes defined by hormone receptor status and HER2 status. The association was further evaluated within each breast cancer subtype in multivariable analyses incorporating random RCB and cohort effects and adjustments for age and pretreatment clinical T category, nodal status, and tumour grade. Kaplan-Meier estimates of event-free survival at 3, 5, and 10 years were computed for each RCB class within each subtype. FINDINGS: We analysed participant-level data from 5161 patients treated with neoadjuvant chemotherapy between Sept 12, 1994, and Feb 11, 2019. Median age was 49 years (IQR 20-80). 1164 event-free survival events occurred during follow-up (median follow-up 56 months [IQR 0-186]). RCB score was prognostic within each breast cancer subtype, with higher RCB score significantly associated with worse event-free survival. The univariable hazard ratio (HR) associated with one unit increase in RCB ranged from 1·55 (95% CI 1·41-1·71) for hormone receptor-positive, HER2-negative patients to 2·16 (1·79-2·61) for the hormone receptor-negative, HER2-positive group (with or without HER2-targeted therapy; p<0·0001 for all subtypes). RCB score remained prognostic for event-free survival in multivariable models adjusted for age, grade, T category, and nodal status at baseline: the adjusted HR ranged from 1·52 (1·36-1·69) in the hormone receptor-positive, HER2-negative group to 2·09 (1·73-2·53) in the hormone receptor-negative, HER2-positive group (p<0·0001 for all subtypes). INTERPRETATION: RCB score and class were independently prognostic in all subtypes of breast cancer, and generalisable to multiple practice settings. Although variability in hormone receptor subtype definitions and treatment across patients are likely to affect prognostic performance, the association we observed between RCB and a patient's residual risk suggests that prospective evaluation of RCB could be considered to become part of standard pathology reporting after neoadjuvant therapy. FUNDING: National Cancer Institute at the US National Institutes of Health.
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Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , Neoplasia Residual , Receptor ErbB-2/análise , Adulto JovemRESUMO
The oncogenic events involved in breast implant-associated anaplastic large cell lymphoma (BI-ALCL) remain elusive. To clarify this point, we have characterized the genomic landscape of 34 BI-ALCLs (15 tumor and 19 in situ subtypes) collected from 54 BI-ALCL patients diagnosed through the French Lymphopath network. Whole-exome sequencing (n = 22, with paired tumor/germline DNA) and/or targeted deep sequencing (n = 24) showed recurrent mutations of epigenetic modifiers in 74% of cases, involving notably KMT2C (26%), KMT2D (9%), CHD2 (15%), and CREBBP (15%). KMT2D and KMT2C mutations correlated with a loss of H3K4 mono- and trimethylation by immunohistochemistry. Twenty cases (59%) showed mutations in ≥1 member of the JAK/STAT pathway, including STAT3 (38%), JAK1 (18%), and STAT5B (3%), and in negative regulators, including SOCS3 (6%), SOCS1 (3%), and PTPN1 (3%). These mutations were more frequent in tumor-type samples than in situ samples (P = .038). All BI-ALCLs expressed pSTAT3, regardless of the mutational status of genes in the JAK/STAT pathway. Mutations in the EOMES gene (12%) involved in lymphocyte development, PI3K-AKT/mTOR (6%), and loss-of-function mutations in TP53 (12%) were also identified. Copy-number aberration (CNA) analysis identified recurrent alterations, including gains on chromosomes 2, 9p, 12p, and 21 and losses on 4q, 8p, 15, 16, and 20. Regions of CNA encompassed genes involved in the JAK/STAT pathway and epigenetic regulators. Our results show that the BI-ALCL genomic landscape is characterized by not only JAK/STAT activating mutations but also loss-of-function alterations of epigenetic modifiers.
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Implantes de Mama/efeitos adversos , Epigênese Genética , Janus Quinases/metabolismo , Linfoma Anaplásico de Células Grandes/etiologia , Linfoma Anaplásico de Células Grandes/genética , Fatores de Transcrição STAT/metabolismo , Transdução de Sinais , Adulto , Idoso , Idoso de 80 Anos ou mais , Variações do Número de Cópias de DNA , Feminino , Genoma Humano , Humanos , Linfoma Anaplásico de Células Grandes/patologia , Pessoa de Meia-Idade , Mutação/genéticaRESUMO
BACKGROUND: Breast cancer (BC) has particular characteristics in young women, with diagnosis at more advanced stages, a poorer prognosis and highly aggressive tumors. In NeoFit, we will use an activity tracker to identify and describe various digital profiles (heart rate, physical activity, and sleep patterns) in women below the age of 45 years on neoadjuvant chemotherapy for BC. METHODS: NeoFit is a prospective, national, multicenter, single-arm open-label study. It will include 300 women below the age of 45 years treated with neoadjuvant chemotherapy for BC. Participants will be asked to wear a Withing Steel HR activity tracker round the clock for 12 months. The principal assessments will be performed at baseline, at the end of neoadjuvant chemotherapy and at 12 months. We will evaluate clinical parameters, such as toxicity and the efficacy of chemotherapy, together with quality of life, fatigue, and parameters relating to lifestyle and physical activity. The women will complete REDCap form questionnaires via a secure internet link. DISCUSSION: In this study, the use of an activity tracker will enable us to visualize changes in the lifestyle of young women on neoadjuvant chemotherapy for BC, over the course of a one-year period. This exploratory study will provide crucial insight into the digital phenotypes of young BC patients on neoadjuvant chemotherapy and the relationship between these phenotypes and the toxicity and efficacy of treatment. This trial will pave the way for interventional studies involving sleep and physical activity interventions. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT05011721 . Registration date: 18/08/2021.
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Neoplasias da Mama , Terapia Neoadjuvante , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/patologia , Feminino , Humanos , Masculino , Estudos Multicêntricos como Assunto , Terapia Neoadjuvante/métodos , Estudos Prospectivos , Qualidade de VidaRESUMO
RESEARCH QUESTION: What are the real-life oncofertility practices in young women diagnosed with breast cancer? DESIGN: The FEERIC (FErtility, prEgnancy, contRaceptIon after breast Cancer in France) study is a web-based cohort study launched with the French collaborative research platform Seintinelles. The current work is based on the enrolment self-administered questionnaire of 517 patients with prior breast cancer diagnosis, free from relapse and aged 18 to 43 years at inclusion (from 12 March 2018 to 27 June 2019). RESULTS: Median age at breast cancer diagnosis was 33.6 years and 424 patients (82.0%) received chemotherapy. Overall, 236 (45.6%) patients were offered specialized oncofertility counselling, 181 patients underwent at least one fertility preservation procedure (FPP); 125 (24.2%) underwent one or more FPP with material preservation (oocytes n = 108, 20.9%; embryos n = 31, 6.0%; ovarian cryopreservation n = 6, 1.2%) and 78 patients received gonadotrophin-releasing hormone agonists (15.1%). With a median follow-up of 26.9 months after the end of treatments, 133 pregnancies had occurred in 85 patients (16.4%), including 20 unplanned pregnancies (15.0%). Most of the pregnancies were natural conceptions (n = 113, 87.6%), while 16 (12.4%) required medical interventions. For the planned pregnancies, median time to the occurrence of an ongoing pregnancy was 3 months. Patients who had an unplanned pregnancy reported lower rates of information on the consequences of the treatments on fertility (P = 0.036) at diagnosis. CONCLUSIONS: Most of the patients were not offered proper specialized oncofertility counselling at the time of breast cancer diagnosis. Naturally conceived pregnancies after breast cancer were much more frequent than pregnancies resulting from the use of cryopreserved gametes. Adequate contraceptive counselling seems as important as information about fertility and might prevent unplanned pregnancies.
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Neoplasias da Mama , Sobreviventes de Câncer , Preservação da Fertilidade , Neoplasias da Mama/tratamento farmacológico , Estudos de Coortes , Criopreservação , Feminino , Preservação da Fertilidade/métodos , Humanos , Recidiva Local de Neoplasia , GravidezRESUMO
PURPOSE: To evaluate the dynamics of the determinants of returning to work (RTW) in a population of patients treated for breast cancer (BC) in a real-world setting. METHOD: We conducted a retrospective study including 1278 BC patients working or looking for work at the time of diagnosis. We performed a focused principal component analysis to highlight the dimensions of a persistent decline in work capacity. Logistic regression analyses were performed to identify correlates of non-RTW 1 and 2 years after treatment. RESULTS: One-third (31%, n = 389) of patients continued working during treatment. At study inclusion, 1100 patients had returned to work (89%). Three-quarters (n = 508, 75%) of the women reported a decline in work capacity 1 year after RTW and 22% (n = 148) presented a persistent decline in work capacity 2 years after the diagnosis. The odds ratio for non-RTW at 1 year was significantly higher for patients treated with a combination of chemotherapy and trastuzumab (OR = 1.72, 95% CI [1.07-2.76]), manual workers (OR = 3.99, 95% CI [1.54-10.81]), patients with lower incomes (OR = 2.33, 95% CI [1.29-4.19]), and patients experiencing fatigue (OR = 1.81, 95% CI [1.34-2.48]). The odds ratio for non-RTW at 2 years was higher for various occupational categories (OR = 3.49, 95% CI [1.89-6.74] for clerks, OR = 4.58, 95% CI [1.48-12.82] for self-employed workers, OR = 8.98, 95% CI [2.69-27.89] for manual workers), patients with comorbidities (OR = 2.80, 95% CI [1.61-4.93]), and patients experiencing anxiety symptoms (OR = 2.54, 95% CI [1.18-5.76]), while the impact of the type of treatment was no longer significantly associated with RTW. CONCLUSION: The determinants of RTW change over time. Patients should be offered supportive interventions tailored to risk factors and time from diagnosis.
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Neoplasias da Mama , Retorno ao Trabalho , Ansiedade , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/epidemiologia , Emprego , Feminino , Humanos , Estudos RetrospectivosRESUMO
BACKGROUND: To compare RCB (Residual Cancer Burden) and Neo-Bioscore in terms of prognostic performance and see if adding pathological variables improve these scores. METHODS: We analysed 750 female patients with invasive breast cancer (BC) treated with neoadjuvant chemotherapy (NAC) at Institut Curie between 2002 and 2012. Scores were compared in global population and by BC subtype using Akaike information criterion (AIC), C-Index (concordance index), calibration curves and after adding lymphovascular invasion (LVI) and pre-/post-NAC TILs levels. RESULTS: RCB and Neo-Bioscore were significantly associated to disease-free and overall survival in global population and for triple-negative BC. RCB had the lowest AICs in every BC subtype, corresponding to a better prognostic performance. In global population, C-Index values were poor for RCB (0.66; CI [0.61-0.71]) and fair for Neo-Bioscore (0.70; CI [0.65-0.75]). Scores were well calibrated in global population, but RCB yielded better prognostic performances in each BC subtype. Concordance between the two scores was poor. Adding LVI and TILs improved the performance of both scores. CONCLUSIONS: Although RCB and Neo-Bioscore had similar prognostic performances, RCB showed better performance in BC subtypes, especially in luminal and TNBC. By generating fewer prognostic categories, RCB enables an easier use in everyday clinical practice.
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Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante/métodos , Neoplasias da Mama/patologia , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Neoplasia Residual , Prognóstico , Análise de Sobrevida , Resultado do TratamentoRESUMO
This corrects the article DOI: 10.1038/bjc.2017.85.
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PURPOSE: Few studies evaluated the prognostic value of the presence of lymphovascular invasion (LVI) after neoadjuvant chemotherapy (NAC) for breast cancer (BC). METHODS: The association between LVI and survival was evaluated in a cohort of BC patients treated by NAC between 2002 and 2011. Five post-NAC prognostic scores (ypAJCC, RCB, CPS, CPS + EG and Neo-Bioscore) were evaluated and compared with or without the addition of LVI. RESULTS: Out of 1033 tumors, LVI was present on surgical specimens in 29.2% and absent in 70.8% of the cases. Post-NAC LVI was associated with impaired disease-free survival (DFS) (HR 2.54; 95% CI 1.96-3.31; P < 0.001), and the magnitude of this effect depended on BC subtype (Pinteraction = 0.003), (luminal BC: HR 1.83; P = 0.003; triple negative BC: HR 3.73; P < 0.001; HER2-positive BC: HR 6.21; P < 0.001). Post-NAC LVI was an independent predictor of local relapse, distant metastasis, and overall survival; and increased the accuracy of all five post-NAC prognostic scoring systems. CONCLUSIONS: Post-NAC LVI is a strong independent prognostic factor that: (i) should be systematically reported in pathology reports; (ii) should be used as stratification factor after NAC to propose inclusion in second-line trials or adjuvant treatment; (iii) should be included in post-NAC scoring systems.
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Neoplasias da Mama/tratamento farmacológico , Recidiva Local de Neoplasia/tratamento farmacológico , Prognóstico , Neoplasias de Mama Triplo Negativas/tratamento farmacológico , Adulto , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Linfonodos/efeitos dos fármacos , Linfonodos/patologia , Metástase Linfática , Pessoa de Meia-Idade , Terapia Neoadjuvante , Invasividade Neoplásica/patologia , Recidiva Local de Neoplasia/epidemiologia , Recidiva Local de Neoplasia/patologia , Estadiamento de Neoplasias , Neoplasias de Mama Triplo Negativas/epidemiologia , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
BACKGROUND: Trastuzumab was introduced a decade ago and has improved outcomes for HER2-positive breast cancer. We investigated the factors predictive of pathological complete response (pCR), prognostic factors for disease-free survival (DFS), and interactions between pCR and DFS after neoadjuvant treatment. METHODS: We identified 287 patients with primary HER2-positive breast cancers given neoadjuvant chemotherapy (NAC) between 2002 and 2011. Univariate and multivariate analyses of clinical and pathological factors associated with pCR and DFS were performed. RESULTS: pCR rates differed between patients receiving neoadjuvant trastuzumab treatment or not (47.7% versus 19.3%, P<0.0001). DFS also differed significantly between patients receiving adjuvant trastuzumab or not (hazard ratio=4.84, 95% CI (2.52; 9.31), P<0.001). We analysed 199 patients given neoadjuvant and adjuvant trastuzumab. Multivariate analysis identified older age and hormone receptor-negative tumours as independent predictors of pCR. T stage (hazard ratio=2.55, 95% CI (1.01; 6.48), P=0.05) and strict pCR (hazard ratio=9.15, 95% CI (1.22; 68.83), P=0.03) were independent predictors of DFS. The latter association was significant in the HR-negative subgroup (P=0.02) but not in the HR-positive subgroup (P=0.12). CONCLUSIONS: Major pCR and DFS gains in HER2-positive BC were observed since 'trastuzumab' era. Further improvements rely on the enrollment of accurately selected patients into clinical trials.
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Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/análise , Trastuzumab/uso terapêutico , Adulto , Idoso , Neoplasias da Mama/química , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Estudos de Coortes , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Terapia Neoadjuvante , PrognósticoRESUMO
Few studies have reported reproductive outcomes after breast cancer chemotherapy. The relationship between anti-Müllerian hormone (AMH) concentrations and the occurrence of subsequent pregnancies in women after chemotherapy for breast cancer was investigated. Women aged 18-43 years treated with chemotherapy for invasive breast cancer between May 2005 and January 2011 were retrospectively identified. Exclusion criteria were previous gonadotoxic treatment, oophorectomy or hysterectomy. Measurement of AMH took place before, during chemotherapy and at distant time points after the end of chemotherapy (4 months to 5.5 years). Seventeen out of 134 patients experienced 28 spontaneous pregnancies (median follow-up: 59 months). Neither baseline AMH (divided into quartiles) nor end-of-chemotherapy AMH (detectable versus undetectable) were significantly associated with the occurrence of pregnancy. Chemotherapy regimen with anthracyclines was associated with a greater probability of pregnancy compared with a taxane-containing regimen (hazard ratio 4.75; (95% CI 1.76 to 12.8); P = 0.002). Five-year disease-free survival and overall survival rates were 60% (95% CI: 51 to 70; relapse, n = 48) and 88% (95% CI 82 to 95; deaths, n = 21), respectively. AMH did not predict the occurrence of pregnancy. Additional studies assessing ovarian reserve and reproductive outcomes after breast cancer are required.
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Hormônio Antimülleriano/sangue , Neoplasias da Mama/tratamento farmacológico , Preservação da Fertilidade , Adolescente , Adulto , Antraciclinas/efeitos adversos , Antraciclinas/uso terapêutico , Hidrocarbonetos Aromáticos com Pontes/efeitos adversos , Hidrocarbonetos Aromáticos com Pontes/uso terapêutico , Intervalo Livre de Doença , Feminino , Humanos , Gravidez , Resultado da Gravidez , Taxa de Gravidez , Estudos Retrospectivos , Análise de Sobrevida , Taxoides/efeitos adversos , Taxoides/uso terapêuticoRESUMO
Anti-Müllerian hormone (AMH) levels fall during chemotherapy. Treatment-induced amenorrhoea is a reversible phenomenon, but few data are available on long-term AMH changes in breast cancer. The aim of the study was to describe serum AMH levels before, during and in the long term after chemotherapy, and to show a potential AMH recovery. Between May 2010 and June 2011, we selected 134 women aged 18-43 years at the time of breast cancer diagnosis who received chemotherapy between 2005 and 2011, and had not undergone an oophorectomy or had previous cytotoxic treatment. The AMH levels were assessed before, during and 4 months to 5.5 years after the end of chemotherapy. During chemotherapy, AMH was undetectable in 69% of women. After chemotherapy, a significant increase in AMH was found, with an average magnitude of +1.2% per month (95% credibility interval: 0.7 to 1.6). Older age and 12 months of amenorrhoea were found to be associated with a lower AMH recovery rate, whereas baseline AMH and number of chemotherapy cycles were not. The process of AMH changes during and after chemotherapy is dynamic, and shows recovery after ovarian injury. Caution should be exercised in interpreting individual AMH assessment in this context.
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Hormônio Antimülleriano/sangue , Neoplasias da Mama/complicações , Neoplasias da Mama/tratamento farmacológico , Reserva Ovariana/efeitos dos fármacos , Ovário/efeitos dos fármacos , Adolescente , Adulto , Amenorreia/induzido quimicamente , Antineoplásicos/efeitos adversos , Feminino , Humanos , Menstruação/efeitos dos fármacos , Ovariectomia , Estudos Retrospectivos , Fatores de Tempo , Resultado do Tratamento , Adulto JovemRESUMO
Discovering causal effects is at the core of scientific investigation but remains challenging when only observational data are available. In practice, causal networks are difficult to learn and interpret, and limited to relatively small datasets. We report a more reliable and scalable causal discovery method (iMIIC), based on a general mutual information supremum principle, which greatly improves the precision of inferred causal relations while distinguishing genuine causes from putative and latent causal effects. We showcase iMIIC on synthetic and real-world healthcare data from 396,179 breast cancer patients from the US Surveillance, Epidemiology, and End Results program. More than 90% of predicted causal effects appear correct, while the remaining unexpected direct and indirect causal effects can be interpreted in terms of diagnostic procedures, therapeutic timing, patient preference or socio-economic disparity. iMIIC's unique capabilities open up new avenues to discover reliable and interpretable causal networks across a range of research fields.
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OBJECTIVE: To study the fertility outcomes of women who tried to conceive after breast cancer (BC) treatment and fertility preservation. DESIGN: Retrospective observational, bicentric cohort study. SETTING: University hospital. PATIENTS: Patients with BC. INTERVENTION: All patients who had undergone fertility preservation before BC treatment between January 2013 and July 2019 were included (n = 844). The endpoint date was March 1, 2022. Patients with missing data on pregnancy attempts after a cancer diagnosis (n = 195) were excluded from the pregnancy analysis. MAIN OUTCOME MEASURES: Cumulative incidences of pregnancy and live birth (LB) were calculated. For women who became pregnant, the time to conception was calculated between the first fertility preservation consultation and the estimated day of conception. For those who did not conceive, we considered the time between the first fertility preservation consultation and the endpoint date, or the date of patient death. A Cox regression model was used to study the predictive factors for pregnancy and LB. RESULTS: Among the 649 patients with available data on pregnancy attempts after BC diagnosis, 255 (39.3% [35.5-43.2]) tried to conceive (median follow-up of 6.5 years). Overall, 135 (52.9% [46.6-59.2]) of these patients achieved a pregnancy, mainly through unassisted conception (79.3% [72.8-84.8]), and 99 reported an LB (representing 38.8% of patients who attempted conception). In our cohort, 48 months after the first fertility preservation consultation, the cumulative incidence of pregnancy was 33.1% ([27.6-37.9]). After adjustment for age, parity, type of chemotherapy administration, and endocrine therapy, only multiparity at diagnosis and absence of chemotherapy were positive predictive factors of pregnancy after cancer. Of the 793 patients who had vitrified oocytes and embryos, 68 used them (27% [21.3-32.5] of the patients who tried to conceive), resulting in 8 LBs (11.8% [5.2-21.9]). Women who used their cryopreserved oocytes and embryos were older at the first consultation of fertility preservation (hazard ratio 1.71 [1.42-2.21]), and chose more often to vitrify embryos (hazard ratio 1.76 [1.28-2.23]). CONCLUSION: Although pregnancy rates after fertility preservation for patients with BC are low, most conceptions are achieved without medical assistance. Our findings provide useful information to advise women on the different techniques of fertility preservation, their efficacy, and safety, as well as the relatively high chances of unassisted conception.
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INTRODUCTION: Recent retrospective studies suggest potential large patient's benefit through proper timing of immune checkpoint blockers (ICB). The association between ICB treatment timing and patient survival, neoplastic response and toxicities was investigated, together with interactions with performance status (PS) and sex. METHODS: A cohort of patients with metastatic or locally advanced solid tumors, who received pembrolizumab, nivolumab, atezolizumab, durvalumab, or avelumab, alone or with concomitant chemotherapy, between November 2015 and March 2021, at the Centre Leon Bérard (France), was retrospectively studied. RESULTS: 361 patients were investigated (80% non-small cell lung cancer patients, mean [SD] age: 63 [11] years, 39% of women, 83% PS0-1 at first infusion, 19% received concomitant chemotherapy). ICB were administered from 07:25 to 17:21 and optimal morning/afternoon cut-off was 11:37. Morning infusions were associated with increased OS as compared to afternoon (median 30.3 vs 15.9 months, p = 0.0024; HR 1.56 [1.17-2.1], p = 0.003). A strong PS-timing interaction was found (PS0-1 patients, HR=1.53 [1.10-2.12], p = 0.011; PS2-3 patients, HR=0.50 [0.25-0.97], p = 0.042). Morning PS0-1 patients displayed increased OS (median 36.7 vs 21.3 months, p = 0.023), partial/complete response rate (58% vs 41%, p = 0.027), and grade1-3 toxicities (49% vs 34%, p = 0.028). Mortality risk ratio between infusions at worst time-of-day, estimated at 13:36 [12:48-14:23], and in early morning was equal to 4.8 ([2.3-10.1], p = 0.008). Timing differences in toxicities resulted significant only in female patients (women vs men: p < 0.001 vs 0.4). CONCLUSIONS: Early morning ICB infusion was associated with increased OS, response, and toxicities in patients with PS0-1 as compared to later infusions within the day. Prospective randomized trials are needed to confirm this retrospective study.
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Carcinoma Pulmonar de Células não Pequenas , Neoplasias Pulmonares , Segunda Neoplasia Primária , Masculino , Humanos , Feminino , Pessoa de Meia-Idade , Carcinoma Pulmonar de Células não Pequenas/patologia , Inibidores de Checkpoint Imunológico/efeitos adversos , Estudos Retrospectivos , Neoplasias Pulmonares/patologia , Cronofarmacoterapia , Estudos Prospectivos , Segunda Neoplasia Primária/tratamento farmacológicoRESUMO
Background: Immune-checkpoint inhibitors (ICI) have revolutionized cancer treatment by harnessing the immune system but ICI can induce life-threatening immune-related adverse events (irAE) affecting every organ. Methods: We extracted irAE from VigiBase, the international pharmacovigilance database, first reported in 2008 until 01/2023 to characterize irAE reporting trends, clinical features, risk factors and outcomes. Findings: We distinguished 25 types of irAE (n = 50,347cases, single irAE/case in 84.9%). Cases mainly involved anti-PD1 (programmed-death-1) monotherapy (62.4%) in male (61.7%) aged 64.3 ± 12.6 years. After 2020 vs. prior to 2016, proportion of anti-CTLA4 (Cytotoxic-T-Lymphocyte-Antigen-4) monotherapy prescription almost vanished (1.6% vs. 47%, respectively) contrasting with increased use of anti-PDL1 (PD1-ligand) monotherapy (18% vs. 0.9%) and anti-CTLA4+anti-PD(L)1 combination (20% vs. 8.9%). Anti-LAG3 (Lymphocyte-Activation-Gene-3) prescription was limited (<1%) in the studied timeframe. After 2020, over 14 different cancer types were treated vs. almost exclusively melanoma and lung cancers before 2016. Overall, the most reported irAE were skin reactions (22.9%), pneumonitis (18.5%), enterocolitis (14.4%) and thyroiditis (12.1%). ICI-myotoxicities (6.6%) included myositis, myocarditis and myasthenia-gravis like syndrome and were the most overlapping irAE (up to 30% overlap, vs. <3% in general for other inter-irAE overlap). The top factors associated with specific irAE (odds-ratio>5) were presence of thymic cancer for ICI-myotoxicities or hepatitis; presence of melanoma for vitiligo, uveitis or sarcoidosis; specific types of ICI regimen (anti-LAG3 for meningitis, anti-CTLA4 for hypophysitis); and specific reporting regions (eastern Asia for cholangitis). Median time-to-onset ranged from 31 to 273 days, being shortest for myotoxicities and most delayed for skin-bullous auto-immune reactions. Overall fatality was highest for myocarditis = 27.6%, myasthenia = 23.1%, severe cutaneous adverse reactions (SCAR) = 22.1%, myositis = 21.9%, pneumonitis = 21%, and encephalomyelitis = 18%; generally decreasing after 2020, except for myasthenia and SCAR. When reported, irAE recurrence rate after rechallenge was 28.9% (n = 275/951). Interpretation: This up-to-date comprehensive worldwide pharmacovigilance study defines the spectrum, characteristics, and evolution of irAE reporting summarizing over a decade of use. Multiple risk factors and clinical peculiarities for specific irAE have been identified as signals to guide clinical practice and future research. Funding: Paul Gougis was supported by the academic program: "Contrats ED: Programme blanc Institut Curie PSL" for the conduct of his PhD. Baptiste Abbar was supported by "the Fondation ARC Pour le Rechercher Sur le Cancer". The RT2L research group (Institut Curie) was supported by the academic program "SHS INCa", Sanofi iTech award, and by Monoprix∗.
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OBJECTIVE: Uterine sarcomas are rare tumors with a poor prognosis. Their diagnosis is often incidental, following surgery. Our goal was to examine the early management strategies for uterine sarcomas, and to assess the impact of guideline adherence and expert center referral on both the management approaches and the clinical outcomes in patients with uterine sarcomas. METHODS: We retrospectively analyzed medical records from patients with uterine sarcoma referred to the Institut Curie and registered in the database of the French NETSARC network. RESULTS: In total, 100 patients, with a median age of 54 years, were included in the analyses. On MRI scans (n = 36), all patients had at least two signs suggestive of malignancy, and 77.8 % had four or more signs. No preoperative biopsy was performed in 65.6 % of cases. Only 14.1 % of patients underwent initial surgery at an expert center. Surgery performed outside the network was significantly associated with morcellation (32.9 % vs. 0 %; p = 0.036), fewer negative margins (R0 margins 52.4 % vs. 100 %; p = 0.006), and poor adherence to surgical guidelines (28.3 vs. 72.7 %; p = 0.013). Multivariate analysis showed that non-adherence to surgical recommendations was not significantly associated with relapse-free survival (HR = 0.54; 95 % CI [0.21-1.38]), but was an independent predictor of poor overall survival (HR = 0.12; 95 % CI [0.03-0.52]; p = 0.005). CONCLUSION: Despite a high frequency of suspicious clinical and radiological signs, a large proportion of women undergoing sarcoma surgery are treated outside of expert networks. We provide guidelines, integrating the clinical context and radiological signs to encourage early referral to reference centers for sarcoma.
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Neoplasias Pélvicas , Sarcoma , Neoplasias de Tecidos Moles , Neoplasias Uterinas , Humanos , Feminino , Pessoa de Meia-Idade , Estudos Retrospectivos , Fidelidade a Diretrizes , Sarcoma/diagnóstico por imagem , Sarcoma/cirurgia , Neoplasias Uterinas/diagnóstico , Neoplasias Uterinas/cirurgia , Neoplasias de Tecidos Moles/cirurgia , Encaminhamento e ConsultaRESUMO
Importance: With the widespread use of immune checkpoint inhibitors (ICIs), concerns about their pregnancy outcomes through maternal exposure have emerged, and clinical comparative data are lacking. Objective: To assess the risk of pregnancy-, fetal-, and/or newborn-related adverse outcomes associated with exposure to ICIs compared with exposure to other anticancer agents. Design, Setting, and Participants: In this cohort study, all reports mentioning a pregnancy-related condition and an antineoplastic agent (Anatomical Therapeutic Chemical classification group L01) used for a cancer indication registered in the World Health Organization international pharmacovigilance database VigiBase up to June 26, 2022, were extracted. Exposure: Anticancer agents, including ICIs, used during pregnancy for a cancer indication. Immune checkpoint inhibitors included blockers of programmed cell death 1 (PD1) or its ligand (PD-L1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA4). Main Outcomes and Measures: The main outcome was the reporting odds ratio (ROR) for maternal, fetal, or newborn complications in patients treated with ICIs vs any other anticancer drug. Adverse events, categorized into 45 individual maternofetal adverse outcomes, were directly mapped to Medical Dictionary for Regulatory Activities preferred terms in VigiBase. Results: A total of 3558 reports (ICI: 91 [2.6%]; other anticancer drugs: 3467 [97.4%]) were included in the analysis. In the ICI group, most reports were from the US (60 [65.9%]), and the mean (SD) patient age was 28.9 (10.2) years; in 24 of 55 reports with data on cancer type (43.6%), patients were treated for melanoma. The molecules involved in the ICI group were anti-PD1 (58 reports [63.7%]), anti-PD1 plus anti-CTLA4 (15 [16.5%]), anti-CTLA4 (13 [14.3%]), anti-PD-L1 (4 [4.4%]), and anti-PD1 plus anti-lymphocyte activation gene 3 (1 [1.1%]). An ICI was used in combination with a non-ICI anticancer agent in 10 participants (11.0%). Compared with other anticancer drugs, none of the 45 adverse outcomes identified were overreported in the group exposed to ICIs. However, preterm birth was significantly overreported for the anti-PD1 plus anti-CTLA4 combination compared with other anticancer drugs (12 of 15 [80.0%] vs 793 of 3452 [23.0%]; ROR, 13.87; 95% CI, 3.90-49.28; P < .001) but not for anti-PD-L1 or anti-CTLA4 monotherapy. Three reports of possibly immune-related maternofetal events were identified: 1 case of maternal antiphospholipid syndrome leading to spontaneous abortion, 1 case of pneumonitis leading to neonatal respiratory distress syndrome and death, and 1 case of transient congenital hypothyroidism. Conclusions and Relevance: In this cohort study of 91 individuals exposed to ICIs during pregnancy, ICI exposure was not associated with overreporting of specific adverse pregnancy, fetal, and/or newborn outcomes compared with other anticancer treatments. However, due to possible rare immune-related neonatal adverse events, ICI use in pregnant women should be avoided when possible, especially the anti-PD1 plus anti-CTLA4 combination.