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Historically, dose selection of anticancer drugs has mainly been based on establishing the maximum tolerated dose in phase 1 clinical trials with a traditional 3 plus 3 design. In the era of targeted therapies and immune-modulating agents, this approach does not necessarily lead to selection of the most favourable dose. This strategy can introduce potentially avoidable toxicity or inconvenience for patients. Multiple changes in drug development could lead to more rational dose selection, such as use of better predictive preclinical models, adaptive and randomised trial design, evaluation of multiple dose levels in late-phase development, assessment of target activity and saturation, and early biomarker use for efficacy and safety evaluation. In this Review, we evaluate the rationale and validation of dose selection in each phase of drug development for anticancer drugs approved by the European Medicines Agency and US Food and Drug Administration from Jan 1, 2020, to June 30, 2023, and give recommendations for dose optimisation to improve safety and patient convenience. In our evaluation, we classified 20 (65%) of the 31 recently registered anticancer agents as potential candidates for dose optimisation, which could be achieved either by reducing the dose (n=10 [32%]) or adjusting the dosage regimen (n=10 [32%]). Dose selection seemed to be adequately justified for nine (29%) of the drugs, whereas the reviewed data were inconclusive for formulating a recommendation on dose optimisation for two (6%) of the drugs.
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Antineoplásicos , Dosis Máxima Tolerada , Neoplasias , Humanos , Antineoplásicos/administración & dosificación , Antineoplásicos/efectos adversos , Neoplasias/tratamiento farmacológico , Desarrollo de Medicamentos , Relación Dosis-Respuesta a DrogaRESUMEN
In the Netherlands, one out of two people will be confronted with the diagnosis of cancer sometime in their life. Against this increased number of patients, a large proportion luckily can be cured. Today, a rather high proportion of people receive treatment to control cancer growth or stabilize the disease, sometimes, for the rest of their lives. If such long-standing treatment is administered for more than 10-20 years, the stage of cancer is presently often not referred to as "palliative" anymore, but much more often as "chronic." It could be argued that regardless of the cancer disease stage you are in and whether you are or can be cured, your cancer diagnosis nevertheless has become part of your life, including the experience of chronicity. Discussions surrounding the chronicity of cancer in the context of cancer are still ongoing. This is especially the case because "experiencing chronicity" is dependent on the type of cancer and is less applicable in cancers where the prognosis is often less than one year, such as is more frequently the case with lung or pancreatic cancer. In all situations, experiencing chronicity nevertheless brings along uncertainty, either with or without chronic stress. Combatting stress by choosing the right wording, maintaining an optimistic stance along with physical activity and/or psychosocial education seems important to optimize well-being and to stabilize tumor growth or remove the tumor. In conclusion, chronicity in the context of treating and caring for cancer seems a somewhat gray area. However, regardless in how we, as medical professionals, speak about cancer with long-standing disease trajectories (that sometimes even can be cured), it first of all seems important to approach, take care, and treat patients well. This can facilitate discussions with patients about their disease and disease experiences. Moreover, it can stimulate patients themselves to take responsibility for their own health, which can be of added value to the entire disease trajectory.
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Neoplasias , Humanos , Neoplasias/terapia , Países BajosRESUMEN
OBJECTIVES: The aim of this study is to investigate the added value of diffusion-weighted imaging (DWI) to dynamic-contrast enhanced (DCE)-MRI to identify a pathological complete response (pCR) in patients with HER2-positive breast cancer and radiological complete response (rCR). MATERIALS AND METHODS: This is a single-center observational study of 102 patients with stage I-III HER2-positive breast cancer and real-world documented rCR on DCE-MRI. Patients were treated between 2015 and 2019. Both 1.5 T/3.0 T single-shot diffusion-weighted echo-planar sequence were used. Post neoadjuvant systemic treatment (NST) diffusion-weighted images were reviewed by two readers for visual evaluation and ADCmean. Discordant cases were resolved in a consensus meeting. pCR of the breast (ypT0/is) was used to calculate the negative predictive value (NPV). Breast pCR-percentages were tested with Fisher's exact test. ADCmean and ∆ADCmean(%) for patients with and without pCR were compared using a Mann-Whitney U-test. RESULTS: The NPV for DWI added to DCE is 86% compared to 87% for DCE alone in hormone receptor (HR)-/HER2-positive and 67% compared to 64% in HR-positive/HER2-positive breast cancer. Twenty-seven of 39 non-rCR DWI cases were false positives. In HR-positive/HER2-positive breast cancer the NPV for DCE MRI differs between MRI field strength (1.5 T: 50% vs. 3 T: 81% [p = 0.02]). ADCmean at baseline, post-NST, and ∆ADCmean were similar between patients with and without pCR. CONCLUSION: DWI has no clinically relevant effect on the NPV of DCE alone to identify a pCR in early HER2-positive breast cancer. The added value of DWI in HR-positive/HER2-positive breast cancer should be further investigated taken MRI field strength into account. CLINICAL RELEVANCE STATEMENT: The residual signal on DWI after neoadjuvant systemic therapy in cases with early HER2-positive breast cancer and no residual pathologic enhancement on DCE-MRI breast should not (yet) be considered in assessing a complete radiologic response. KEY POINTS: Radiologic complete response is associated with a pathologic complete response (pCR) in HER2+ breast cancer but further improvement is warranted. No relevant increase in negative predictive value was observed when DWI was added to DCE. Residual signal on DW-images without pathologic enhancement on DCE-MRI, does not indicate a lower chance of pCR.
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The European Breast Cancer Council (EBCC) traditionally identifies controversies or major deficiencies in the management of patients with breast cancer and selects a multidisciplinary expert team to collaborate in setting crucial principles and recommendations to improve breast cancer care. The 2024 EBCC manifesto focuses on disparities in the care of patients with metastatic breast cancer. There are several reasons for existing disparities both between and within countries. Our recommendations aim to address the stigma of metastatic disease, which has led to significant disparities in access to innovative care regardless of the gross national income of a country. These recommendations are for different stakeholders to promote the care of patients with metastatic breast cancer across Europe and worldwide.
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Neoplasias de la Mama , Accesibilidad a los Servicios de Salud , Disparidades en Atención de Salud , Humanos , Neoplasias de la Mama/terapia , Neoplasias de la Mama/patología , Europa (Continente) , Femenino , Metástasis de la NeoplasiaRESUMEN
BACKGROUND: Hyperthermic intraperitoneal chemotherapy (HIPEC) improves survival in patients with Stage III ovarian cancer following interval cytoreductive surgery (CRS). Optimising patient selection is essential to maximise treatment efficacy and avoid overtreatment. This study aimed to identify biomarkers that predict HIPEC benefit by analysing gene signatures and cellular composition of tumours from participants in the OVHIPEC-1 trial. METHODS: Whole-transcriptome RNA sequencing data were retrieved from high-grade serous ovarian cancer (HGSOC) samples from 147 patients obtained during interval CRS. We performed differential gene expression analysis and applied deconvolution methods to estimate cell-type proportions in bulk mRNA data, validated by histological assessment. We tested the interaction between treatment and potential predictors on progression-free survival using Cox proportional hazards models. RESULTS: While differential gene expression analysis did not yield any predictive biomarkers, the cellular composition, as characterised by deconvolution, indicated that the absence of macrophages and the presence of B cells in the tumour microenvironment are potential predictors of HIPEC benefit. The histological assessment confirmed the predictive value of macrophage absence. CONCLUSION: Immune cell composition, in particular macrophages absence, may predict response to HIPEC in HGSOC and these hypothesis-generating findings warrant further investigation. CLINICAL TRIAL REGISTRATION: NCT00426257.
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Procedimientos Quirúrgicos de Citorreducción , Quimioterapia Intraperitoneal Hipertérmica , Neoplasias Ováricas , Microambiente Tumoral , Humanos , Femenino , Neoplasias Ováricas/patología , Neoplasias Ováricas/terapia , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Quimioterapia Intraperitoneal Hipertérmica/métodos , Persona de Mediana Edad , Cistadenocarcinoma Seroso/patología , Cistadenocarcinoma Seroso/terapia , Cistadenocarcinoma Seroso/tratamiento farmacológico , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/análisis , Macrófagos/patología , Macrófagos/metabolismoRESUMEN
Importance: The absolute benefit of chemotherapy for all patients with stage I triple-negative breast cancer (TNBC) is unclear, and biomarkers are not currently available for selecting patients with an excellent outcome for whom neoadjuvant or adjuvant chemotherapy may have negligible benefit. High levels of stromal tumor-infiltrating lymphocytes (sTILs) are associated with favorable survival in TNBC, but data solely in stage I TNBC are lacking. Objective: To examine the outcomes of patients of all ages with stage I TNBC solely and who received neither neoadjuvant nor adjuvant chemotherapy, according to centrally reviewed sTIL levels at prespecified cutoffs. Design, Setting, and Participants: This cohort study used the Netherlands Cancer Registry to identify patients diagnosed with stage I TNBC between January 1, 2005, and December 31, 2015, who were not treated with chemotherapy. Only patients who did not receive neoadjuvant and/or adjuvant chemotherapy were selected. The clinical data were matched with their corresponding pathology data provided by the Dutch Pathology Registry. Data analysis was performed between February and October 2023. Main Outcomes and Measures: The primary end point was breast cancer-specific survival (BCSS) at 5, 10, and 15 years for the prespecified sTIL level cutoffs of 30%, 50%, and 75%. Hematoxylin and eosin-stained slides were used for central review of histologic subtype, grade, and lymphovascular invasion. The International Immuno-Oncology Biomarker Working Group guidelines were used to score the sTIL levels; these levels were determined for 1041 patients. Results: Of a total of 4511 females with stage I TNBC, patients who were not treated with chemotherapy were selected and tissue blocks requested; sTILs were scored in 1041 patients (mean [SD] age at diagnosis, 64.4 [11.1] years, median follow-up 11.4 [95% CI, 10.9-11.9] years) who were included in the analyses.. Most tumors (952 [91.5%]) were invasive carcinomas of nonspecial histologic subtype. Most patients (548 [52.6%]) had pT1cN0 tumors. Median (range) sTIL level was 5% (1%-99%). A total of 775 patients (74.4%) had sTIL levels below 30%, 266 (25.6%) had 30% or greater, 203 (19.5%) had 50% or greater, and 141 (13.5%) had 75% or greater. Patients with pT1abN0 tumors had a more favorable outcome vs patients with pT1cN0 tumors, with a 10-year BCSS of 92% (95% CI, 89%-94%) vs 86% (95% CI, 82%-89%). In the overall cohort, sTIL levels of at least 30% were associated with better BCSS compared with sTIL levels less than 30% (96% and 87%, respectively; hazard ratio [HR], 0.45; 95% CI, 0.26-0.77). High sTIL levels of 50% or greater were associated with a better outcome than low sTIL levels of less than 50% (HR, 0.27; 95% CI, 0.10-0.74) in patients with pT1C tumors, with a 10-year BCSS of 95% increasing to 98% with sTIL levels of 75% or greater. Conclusions and Relevance: Results of this study showed that patients with stage I TNBC and high level of sTILs who did not receive neoadjuvant or adjuvant chemotherapy had excellent 10-year BCSS. The findings further support the role of sTILs as integral biomarkers in prospective clinical trials of therapy optimization for this patient population.
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Linfocitos Infiltrantes de Tumor , Estadificación de Neoplasias , Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Neoplasias de la Mama Triple Negativas/inmunología , Neoplasias de la Mama Triple Negativas/mortalidad , Linfocitos Infiltrantes de Tumor/inmunología , Femenino , Persona de Mediana Edad , Anciano , Adulto , Países Bajos , Terapia Neoadyuvante , Quimioterapia Adyuvante , Estudios de CohortesRESUMEN
INTRODUCTION: High-grade serous ovarian cancer (HGSOC) is characterized by high mortality and prevalent recurrences. This study investigates the prognostic value of phosphoglycerate dehydrogenase (PHGDH) in HGSOC which has been linked to metabolic reprogramming and recurrences in other cancers. METHODS: Data from 306 patients with advanced-stage HGSOC treated between 2008 and 2015 were analyzed. PHGDH expression levels were determined using immunohistochemistry and categorized as "low" or "high." RESULTS: PHGDH-high was associated with higher FIGO stage and increased use of neoadjuvant chemotherapy. Patients with PHGDH-high tumors had significantly worse survival than PHDH-low, even after adjusting for confounding factors.
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In this study, we measured the kinase activity profiles of 32 pre-treatment tumor biopsies of HER2-positive breast cancer patients. The aim of this study was to assess the prognostic potential of kinase activity levels, to identify potential mechanisms of resistance and to predict treatment success of HER2-targeted therapy combined with chemotherapy. Indeed, our system-wide kinase activity analysis allowed us to link kinase activity to treatment response. Overall, high kinase activity in the HER2-pathway was associated with good treatment outcome. We found eleven kinases differentially regulated between treatment outcome groups, including well-known players in therapy resistance, such as p38a, ERK, and FAK, and an unreported one, namely MARK1. Lastly, we defined an optimal signature of four kinases in a multiple logistic regression diagnostic test for prediction of treatment outcome (AUC = 0.926). This kinase signature showed high sensitivity and specificity, indicating its potential as predictive biomarker for treatment success of HER2-targeted therapy.
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The tumour-agnostic authorisations of larotrectinib and entrectinib shifted the paradigm for indication setting. European healthcare decision-makers agreed on their therapeutic potential but diverged primarily in identified uncertainties concerning basket trial designs and endpoints, prognostic value of neurotrophic tropomyosin receptor kinase (NTRK) gene fusions, and resistance mechanisms. In addition, assessments of relevant comparators, unmet medical needs (UMNs), and implementation of NTRK-testing strategies diverged. In particular, the tumour-specific reimbursement recommendations and guidelines do not reflect tumour-agnostic thinking. These differences indicate difficulties experienced in these assessments and provide valuable lessons for future disruptive therapies. As we discuss here, early multistakeholder dialogues concerning minimum evidence requirements and involving clinicians are essential.
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Benzamidas , Neoplasias , Pirimidinas , Humanos , Europa (Continente) , Neoplasias/tratamiento farmacológico , Benzamidas/uso terapéutico , Pirimidinas/uso terapéutico , Pirimidinas/farmacología , Indazoles/uso terapéutico , Pirazoles/uso terapéutico , Toma de Decisiones , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Toma de Decisiones Clínicas , Inhibidores de Proteínas Quinasas/uso terapéutico , Inhibidores de Proteínas Quinasas/farmacologíaRESUMEN
BACKGROUND: Patients with stage II-III HER2-positive breast cancer have good outcomes with the combination of neoadjuvant chemotherapy and HER2-targeted agents. Although increasing the number of chemotherapy cycles improves pathological complete response rates, early complete responses are common. We investigated whether the duration of chemotherapy could be tailored on the basis of radiological response. METHODS: TRAIN-3 is a single-arm, phase 2 study in 43 hospitals in the Netherlands. Patients with stage II-III HER2-positive breast cancer aged 18 years or older and a WHO performance status of 0 or 1 were enrolled. Patients received neoadjuvant chemotherapy consisting of paclitaxel (80 mg/m2 of body surface area on day 1 and 8 of each 21 day cycle), trastuzumab (loading dose on day 1 of cycle 1 of 8 mg/kg bodyweight, and then 6 mg/kg on day 1 on all subsequent cycles), and carboplatin (area under the concentration time curve 6 mg/mL per min on day 1 of each 3 week cycle) and pertuzumab (loading dose on day 1 of cycle 1 of 840 mg, and then 420 mg on day 1 of each subsequent cycle), all given intravenously. The response was monitored by breast MRI every three cycles and lymph node biopsy. Patients underwent surgery when a complete radiological response was observed or after a maximum of nine cycles of treatment. The primary endpoint was event-free survival at 3 years; however, follow-up for the primary endpoint is ongoing. Here, we present the radiological and pathological response rates (secondary endpoints) of all patients who underwent surgery and the toxicity data for all patients who received at least one cycle of treatment. Analyses were done in hormone receptor-positive and hormone receptor-negative patients separately. This trial is registered with ClinicalTrials.gov, number NCT03820063, recruitment is closed, and the follow-up for the primary endpoint is ongoing. FINDINGS: Between April 1, 2019, and May 12, 2021, 235 patients with hormone receptor-negative cancer and 232 with hormone receptor-positive cancer were enrolled. Median follow-up was 26·4 months (IQR 22·9-32·9) for patients who were hormone receptor-negative and 31·6 months (25·6-35·7) for patients who were hormone receptor-positive. Overall, the median age was 51 years (IQR 43-59). In 233 patients with hormone receptor-negative tumours, radiological complete response was seen in 84 (36%; 95% CI 30-43) patients after one to three cycles, 140 (60%; 53-66) patients after one to six cycles, and 169 (73%; 66-78) patients after one to nine cycles. In 232 patients with hormone receptor-positive tumours, radiological complete response was seen in 68 (29%; 24-36) patients after one to three cycles, 118 (51%; 44-57) patients after one to six cycles, and 138 (59%; 53-66) patients after one to nine cycles. Among patients with a radiological complete response after one to nine cycles, a pathological complete response was seen in 147 (87%; 95% CI 81-92) of 169 patients with hormone receptor-negative tumours and was seen in 73 (53%; 44-61) of 138 patients with hormone receptor-positive tumours. The most common grade 3-4 adverse events were neutropenia (175 [37%] of 467), anaemia (75 [16%]), and diarrhoea (57 [12%]). No treatment-related deaths were reported. INTERPRETATION: In our study, a third of patients with stage II-III hormone receptor-negative and HER2-positive breast cancer had a complete pathological response after only three cycles of neoadjuvant systemic therapy. A complete response on breast MRI could help identify early complete responders in patients who had hormone receptor negative tumours. An imaging-based strategy might limit the duration of chemotherapy in these patients, reduce side-effects, and maintain quality of life if confirmed by the analysis of the 3-year event-free survival primary endpoint. Better monitoring tools are needed for patients with hormone receptor-positive and HER2-positive breast cancer. FUNDING: Roche Netherlands.
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Anticuerpos Monoclonales Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias de la Mama , Imagen por Resonancia Magnética , Terapia Neoadyuvante , Estadificación de Neoplasias , Paclitaxel , Receptor ErbB-2 , Humanos , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Neoplasias de la Mama/diagnóstico por imagen , Femenino , Persona de Mediana Edad , Receptor ErbB-2/metabolismo , Receptor ErbB-2/análisis , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Adulto , Anciano , Paclitaxel/administración & dosificación , Trastuzumab/administración & dosificación , Carboplatino/administración & dosificación , Quimioterapia Adyuvante , Países Bajos , Esquema de MedicaciónRESUMEN
In the past decade, there have been a record number of oncology therapy approvals by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Besides the EMA's conditional marketing authorisation programme and the FDA's Accelerated Approval Program, we observe a tendency towards fast approval for exploratory studies with non-randomised, uncontrolled designs and surrogate endpoints. This issue raises concerns about the robustness and effectiveness of accepted treatments, leaving patients and health-care professionals in a state of uncertainty. A substantial number of accelerated approvals have recently been withdrawn in the USA, with some still authorised in Europe, emphasising discrepancies in regulatory standards that affect both patients and society as a whole. We highlight examples of drugs, authorised on the basis of surrogate endpoints, that were later withdrawn due to an absence of overall survival benefit. Our findings address the challenges and consequences of accelerated approval pathways in oncology. In conclusion, this Policy Review calls for regulatory bodies to better align their procedures and insist on robust evidence, preferably through unbiased randomised controlled trials. Drug approval processes should prioritise patient benefit, overall survival, and quality of life to minimise risks and uncertainties for patients.
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Aprobación de Drogas , Oncología Médica , Humanos , Europa (Continente) , Vigilancia de Productos Comercializados , Retirada de Medicamento por SeguridadRESUMEN
INTRODUCTION: The number of randomized controlled trials (RCTs) investigating the effects of exercise among cancer survivors has increased in recent years; however, participants dropping out of the trials are rarely described. The objective of the present study was to assess which combinations of participant and exercise program characteristics were associated with dropout from the exercise arms of RCTs among cancer survivors. METHODS: This study used data collected in the Predicting OptimaL cAncer RehabIlitation and Supportive care (POLARIS) study, an international database of RCTs investigating the effects of exercise among cancer survivors. Thirty-four exercise trials, with a total of 2467 patients without metastatic disease randomized to an exercise arm were included. Harmonized studies included a pre and a posttest, and participants were classified as dropouts when missing all assessments at the post-intervention test. Subgroups were identified with a conditional inference tree. RESULTS: Overall, 9.6% of the participants dropped out. Five subgroups were identified in the conditional inference tree based on four significant associations with dropout. Most dropout was observed for participants with BMI >28.4 kg/m2 , performing supervised resistance or unsupervised mixed exercise (19.8% dropout) or had low-medium education and performed aerobic or supervised mixed exercise (13.5%). The lowest dropout was found for participants with BMI >28.4 kg/m2 and high education performing aerobic or supervised mixed exercise (5.1%), and participants with BMI ≤28.4 kg/m2 exercising during (5.2%) or post (9.5%) treatment. CONCLUSIONS: There are several systematic differences between cancer survivors completing and dropping out from exercise trials, possibly affecting the external validity of exercise effects.
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Supervivientes de Cáncer , Neoplasias , Humanos , Calidad de Vida , Ejercicio Físico , Terapia por Ejercicio , Neoplasias/rehabilitación , Ensayos Clínicos Controlados Aleatorios como AsuntoRESUMEN
OBJECTIVE: The modeled CA-125 ELIMination rate constant K (KELIM) has been validated as a marker of response to chemotherapy in >12,000 patients with advanced epithelial ovarian carcinoma (EOC) treated in first-line setting enrolled in >12 clinical trials. Patient KELIM is calculable online https://www.biomarker-kinetics.org/presentation. The objective was to investigate the prognostic value of KELIM in a large real-life national cancer registry with non-selected patients. METHODS: We investigated 4,025 EOC patients from the Netherlands Cancer Registry treated with neoadjuvant chemotherapy (NACT) ± followed by interval debulking surgery (IDS). Patient KELIM values were calculated in patients with ≥ 3 CA-125 measurements during NACT. KELIM was standardized with a pre-specified cut-off and scored as unfavorable/favorable (<1.0/≥1.0). KELIM's prognostic value regarding radiological response, completeness of IDS, progression-free survival (PFS), and overall survival (OS) was assessed using univariate/multivariate analyses. RESULTS: The data from 1,582 patients treated with heterogeneous chemotherapy regimens and sequences were assessable. KELIM was prognostic for radiological response and the likelihood of complete IDS after NACT (odds ratio=2.59; 95% confidence interval [CI]=2.04-3.29). Moreover, KELIM was independently associated with PFS (hazard ratio [HR]=0.76; 95% CI=0.66-0.87), and OS (HR=0.79; 95% CI=0.69-0.91). Combining KELIM with the completeness of the IDS resulted in 3 prognostic groups (satisfactory, intermediate, and poor) with significant OS differences, namely a good, intermediate, and poor survival respectively. CONCLUSION: The value of KELIM, as a pragmatic indicator of response to chemotherapy, was maintained in a large real-life population-based cohort, highlighting its applicability in routine conditions.
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Antígeno Ca-125 , Carcinoma Epitelial de Ovario , Procedimientos Quirúrgicos de Citorreducción , Terapia Neoadyuvante , Neoplasias Ováricas , Humanos , Femenino , Antígeno Ca-125/sangre , Persona de Mediana Edad , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/patología , Neoplasias Ováricas/mortalidad , Neoplasias Ováricas/terapia , Carcinoma Epitelial de Ovario/tratamiento farmacológico , Carcinoma Epitelial de Ovario/patología , Carcinoma Epitelial de Ovario/mortalidad , Carcinoma Epitelial de Ovario/terapia , Anciano , Terapia Neoadyuvante/métodos , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Países Bajos , Sistema de Registros , Pronóstico , Estadificación de Neoplasias , Supervivencia sin Progresión , Quimioterapia Adyuvante , Anciano de 80 o más Años , Biomarcadores de Tumor/sangreRESUMEN
PURPOSE: The MONALEESA-2, -3, -7 trials demonstrated statistically significant and clinically meaningful progression-free survival and overall survival (OS) benefits with ribociclib plus endocrine therapy (ET) versus ET alone in hormone receptor-positive, HER2-negative (HR+/HER2-) advanced breast cancer (ABC). Understanding the association of intrinsic subtypes with survival outcomes could potentially guide treatment decisions. Here, we evaluated the association of intrinsic subtypes with OS in MONALEESA-2, -3, -7. EXPERIMENTAL DESIGN: Tumor samples from MONALEESA-2, -3, -7 underwent PAM50-based subtyping. The relationship between subtypes and OS was assessed using univariable and multivariable Cox proportional hazards models. Multivariable models were adjusted for clinical prognostic factors. RESULTS: Overall, 990 tumors (among 2,066 patients) from ribociclib (n = 580) and placebo (n = 410) arms were profiled. Subtype distribution was luminal A, 54.5%; luminal B, 28.0%; HER2-enriched (HER2E) 14.6%; and basal-like, 2.8%; and was consistent across treatment arms. The luminal A subtype had the best OS outcomes in both arms, while basal-like had the worst. Patients with HER2E (HR, 0.60; P = 0.018), luminal B (HR, 0.69; P = 0.023), and luminal A (HR, 0.75; P = 0.021) subtypes derived OS benefit with ribociclib. Patients with basal-like subtype did not derive benefit from ribociclib (HR, 1.92; P = 0.137); however, patient numbers were small (n = 28). CONCLUSIONS: The prognostic value of intrinsic subtypes for OS was confirmed in this pooled analysis of the MONALEESA trials (largest dataset in HR+/HER2- ABC). While basal-like subtype did not benefit, a consistent OS benefit was observed with ribociclib added to ET across luminal and HER2E subtypes.
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Neoplasias de la Mama , Humanos , Femenino , Neoplasias de la Mama/patología , Letrozol , Aminopiridinas , Receptor ErbB-2/genética , Receptor ErbB-2/uso terapéutico , Purinas , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: Exercise is a promising intervention to alleviate cognitive problems in breast cancer patients, but studies on mechanisms underlying these effects are lacking. PURPOSE: Investigating whether an exercise intervention can affect cerebral blood flow (CBF) in cognitively impaired breast cancer patients and to determine if CBF changes relate to memory function. STUDY TYPE: Prospective. POPULATION: A total of 181 chemotherapy-treated stage I-III breast cancer patients with cognitive problems and relatively low physical activity levels (≤150 minutes moderate to vigorous physical activity per week), divided into an exercise (N = 91) or control group (N = 90). FIELD STRENGTH/SEQUENCE: Two-dimensional echo planar pseudo-continuous arterial spin labeling CBF sequence at 3 T. ASSESSMENT: The 6-month long intervention consisted of (supervised) aerobic and strength training, 4 × 1 hour/week. Measurements at baseline (2-4 years post-diagnosis) and after 6 months included gray matter CBF in the whole brain, hippocampus, anterior cingulate cortex, and posterior cingulate cortex. Physical fitness and memory function were also assessed. Subgroup analyses were performed in patients with high fatigue levels at baseline. STATISTICAL TESTS: Multiple regression analyses with a two-sided alpha of 0.05 for all analyses. RESULTS: There was a significant improvement in physical fitness (VO2peak in mL/minute/kg) in the intervention group (N = 53) compared to controls (N = 51, ß = 1.47 mL/minute/kg, 95% CI: 0.44-2.50). However, no intervention effects on CBF were found (eg, whole brain: P = 0.565). Highly fatigued patients showed larger but insignificant treatment effects on CBF (eg, whole brain: P = 0.098). Additionally, irrespective of group, a change in physical fitness was positively associated with changes in CBF (eg, whole brain: ß = 0.75, 95% CI: 0.07-1.43). There was no significant relation between CBF changes and changes in memory performance. DATA CONCLUSION: The exercise intervention did not affect CBF of cognitively affected breast cancer patients. A change in physical fitness was associated with changes in CBF, but changes in CBF were not associated with memory functioning. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 5.