RESUMEN
BACKGROUND: AKT pathway activation is implicated in endocrine-therapy resistance. Data on the efficacy and safety of the AKT inhibitor capivasertib, as an addition to fulvestrant therapy, in patients with hormone receptor-positive advanced breast cancer are limited. METHODS: In a phase 3, randomized, double-blind trial, we enrolled eligible pre-, peri-, and postmenopausal women and men with hormone receptor-positive, human epidermal growth factor receptor 2-negative advanced breast cancer who had had a relapse or disease progression during or after treatment with an aromatase inhibitor, with or without previous cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitor therapy. Patients were randomly assigned in a 1:1 ratio to receive capivasertib plus fulvestrant or placebo plus fulvestrant. The dual primary end point was investigator-assessed progression-free survival assessed both in the overall population and among patients with AKT pathway-altered (PIK3CA, AKT1, or PTEN) tumors. Safety was assessed. RESULTS: Overall, 708 patients underwent randomization; 289 patients (40.8%) had AKT pathway alterations, and 489 (69.1%) had received a CDK4/6 inhibitor previously for advanced breast cancer. In the overall population, the median progression-free survival was 7.2 months in the capivasertib-fulvestrant group, as compared with 3.6 months in the placebo-fulvestrant group (hazard ratio for progression or death, 0.60; 95% confidence interval [CI], 0.51 to 0.71; P<0.001). In the AKT pathway-altered population, the median progression-free survival was 7.3 months in the capivasertib-fulvestrant group, as compared with 3.1 months in the placebo-fulvestrant group (hazard ratio, 0.50; 95% CI, 0.38 to 0.65; P<0.001). The most frequent adverse events of grade 3 or higher in patients receiving capivasertib-fulvestrant were rash (in 12.1% of patients, vs. in 0.3% of those receiving placebo-fulvestrant) and diarrhea (in 9.3% vs. 0.3%). Adverse events leading to discontinuation were reported in 13.0% of the patients receiving capivasertib and in 2.3% of those receiving placebo. CONCLUSIONS: Capivasertib-fulvestrant therapy resulted in significantly longer progression-free survival than treatment with fulvestrant alone among patients with hormone receptor-positive advanced breast cancer whose disease had progressed during or after previous aromatase inhibitor therapy with or without a CDK4/6 inhibitor. (Funded by AstraZeneca and the National Cancer Institute; CAPItello-291 ClinicalTrials.gov number, NCT04305496.).
Asunto(s)
Inhibidores de la Aromatasa , Neoplasias de la Mama , Femenino , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de la Aromatasa/efectos adversos , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/patología , Método Doble Ciego , Fulvestrant/efectos adversos , Fulvestrant/uso terapéutico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Proteínas Proto-Oncogénicas c-akt , Receptor ErbB-2RESUMEN
Current models imply that the FERM domain protein Merlin, encoded by the tumor suppressor NF2, inhibits mitogenic signaling at or near the plasma membrane. Here, we show that the closed, growth-inhibitory form of Merlin accumulates in the nucleus, binds to the E3 ubiquitin ligase CRL4(DCAF1), and suppresses its activity. Depletion of DCAF1 blocks the promitogenic effect of inactivation of Merlin. Conversely, enforced expression of a Merlin-insensitive mutant of DCAF1 counteracts the antimitogenic effect of Merlin. Re-expression of Merlin and silencing of DCAF1 implement a similar, tumor-suppressive program of gene expression. Tumor-derived mutations invariably disrupt Merlin's ability to interact with or inhibit CRL4(DCAF1). Finally, depletion of DCAF1 inhibits the hyperproliferation of Schwannoma cells from NF2 patients and suppresses the oncogenic potential of Merlin-deficient tumor cell lines. We propose that Merlin suppresses tumorigenesis by translocating to the nucleus to inhibit CRL4(DCAF1).
Asunto(s)
Proteínas Portadoras/metabolismo , Genes Supresores de Tumor , Mesotelioma/metabolismo , Neurilemoma/metabolismo , Neurofibromina 2/metabolismo , Transporte Activo de Núcleo Celular , Animales , Proteínas Portadoras/química , Línea Celular , Línea Celular Tumoral , Proliferación Celular , Células Cultivadas , Humanos , Modelos Moleculares , Proteínas Serina-Treonina Quinasas , Ubiquitina-Proteína LigasasRESUMEN
BACKGROUND: Capivasertib, an AKT inhibitor, added to fulvestrant, was previously reported to improve progression-free survival in women with aromatase inhibitor-resistant oestrogen receptor (ER)-positive, HER2-negative advanced breast cancer. The benefit appeared to be independent of the phosphoinositide 3-kinase (PI3K)/AKT/phosphatase and tensin homologue (PTEN) pathway alteration status of tumours, as ascertained using assays available at the time. Here, we report updated progression-free survival and overall survival results, and a prespecified examination of the effect of PI3K/AKT/PTEN pathway alterations identified by an expanded genetic testing panel on treatment outcomes. METHODS: This randomised, multicentre, double-blind, placebo-controlled, phase 2 trial recruited postmenopausal adult women aged at least 18 years with ER-positive, HER2-negative, metastatic or locally advanced inoperable breast cancer and an Eastern Cooperative Oncology Group performance status of 0-2, who had relapsed or progressed on an aromatase inhibitor, from across 19 hospitals in the UK. Participants were randomly assigned (1:1) to receive intramuscular fulvestrant 500 mg (day 1) every 28 days (plus a 500 mg loading dose on day 15 of cycle 1) with either capivasertib 400 mg or matching placebo, orally twice daily on an intermittent weekly schedule of 4 days on and 3 days off, starting on cycle 1 day 15. Treatment continued until disease progression, unacceptable toxicity, loss to follow-up, or withdrawal of consent. Treatment was allocated by an interactive web-response system using a minimisation method (with a 20% random element) and the following minimisation factors: measurable or non-measurable disease, primary or secondary aromatase inhibitor resistance, PIK3CA status, and PTEN status. The primary endpoint was progression-free survival in the intention-to-treat population. Secondary endpoints shown in this Article were overall survival and safety in the intention-to-treat population, and the effect of tumour PI3K/AKT/PTEN pathway status identified by an expanded testing panel that included next-generation sequencing assays. Recruitment is complete. The trial is registered with ClinicalTrials.gov, number NCT01992952. FINDINGS: Between March 16, 2015, and March 6, 2018, 183 participants were screened for eligibility and 140 (77%) were randomly assigned to receive fulvestrant plus capivasertib (n=69) or fulvestrant plus placebo (n=71). Median follow-up at the data cut-off of Nov 25, 2021, was 58·5 months (IQR 45·9-64·1) for participants treated with fulvestrant plus capivasertib and 62·3 months (IQR 62·1-70·3) for fulvestrant plus placebo. Updated median progression-free survival was 10·3 months (95% CI 5·0-13·4) in the group receiving fulvestrant plus capivasertib compared with 4·8 months (3·1-7·9) for fulvestrant plus placebo (adjusted hazard ratio [HR] 0·56 [95% CI 0·38-0·81]; two-sided p=0·0023). Median overall survival in the capivasertib versus placebo groups was 29·3 months (95% CI 23·7-39·0) versus 23·4 months (18·7-32·7; adjusted HR 0·66 [95% CI 0·45-0·97]; two-sided p=0·035). The expanded biomarker panel identified an expanded pathway-altered subgroup that contained 76 participants (54% of the intention-to-treat population). Median progression-free survival in the expanded pathway-altered subgroup for participants receiving capivasertib (n=39) was 12·8 months (95% CI 6·6-18·8) compared with 4·6 months (2·8-7·9) in the placebo group (n=37; adjusted HR 0·44 [95% CI 0·26-0·72]; two-sided p=0·0014). Median overall survival for the expanded pathway-altered subgroup receiving capivasertib was 38·9 months (95% CI 23·3-50·7) compared with 20·0 months (14·8-31·4) for those receiving placebo (adjusted HR 0·46 [95% CI 0·27-0·79]; two-sided p=0·0047). By contrast, there were no statistically significant differences in progression-free or overall survival in the expanded pathway non-altered subgroup treated with capivasertib (n=30) versus placebo (n=34). One additional serious adverse event (pneumonia) in the capivasertib group had occurred subsequent to the primary analysis. One death, due to atypical pulmonary infection, was assessed as possibly related to capivasertib treatment. INTERPRETATION: Updated FAKTION data showed that capivasertib addition to fulvestrant extends the survival of participants with aromatase inhibitor-resistant ER-positive, HER2-negative advanced breast cancer. The expanded biomarker testing suggested that capivasertib predominantly benefits patients with PI3K/AKT/PTEN pathway-altered tumours. Phase 3 data are needed to substantiate the results, including in patients with previous CDK4/6 inhibitor exposure who were not included in the FAKTION trial. FUNDING: AstraZeneca and Cancer Research UK.
Asunto(s)
Inhibidores de la Aromatasa , Neoplasias de la Mama , Adolescente , Adulto , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Método Doble Ciego , Femenino , Fulvestrant , Humanos , Recurrencia Local de Neoplasia/patología , Fosfatidilinositol 3-Quinasas/genética , Supervivencia sin Progresión , Proteínas Proto-Oncogénicas c-akt , Pirimidinas , Pirroles , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismoRESUMEN
Pharmacokinetics-matched digital electrocardiogram data (n = 503 measurements from 180 patients) collected in a first-in-human, multi-part, dose-escalation (from 80 to 800 mg) and dose expansion (at 480 mg) phase 1 study in patients with advanced solid malignancies, were used to assess potential risk of QT prolongation associated with the AKT inhibitor capivasertib. The relationship between plasma drug concentrations and baseline-adjusted Fridericia-corrected QT (ΔQTcF) values was estimated using a prespecified linear mixed-effects model. The model provided an unbiased reproduction of the experimental data set, estimating a small but positive correlation between capivasertib concentration and ΔQTcF. At the expected therapeutic dose (400 mg twice daily) the predicted mean ΔQTcF at the steady state maximum concentration was 3.97 ms with an upper limit of the 90% CI of 5.07 ms; below the 10 ms limit proposed by ICH E14 guidance. This analysis suggests that capivasertib is not expected to present a clinically significant risk for QT prolongation that is associated with pro-arrhythmic effects.
Asunto(s)
Síndrome de QT Prolongado , Neoplasias , Relación Dosis-Respuesta a Droga , Electrocardiografía , Frecuencia Cardíaca , Humanos , Síndrome de QT Prolongado/inducido químicamente , Neoplasias/tratamiento farmacológico , Pirimidinas , PirrolesRESUMEN
Adjuvant endocrine therapy reduces the risk of recurrence and death from breast cancer in women with hormone receptor-positive early breast cancer.Tamoxifen has been the standard therapy for decades, and this is still the case for pre-menopausal women.Ovarian suppression is of similar efficacy but currently there is no strong evidence for adding this to tamoxifen and the additional morbidity can be considerable. Results from two important trials addressing this issueare imminent. In post-menopausal women, aromatase inhibitors (AIs) (letrozole, anastrozole, or exemestane)are superior to tamoxifen in preventing recurrence but only letrozole has been shown to improve survival. The main gain is against high-risk cancers, and tamoxifen gives very similar benefit for low-risk disease. Traditionally, treatment has been given for around 5 years, but many women remain at risk of relapse for 10 years or more.The AIs, and more recently tamoxifen, have been shown to reduce further the risk of late recurrence in women still in remission after 5 years of tamoxifen if given for a further 5 years. The comparative benefits of these two options and the selection of patients most likely to benefit from long-term adjuvant endocrine therapy are important topics for further research, as is the optimum duration of AI therapy started upfront.
Asunto(s)
Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Antineoplásicos Hormonales/administración & dosificación , Inhibidores de la Aromatasa/administración & dosificación , Quimioterapia Adyuvante , Femenino , Humanos , Recurrencia Local de Neoplasia , Análisis de Supervivencia , Resultado del TratamientoRESUMEN
INTRODUCTION: For anticancer drug development, it is crucial that patients participate in early-phase clinical trials. The main aim of this study was to gain insight into the motivations and other variables influencing patients in their decision to participate in phase I oncology trials. MATERIALS AND METHODS: Over a period of 25 months, all patients who were informed about (specific) phase I trials in our cancer center were retrospectively included in this study. Data on providing informed consent and final phase I enrollment were collected. RESULTS: In total, 365 patients, with a median age of 59 years and a median World Health Organization performance status score of 1, were evaluated. The majority of patients (71%) were pretreated with systemic therapy, with a median of two lines. After specific study information had been given, 145 patients (40%) declined informed consent, 54% of them mainly because of low expectations regarding treatment benefits and concerns about potential side effects. Patients who had received previous systemic therapy consented more frequently than others. After initial consent, 61 patients (17%) still did not receive study treatment, mostly because of secondary withdrawal of consent or rapid clinical deterioration prior to first dosing. DISCUSSION: After specific referral to our hospital for participation in early clinical trials, only 44% of all patients who were informed about a specific phase I trial eventually participated. Reasons for both participation and nonparticipation were diverse. Patient participation rates could be improved by forming an experienced and dedicated study team.
Asunto(s)
Ensayos Clínicos como Asunto/psicología , Ensayos Clínicos como Asunto/estadística & datos numéricos , Oncología Médica/métodos , Oncología Médica/estadística & datos numéricos , Participación del Paciente/psicología , Participación del Paciente/estadística & datos numéricos , Adolescente , Adulto , Anciano , Bélgica/epidemiología , Ensayos Clínicos como Asunto/métodos , Humanos , Persona de Mediana Edad , Neoplasias/epidemiología , Neoplasias/psicología , Neoplasias/terapia , Países Bajos/epidemiología , Adulto JovenRESUMEN
Most gastrointestinal stromal tumors (GISTs) harbor oncogenic mutations in KIT or platelet-derived growth factor receptor-α. However, a small subset of GISTs lacks such mutations and is termed 'wild-type GISTs'. Germline mutation in any of the subunits of succinate dehydrogenase (SDH) predisposes individuals to hereditary paragangliomas and pheochromocytomas. However, germline mutations of the genes encoding SDH subunits A, B, C or D (SDHA, SDHB, SDHC or SDHD; collectively SDHx) are also identified in GISTs. SDHA and SDHB immunohistochemistry are reliable techniques to identify pheochromocytomas and paragangliomas with mutations in SDHA, SDHB, SDHC and SDHD. In this study, we investigated if SDHA immunohistochemistry could also identify SDHA-mutated GISTs. Twenty-four adult wild-type GISTs and nine pediatric/adolescent wild-type GISTs were analyzed with SDHB, and where this was negative, then with SDHA immunohistochemistry. If SDHA immunohistochemistry was negative, sequencing analysis of the entire SDHA coding sequence was performed. All nine pediatric/adolescent GISTs and seven adult wild-type GISTs were negative for SDHB immunohistochemistry. One pediatric GIST and three SDHB-immunonegative adult wild-type GISTs were negative for SDHA immunohistochemistry. In all four SDHA-negative GISTs, a germline SDHA c.91C>T transition was found leading to a nonsense p.Arg31X mutation. Our results demonstrate that SDHA immunohistochemistry on GISTs can identify the presence of an SDHA germline mutation. Identifying GISTs with deficient SDH activity warrants additional genetic testing, evaluation and follow-up for inherited disorders and paragangliomas.
Asunto(s)
Biomarcadores de Tumor , Complejo II de Transporte de Electrones , Tumores del Estroma Gastrointestinal/enzimología , Mutación de Línea Germinal , Adolescente , Adulto , Factores de Edad , Anciano , Biomarcadores de Tumor/genética , Biomarcadores de Tumor/inmunología , Niño , Análisis Mutacional de ADN , Complejo II de Transporte de Electrones/genética , Complejo II de Transporte de Electrones/inmunología , Tumores del Estroma Gastrointestinal/genética , Tumores del Estroma Gastrointestinal/inmunología , Tumores del Estroma Gastrointestinal/patología , Predisposición Genética a la Enfermedad , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Fenotipo , Adulto JovenRESUMEN
PURPOSE: Oxaliplatin-induced neuropathy is a dose-related side effect which occurs in almost 40 % of patients treated with oxaliplatin. Aim of the present study was to identify reliable clinical factors predicting its development and duration. METHODS: One hundred sixty-nine completely resected colorectal cancer patients treated with adjuvant Folfox IV regimen were retrospectively included. The following pre-treatment clinical parameters were collected: hypocalcaemia, hypomagnesaemia, hypoalbuminaemia, anaemia, diabetes, chronic renal failure (CRF), folate deficiency, vitamin B(12) deficiency, number of cycles received and habit to alcohol consumption. Incidence, grade (NCI-CTCAE v.3) and duration of neuropathy were recorded. RESULTS: Incidence of neuropathy was found to be higher in patients with pre-treatment anaemia (p = 0.001), hypoalbuminaemia (p = 0.01) and hypomagnesaemia (p = 0.001) as well in those with habit to alcohol consumption (p = 0.003). Neuropathy durations were conversely associated with age, being longer in younger patients (p = 0.03), and again with hypoalbuminaemia (p = 0.04) and hypomagnesaemia (p = 0.002). No correlation was found with gender, hypocalcaemia, diabetes and CRF. The correlation between vitamin B(12) and folate levels and the development of neurotoxicity were not analysed because of the high number of missing data in the population. CONCLUSIONS: Age, anaemia, hypoalbuminaemia, hypomagnesaemia and alcohol consumption are reliable and easily assessable clinical factors predicting incidence and length of oxaliplatin-induced neuropathy.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias Colorrectales/tratamiento farmacológico , Enfermedades del Sistema Nervioso Periférico/inducido químicamente , Factores de Edad , Anciano , Consumo de Bebidas Alcohólicas/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/métodos , Neoplasias Colorrectales/cirugía , Relación Dosis-Respuesta a Droga , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/efectos adversos , Fluorouracilo/uso terapéutico , Humanos , Incidencia , Leucovorina/administración & dosificación , Leucovorina/efectos adversos , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/administración & dosificación , Compuestos Organoplatinos/efectos adversos , Compuestos Organoplatinos/uso terapéutico , Oxaliplatino , Enfermedades del Sistema Nervioso Periférico/epidemiología , Enfermedades del Sistema Nervioso Periférico/fisiopatología , Reproducibilidad de los Resultados , Estudios Retrospectivos , Factores de Riesgo , Factores de TiempoRESUMEN
BACKGROUND: Itch is a common side-effect of treatment with anti-EGFR antibodies and tyrosine-kinase inhibitors. We designed a pilot single-centre study to assess the effects of aprepitant-a neurokinin receptor inhibitor-for management of severe pruritus induced by biological drugs. METHODS: In this single-group, prospective study, we consecutively enrolled 45 outpatients with metastatic solid tumours treated with biological drugs at the Campus Bio-Medico Hospital of Rome, Rome, Italy, between September, 2010, and November, 2011. We classified patients into two groups: a refactory group, for patients with pruritis refractory to standard treatment, or a naive group, for patients who had not been previously treated for pruritis. Aprepitant (125 mg on day 1; 80 mg on day 3; 80 mg on day 5) was given to patients in the refractory group after at least 1 week of standard systemic treatment. In the naive group, aprepitant was given in the same schedule as the refractory group, after first onset of severe pruritus. Intensity of itch was evaluated by Visual Analogue Scale (VAS) score. The primary endpoint was change in median VAS score. This trial is registered with ClinicalTrials.gov, number NCT01683552. FINDINGS: Median VAS in the refractory group was 8·00 (95% CI 7·93-8·57) at baseline and 1·00 (0·00-2·00) after 1 week of treatment with aprepitant (p<0·0001). In the naive group, VAS score was 8·00 (7·43-8·37) at baseline and 0·00 (0·06-1·08) after 1 week of treatment (p<0·0001). 41 (91%) patients responded to aprepitant (ie, had a >50% reduction in intensity of pruritis) and pruritus recurred in only six (13%) patients. No adverse events related to aprepitant occurred. INTERPRETATION: Aprepitant decreases severe pruritus induced by biological treatments; it is an old drug, widely available, and therefore easy to add to the armamentarium of supportive treatment. Although to our knowledge no other studies of the anti-itch activity of aprepitant are planned, the results of our trial warrant confirmation in phase 2 and 3 trials. FUNDING: None.
Asunto(s)
Antineoplásicos/efectos adversos , Receptores ErbB/antagonistas & inhibidores , Morfolinas/uso terapéutico , Neoplasias/tratamiento farmacológico , Antagonistas del Receptor de Neuroquinina-1 , Prurito/tratamiento farmacológico , Adulto , Anciano , Aprepitant , Femenino , Humanos , Masculino , Persona de Mediana Edad , Morfolinas/efectos adversos , Dimensión del Dolor , Proyectos Piloto , Estudios ProspectivosRESUMEN
BACKGROUND: Designing clinical trials with the emphasis on the patient-centered approach and focusing on clinical outcomes that are meaningful to patients is viewed as a priority by drug developers, regulatory agencies, payers, clinicians, and patients. This study aimed to capture information on clinical trial endpoints that would be most important and relevant for patients with advanced breast cancer, based on patient-reported outcomes. METHODS: Patients with either advanced triple-negative breast cancer [TNBC] and a maximum of two lines of systemic therapy or hormone receptor-positive/human epidermal growth factor receptor 2-negative [HR+/HER2-] breast cancer and a maximum of three lines of systemic therapy, participated in semi-structured concept elicitation interviews. Concept saturation was assessed. A sign, symptom, or impact was defined as "salient" if mentioned by ≥ 60% of participants, with an average bother rating of ≥ 5 (0-10 Scale). Participants were also asked about treatment priorities and to evaluate hypothetical scenarios showing different health-related functioning and quality-of-life treatment outcomes, using graphical representations. RESULTS: Thirty-two participants (97% women; aged 29+ years) with TNBC (n = 17) or HR+/HER2- breast cancer (n = 15) provided generally similar reports on symptom experience, with fatigue and pain being most salient, though importance of certain treatment-related symptoms varied between the two groups. Patients reported consistent perspectives on the importance of treatment outcomes: when considering a new treatment, they prioritized efficacy of the therapy, acceptable tolerability, stability, predictability of symptoms over time, and the duration of preserved health-related quality of life and physical functioning. The meaningful difference in preserved physical functioning was 2-3 months for 46% of participants with TNBC, whereas for most participants with HR+/HER2- breast cancer it started from 6-7 months. Both groups of participants found it easier to accept some toxicity at the beginning of therapy if it was followed by improvement, as opposed to improvement followed by deterioration. CONCLUSION: The results may help to inform the design of patient-centered clinical trials, to interpret health-related quality of life and/or patient-reported outcomes, and to optimize care for patients with advanced breast cancer.
Asunto(s)
Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Femenino , Humanos , Masculino , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Medición de Resultados Informados por el Paciente , Calidad de Vida , Receptor ErbB-2/metabolismo , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , AdultoRESUMEN
Despite some notable successes, there are still relatively few agents approved for cancer prevention. Here we review progress thus far in the development of medicines for cancer prevention, and we outline some key concepts that could further enable or accelerate drug development for cancer prevention in the future. These are summarized under six key themes: (i) unmet clinical need, (ii) patient identification, (iii) risk stratification, (iv) pharmacological intervention, (v) clinical trials, and (vi) health care policy. These concepts, if successfully realized, may help to increase the number of medicines available for cancer prevention. SIGNIFICANCE: The huge potential public health benefits of preventing cancer, combined with recent advances in the availability of novel early detection technologies and new treatment modalities, has caused us to revisit the opportunities and challenges associated with developing medicines to prevent cancer. Here we review progress in the field of developing medicines to prevent cancer to date, and we present a series of ideas that might help in the development of more medicines to prevent cancer in the future.
Asunto(s)
Neoplasias , Humanos , Neoplasias/tratamiento farmacológico , Neoplasias/prevención & control , Desarrollo de MedicamentosRESUMEN
Soft tissue sarcomas are aggressive tumors representing <1% of all adult neoplasms. Aim of our study was to evaluate promyelocytic leukemia gene expression value as prognostic factor and as a factor predicting response to alkylating agents/antracycline-based first line therapy. One hundred eleven patients affected by locally advanced and metastatic soft tissue sarcoma were selected. PML expression was evaluated by immunohistochemical analysis in pathological samples and in the corresponding normal tissue from each case. PML immunohistochemical results were correlated with prognosis and with radiological response to alkylating agents/antracycline-based first line therapy. PML expression was significantly reduced in synovial sarcomas (P < 0.0001), in myofibroblastic sarcomas (P < 0.0001), angiosarcomas (P < 0.0001), in leiomyosarcomas (P = 0.003), in mixoid liposarcomas (P < 0.0001), and in dedifferentiated liposarcomas (P < 0.0001). No significant difference was found for pleomorphic sarcoma [31.8 (95% CI: 16.7-41.0); P = 0.21]. and pleomorphic liposarcomas (P = 0.51). Loss of PML expression was found to be statistically correlated with TTP (P < 0.0001), median duration of response (P = 0.007), and OS (P = 0.02). No correlation was observed between PML expression and treatment efficacy. PML IHC expression is down-regulated in synovial sarcomas, myofibroblastic sarcomas, angiosarcomas, liposarcoma, and leiomyosarcomas and its expression correlated with prognosis.
Asunto(s)
Antraciclinas/uso terapéutico , Antineoplásicos Alquilantes/uso terapéutico , Proteínas Nucleares/metabolismo , Sarcoma/tratamiento farmacológico , Sarcoma/metabolismo , Neoplasias de los Tejidos Blandos/tratamiento farmacológico , Neoplasias de los Tejidos Blandos/metabolismo , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Regulación hacia Abajo , Resistencia a Antineoplásicos , Femenino , Humanos , Inmunohistoquímica , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Pronóstico , Proteína de la Leucemia Promielocítica , Estudios Retrospectivos , Sarcoma/secundario , Adulto JovenRESUMEN
PML regulates a wide range of pathways involved in tumorigenesis, such as apoptosis, which is also one of the main mechanisms through which oxaliplatin and fluoropyrimidine exert their antineoplastic activity. The present study aims to investigate PML expression as a predictive factor of oxaliplatin/fluoropyrimidine therapy efficacy. Seventy-four metastatic colorectal cancer patients who received oxaliplatin/floropyrimidine-based first line therapy have been included in this retrospective study. PML expression was assessed by immunohistochemistry. PML down-regulation was detected in 39 (52.7%) patients (14 complete and 25 partial PML loss). RR was significantly lower (25.6%) in patients with PML down-regulation than in patients with preserved PML expression (60%) (P = 0.006). Median TTP was 5.5 months when PML was down-regulated versus 11.9 months in case of preserved PML expression (P < 0.0001). A statistical significant difference was also detected in OS (15.6 and 24.5 months, respectively, P = 0.003). The impact of PML down-regulation on TTP and OS was statistically significant also in a multivariate model. This study represents the first evidence of a possible correlation between PML protein expression and outcome of metastatic colorectal cancer patients treated with oxaliplatin/fluoropyrimidine-based first line therapy.
Asunto(s)
Antineoplásicos/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Fluorouracilo/uso terapéutico , Proteínas Nucleares/metabolismo , Factores de Transcripción/metabolismo , Proteínas Supresoras de Tumor/metabolismo , Adulto , Anciano , Antimetabolitos Antineoplásicos/uso terapéutico , Capecitabina , Neoplasias Colorrectales/secundario , Desoxicitidina/análogos & derivados , Desoxicitidina/uso terapéutico , Resistencia a Antineoplásicos/fisiología , Femenino , Fluorouracilo/análogos & derivados , Humanos , Leucovorina/uso terapéutico , Masculino , Persona de Mediana Edad , Compuestos Organoplatinos/uso terapéutico , Oxaliplatino , Oxaloacetatos , Valor Predictivo de las Pruebas , Proteína de la Leucemia Promielocítica , Estudios Retrospectivos , Tasa de SupervivenciaRESUMEN
BACKGROUND: The combination of docetaxel, cisplatin, and 5-fluorouracil (5-FU) has demonstrated a survival advantage over cisplatin and 5-FU, but with substantial hematological toxicity. We aimed to evaluate the efficacy and toxicity of a sequential regimen with cisplatin, leucovorin, and 5-FU (PLF) followed by docetaxel in metastatic gastric cancer patients. METHODS: Treatment consisted of 4 cycles of biweekly PLF (cisplatin 50 mg/m(2) as a 30-min infusion on day 1, leucovorin 200 mg/m(2) in a 2-h infusion, and 5-FU 2,800 mg/m(2) in a 48-h continuous infusion starting on day 1) followed, in cases of response or stable disease, by 3 cycles of docetaxel (75 mg/m(2), every 3 weeks). RESULTS: Thirty-four patients were enrolled, with an average age of 64 years (range 34-69). The main cumulative grade 3-4 toxicities were: neutropenia (38.2%), febrile neutropenia (11.8%), and fatigue (14.7%). After the planned 7 cycles of treatment, the overall response rate was 38.2% (95% confidence interval [CI] 21.9-54.6), with 3 complete and 10 partial responses. Median progression-free survival and overall survival were 4.8 and 10.6 months, respectively. CONCLUSIONS: For patients with metastatic gastric cancer, the sequential administration of cisplatin, leucovorin, 5-FU, and docetaxel may be an effective palliative option and offers a far more favorable toxicity profile than the simultaneous use of docetaxel, cisplatin, and 5-FU.
Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias Gástricas/tratamiento farmacológico , Neoplasias Gástricas/mortalidad , Adulto , Anciano , Cisplatino/administración & dosificación , Supervivencia sin Enfermedad , Docetaxel , Esquema de Medicación , Femenino , Fluorouracilo/administración & dosificación , Humanos , Leucovorina/administración & dosificación , Masculino , Persona de Mediana Edad , Neoplasias Gástricas/patología , Análisis de Supervivencia , Taxoides/administración & dosificación , Resultado del TratamientoRESUMEN
Nearly all estrogen receptor (ER)-positive (POS) metastatic breast cancers become refractory to endocrine (ET) and other therapies, leading to lethal disease presumably due to evolving genomic alterations. Timely monitoring of the molecular events associated with response/progression by serial tissue biopsies is logistically difficult. Use of liquid biopsies, including circulating tumor cells (CTC) and circulating tumor DNA (ctDNA), might provide highly informative, yet easily obtainable, evidence for better precision oncology care. Although ctDNA profiling has been well investigated, the CTC precision oncology genomic landscape and the advantages it may offer over ctDNA in ER-POS breast cancer remain largely unexplored. Whole-blood (WB) specimens were collected at serial time points from patients with advanced ER-POS/HER2-negative (NEG) advanced breast cancer in a phase I trial of AZD9496, an oral selective ER degrader (SERD) ET. Individual CTC were isolated from WB using tandem CellSearch® /DEPArray™ technologies and genomically profiled by targeted single-cell DNA next-generation sequencing (scNGS). High-quality CTC (n = 123) from 12 patients profiled by scNGS showed 100% concordance with ctDNA detection of driver estrogen receptor α (ESR1) mutations. We developed a novel CTC-based framework for precision medicine actionability reporting (MI-CTCseq) that incorporates novel features, such as clonal predominance and zygosity of targetable alterations, both unambiguously identifiable in CTC compared to ctDNA. Thus, we nominated opportunities for targeted therapies in 73% of patients, directed at alterations in phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA), fibroblast growth factor receptor 2 (FGFR2), and KIT proto-oncogene, receptor tyrosine kinase (KIT). Intrapatient, inter-CTC genomic heterogeneity was observed, at times between time points, in subclonal alterations. Our analysis suggests that serial monitoring of the CTC genome is feasible and should enable real-time tracking of tumor evolution during progression, permitting more combination precision medicine interventions.
Asunto(s)
Neoplasias de la Mama , ADN Tumoral Circulante , Células Neoplásicas Circulantes , Biomarcadores de Tumor/genética , Neoplasias de la Mama/patología , ADN Tumoral Circulante/genética , Antagonistas de Estrógenos , Estudios de Factibilidad , Femenino , Genómica , Humanos , Mutación/genética , Células Neoplásicas Circulantes/patología , Medicina de PrecisiónRESUMEN
Receptor activator of NFκB ligand (RANKL), RANK, and osteoprotegerin (OPG) represent the key regulators of bone metabolism both in normal and pathological conditions, including bone metastases. To our knowledge, no previous studies investigated and compared RANK expression in primary tumors and in bone metastases from the same patient. We retrospectively examined RANK expression by immunohistochemistry in 74 bone metastases tissues from solid tumors, mostly breast, colorectal, renal, lung, and prostate cancer. For 40 cases, tissue from the corresponding primary tumor was also analyzed. Sixty-six (89%) of the 74 bone metastases were RANK-positive and, among these, 40 (59.5%) showed more than 50% of positive tumor cells. The median percentage of RANK-positive cells was 60% in primary tumors and metastases, without any statistically significant difference between the two groups (P=0.194). The same percentage was obtained by considering only cases with availability of samples both from primary and metastasis. Our study shows that RANK is expressed by solid tumors, with high concordance between bone metastasis and corresponding primary tumor. These data highlight the central role of RANK/RANKL/OPG pathway as potential therapeutic target not only in bone metastasis management, but also in the adjuvant setting.
Asunto(s)
Neoplasias Óseas/metabolismo , Neoplasias Óseas/secundario , Receptor Activador del Factor Nuclear kappa-B/metabolismo , Neoplasias Óseas/patología , Humanos , InmunohistoquímicaRESUMEN
PURPOSE: Cell-free DNA (cfDNA) analysis offers a noninvasive means to access the tumor genome. Despite limited sensitivity of broad-panel sequencing for detecting low-frequency mutations in cfDNA, it may enable more comprehensive genomic characterization in patients with sufficiently high disease burden. We investigated the utility of large-panel cfDNA sequencing in patients enrolled to a Phase I AKT1-mutant solid tumor basket study. METHODS: Patients had AKT1 E17K-mutant solid tumors and were treated on the multicenter basket study (ClinicalTrials.gov identifier: NCT01226316) of capivasertib, an AKT inhibitor. Serial plasma samples were prospectively collected and sequenced using exon-capture next-generation sequencing (NGS) analysis of 410 genes (Memorial Sloan Kettering [MSK]-Integrated Molecular Profiling of Actionable Cancer Target [IMPACT]) and allele-specific droplet digital polymerase chain reaction (ddPCR) for AKT1 E17K. Tumor DNA (tDNA) NGS (MSK-IMPACT) was also performed on available pretreatment tissue biopsy specimens. RESULTS: Among 25 patients, pretreatment plasma samples were sequenced to an average coverage of 504×. Somatic mutations were called in 20/25 (80%), with mutant allele fractions highly concordant with ddPCR of AKT1 E17K (r 2 = 0.976). Among 17 of 20 cfDNA-positive patients with available tDNA for comparison, mutational concordance was acceptable, with 82% of recurrent mutations shared between tissue and plasma. cfDNA NGS captured additional tumor heterogeneity, identifying mutations not observed in tDNA in 38% of patients, and revealed oncogenic mutations in patients without available baseline tDNA. Longitudinal cfDNA NGS (n = 98 samples) revealed distinct patterns of clonal dynamics in response to therapy. CONCLUSION: Large gene panel cfDNA NGS is feasible for patients with high disease burden and is concordant with single-analyte approaches, providing a robust alternative to ddPCR with greater breadth. cfDNA NGS can identify heterogeneity and potentially biologically informative and clinically relevant alterations.
Asunto(s)
ADN Tumoral Circulante/genética , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Mutación , Neoplasias/genética , Genoma , Humanos , Estudios ProspectivosRESUMEN
Five to ten percent of ER+ metastatic breast cancer (MBC) tumors harbor somatic PTEN mutations. Loss of function of this tumor-suppressor gene defines a highly aggressive, treatment-refractory disease for which new therapies are urgently needed. This Phase I multipart expansion study assessed oral capivasertib with fulvestrant in patients with PTEN-mutant ER+ MBC. Safety and tolerability were assessed by standard methods. Plasma and tumor were collected for NGS and immunohistochemistry analyses of PTEN protein expression. In 31 eligible patients (12 fulvestrant naive; 19 fulvestrant pretreated), the 24-week clinical benefit rate was 17% in fulvestrant-naive and 42% in fulvestrant-pretreated patients, with objective response rate of 8% and 21%, respectively. Non-functional PTEN was centrally confirmed in all cases by NGS or immunohistochemistry. Co-mutations occurred in PIK3CA (32%), with less ESR1 (10% vs 72%) and more TP53 (40% vs 28%) alterations in fulvestrant-naive versus fulvestrant-pretreated patients, respectively. PTEN was clonally dominant in most patients. Treatment-related grade ≥3 adverse events occurred in 32% of patients, most frequently diarrhea and maculopapular rash (both n = 2). In this clinical study, which selectively targeted the aggressive PTEN-mutant ER+ MBC, capivasertib plus fulvestrant was tolerable and clinically active. Phenotypic and genomic differences were apparent between fulvestrant-naive and -pretreated patients.Trial registration number for the study is NCT01226316.
RESUMEN
Circulating tumour DNA (ctDNA) allows tracking of the evolution of human cancers at high resolution, overcoming many limitations of tissue biopsies. However, exploiting ctDNA to determine how a patient's cancer is evolving in order to aid clinical decisions remains difficult. This is because ctDNA is a mix of fragmented alleles, and the contribution of different cancer deposits to ctDNA is largely unknown. Profiling ctDNA almost invariably requires prior knowledge of what genomic alterations to track. Here, we leverage on a rapid autopsy programme to demonstrate that unbiased genomic characterisation of several metastatic sites and concomitant ctDNA profiling at whole-genome resolution reveals the extent to which ctDNA is representative of widespread disease. We also present a methylation profiling method that allows tracking evolutionary changes in ctDNA at single-molecule resolution without prior knowledge. These results have critical implications for the use of liquid biopsies to monitor cancer evolution in humans and guide treatment.
Asunto(s)
Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , ADN Tumoral Circulante/genética , Epigénesis Genética , Neoplasias de la Mama/sangre , Evolución Clonal , Células Clonales , Metilación de ADN/genética , Resistencia a Antineoplásicos/genética , Femenino , Genoma Humano , Humanos , Metástasis de la NeoplasiaRESUMEN
PURPOSE: ESR1 mutations are acquired frequently in hormone receptor-positive metastatic breast cancer after prior aromatase inhibitors. We assessed the clinical utility of baseline ESR1 circulating tumor DNA (ctDNA) analysis in the two phase III randomized trials of fulvestrant versus exemestane. EXPERIMENTAL DESIGN: The phase III EFECT and SoFEA trials randomized patients with hormone receptor-positive metastatic breast cancer who had progressed on prior nonsteroidal aromatase inhibitor therapy, between fulvestrant 250 mg and exemestane. Baseline serum samples from 227 patients in EFECT, and baseline plasma from 161 patients in SoFEA, were analyzed for ESR1 mutations by digital PCR. The primary objectives were to assess the impact of ESR1 mutation status on progression-free (PFS) and overall survival (OS) in a combined analysis of both studies. RESULTS: ESR1 mutations were detected in 30% (151/383) baseline samples. In patients with ESR1 mutation detected, PFS was 2.4 months [95% confidence interval (CI), 2.0-2.6] on exemestane and 3.9 months (95% CI, 3.0-6.0) on fulvestrant [hazard ratio (HR), 0.59; 95% CI, 0.39-0.89; P = 0.01). In patients without ESR1 mutations detected, PFS was 4.8 months (95% CI, 3.7-6.2) on exemestane and 4.1 months (95% CI, 3.6-5.5) on fulvestrant (HR, 1.05; 95% CI, 0.81-1.37; P = 0.69). There was an interaction between ESR1 mutation and treatment (P = 0.02). Patients with ESR1 mutation detected had 1-year OS of 62% (95% CI, 45%-75%) on exemestane and 80% (95% CI, 68%-87%) on fulvestrant (P = 0.04; restricted mean survival analysis). Patients without ESR1 mutations detected had 1-year OS of 79% (95% CI, 71%-85%) on exemestane and 81% (95% CI, 74%-87%) on fulvestrant (P = 0.69). CONCLUSIONS: Detection of ESR1 mutations in baseline ctDNA is associated with inferior PFS and OS in patients treated with exemestane versus fulvestrant.