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BACKGROUND: The phase III GIM2 trial showed improved disease-free survival (DFS) and overall survival (OS) with adjuvant dose-dense (DD) as compared with standard-interval (SI) chemotherapy in women with node-positive early-stage breast cancer (BC). This exploratory analysis aimed to investigate the benefit of different schedules according to body mass index (BMI) in this trial. PATIENTS AND METHODS: This analysis explored the efficacy, in terms of DFS and OS, of different chemotherapy schedules according to BMI. Univariate and multivariable Cox proportional hazard models, adjusted for relevant prognostic factors, were used. RESULTS: Out of 2091 patients enrolled, 1925 with known baseline BMI were randomized in the DD versus SI comparison and therefore included in this analysis: 31.6% were overweight and 19.3% obese. Overweight and obesity were significantly associated with postmenopausal status, pT >2, and pN >2 tumors. After a median follow-up of 15.0 years (interquartile range 8.4-16.3 years), multivariable Cox survival models demonstrated no association of different BMI categories on DFS [adjusted hazard ratio (adjHR) 0.96, 95% confidence interval (CI) 0.80-1.15 and adjHR 1.11, 95% CI 0.91-1.35 for overweight and obese patients, respectively, compared to patients with normal BMI] or OS (adjHR 0.90, 95% CI 0.71-1.14 and adjHR 1.18, 95% CI 0.92-1.52 for overweight and obese patients, respectively). No significant interaction was found between BMI and treatment schedule in terms of DFS (Pfor interaction = 0.56) or OS (Pfor interaction = 0.19). The survival benefit of DD chemotherapy was observed irrespective of different BMI categories, with a more pronounced benefit for overweight and obese patients. CONCLUSION: In node-positive BC patients, DD schedule should be considered the preferred schedule irrespective of BMI.
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BACKGROUND: BRCA1/2-related metastatic breast cancers (mBC) are sensitive to DNA-damage agents and show high tumor-infiltrated lymphocytes. We hypothesized that the association between pembrolizumab and carboplatin could be active in BRCA-related mBC. PATIENTS AND METHODS: In this phase II Simon's design multicenter single-arm study, BRCA1/2-related mBC patients received carboplatin at area under the curve 6 every 3 weeks for six courses associated with 200 mg pembrolizumab every 3 weeks until disease progression or unacceptable toxicity. The primary aim at first stage was overall response rate (ORR) ≥70%. Disease control rate (DCR), time to progression (TTP), duration of response (DOR), and overall survival (OS) were the secondary aims. RESULTS: Among 22 patients enrolled at the first stage, 5 BRCA1 and 17 BRCA2, 16 (76%) were luminal tumors and 6 (24%) triple-negative BC (TNBC). In 21 patients, ORR and DCR were 43% and 76% (47% and 87% in luminal, 33% and 50% in TNBC), respectively. TTP was 7.1 months, DOR was 6.3 months, and median OS was not reached. Grade ≥3 adverse events (AEs) or serious AEs occurred in 5/22 patients (22.7%). Since the primary aim was not met, the study was terminated at the first stage. CONCLUSIONS: Although the primary aim was not reached, data on efficacy and safety of pembrolizumab plus carboplatin in first-line visceral disease BRCA-related luminal mBC were provided and they need to be further investigated.
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Proteína BRCA1 , Neoplasias de la Mama Triple Negativas , Humanos , Carboplatino/efectos adversos , Proteína BRCA1/genética , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/patología , Proteína BRCA2/genética , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversosRESUMEN
BACKGROUND: In human epidermal growth factor receptor 2 (HER2+) breast cancers, neoadjuvant trials of chemotherapy plus anti-HER2 treatment consistently showed lower pathologic complete response (pCR) rates in hormone receptor (HR) positive versus negative tumors. The PerELISA study was aimed to evaluate the efficacy of a de-escalated, chemotherapy-free neoadjuvant regimen in HR+/HER2+ breast cancer patients selected on the basis of Ki67 inhibition after 2-week letrozole. PATIENTS AND METHODS: PerELISA is a phase II, multicentric study for postmenopausal patients with HR+/HER2+ operable breast cancer. Patients received 2-week letrozole, and then underwent re-biopsy for Ki67 evaluation. Patients classified as molecular responders (Ki67 relative reduction >20% from baseline) continued letrozole and started trastuzumab-pertuzumab for five cycles. Patients classified as molecular non-responders started weekly paclitaxel for 13 weeks combined with trastuzumab-pertuzumab. Primary aim was breast and axillary pCR. According to a two-stage Simon's design, to reject the null hypothesis, at least 8/43 pCR had to be documented. RESULTS: Sixty-four patients were enrolled, 44 were classified as molecular responders. All these patients completed the assigned treatment with letrozole-trastuzumab-pertuzumab and underwent surgery. A pCR was observed in 9/44 cases (20.5%, 95% confidence interval 11.1% to 34.5%). Among molecular non-responders, 16/17 completed treatment and underwent surgery, with pCR observed in 81.3% of the cases. PAM50 intrinsic subtype was significantly associated with Ki67 response and pCR. Among molecular responders, the pCR rate was significantly higher in HER2-enriched than in other subtypes (45.5% versus 13.8%, P = 0.042). CONCLUSIONS: The primary end point of the study was met, by reaching the pre-specified pCRs. In patients selected using Ki67 reduction after short-term letrozole exposure, a meaningful pCR rate can be achieved without chemotherapy. PAM50 intrinsic subtyping further refines our ability to identify a subset of patients for whom chemotherapy might be spared. EUDRACT NUMBER: 2013-002662-40. CLINICALTRIALS.GOV IDENTIFIER: NCT02411344.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Antígeno Ki-67/metabolismo , Receptor ErbB-2/metabolismo , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/patología , Carcinoma Ductal de Mama/cirugía , Carcinoma Lobular/tratamiento farmacológico , Carcinoma Lobular/metabolismo , Carcinoma Lobular/patología , Carcinoma Lobular/cirugía , Relación Dosis-Respuesta a Droga , Femenino , Estudios de Seguimiento , Humanos , Letrozol/administración & dosificación , Persona de Mediana Edad , Terapia Neoadyuvante , Invasividad Neoplásica , Pronóstico , Inducción de Remisión , Trastuzumab/administración & dosificaciónRESUMEN
BACKGROUND: There is the need to identify new prognostic markers to refine risk stratification for HER2-positive early breast cancer patients. The aim of this study was to evaluate the association of tumor-infiltrating lymphocytes (TILs) with distant disease-free survival (DDFS) in patients with HER2-positive early breast cancer enrolled in the ShortHER adjuvant trial which compared 9 weeks versus 1-year trastuzumab in addition to chemotherapy, and to test the interaction between TILs and treatment arm. PATIENTS AND METHODS: Stromal TILs were assessed for 866 cases on centralized hematoxylin and eosin-stained tumor slides. The association of TILs as 10% increments with DDFS was assessed with Cox models. Kaplan-Meier curves were estimated for patients with TILs ≥20% and TILs <20%. Median follow-up was 6.1 years. RESULTS: Median TILs was 5% (Q1-Q3 1%-15%). Increased TILs were independently associated with better DDFS in multivariable model [hazard ratio (HR) 0.73, 95% confidence interval (CI) 0.59-0.89, P = 0.006, for each 10% TILs increment]. Five years DDFS rates were 91.1% for patients with TILs <20% and 95.7% for patients with TILs ≥20% (P = 0.025). The association between 10% TILs increments and DDFS was significant for patients randomized to 9 weeks of trastuzumab (HR 0.60, 95% CI 0.41-0.88) but not for patients treated with 1 year of trastuzumab (HR 0.89, 95% CI 0.71-1.12; test for interaction P = 0.088). For patients with TILs <20%, the HR for the comparison between the short versus the long arm was 1.75 (95% CI 1.09-2.80, P=0.021); whereas, for patients with TILs ≥20% the HR for the comparison of short versus long arm was 0.23 (95% CI 0.05-1.09, P = 0.064), resulting in a significant interaction (P = 0.015). CONCLUSIONS: TILs are an independent prognostic factor for HER2-positive early breast cancer patients treated with adjuvant chemotherapy and trastuzumab and may refine the ability to identify patients at low risk of relapse eligible for de-escalated adjuvant therapy.
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Neoplasias de la Mama/tratamiento farmacológico , Linfocitos Infiltrantes de Tumor/efectos de los fármacos , Receptor ErbB-2/genética , Trastuzumab/administración & dosificación , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Quimioterapia Adyuvante/efectos adversos , Supervivencia sin Enfermedad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/clasificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/patología , Femenino , Humanos , Estimación de Kaplan-Meier , Persona de Mediana Edad , Recurrencia Local de Neoplasia/tratamiento farmacológico , Recurrencia Local de Neoplasia/genética , Recurrencia Local de Neoplasia/patología , Trastuzumab/efectos adversos , Resultado del TratamientoRESUMEN
Background: Chemotherapy plus 1-year trastuzumab is the standard adjuvant treatment of HER2-positive breast cancer. The efficacy of less extended trastuzumab exposure is under investigation. The short-HER study was aimed to assess the non-inferiority of 9 weeks versus 1 year of adjuvant trastuzumab combined with chemotherapy. Patients and methods: HER2-positive breast cancer patients with node-positive or, if node negative, with at least one risk factor (pT>2 cm, G3, lympho-vascular invasion, Ki-67 > 20%, age ≤35 years, or hormone receptor negativity) were randomly assigned to receive sequential anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or plus 9 weeks trastuzumab (arm B, short). This study was designed as a non-inferiority trial with disease-free survival (DFS) as primary end point. A DFS hazard ratio (HR) <1.29 was chosen as the non-inferiority margin. Analyses according to the frequentist and Bayesian approach were planned. Secondary end points included 2-year failure rate and cardiac safety. Results: A total of 1254 patients from 82 centers were randomized (arm A, long: n = 627; arm B, short: n = 626). Five-year DFS is 88% in the long and 85% in the short arm. The HR is 1.13 (90% CI 0.89-1.42), with the upper limit of the CI crossing the non-inferiority margin. According to the Bayesian analysis, the probability that the short arm is non-inferior to the long one is 80%. The 5-year overall survival (OS) is 95.2% in the long and 95.0% in the short arm (HR 1.07, 90% CI 0.74-1.56). Cardiac events are significantly lower in the short arm (risk-ratio 0.33, 95% CI 0.22-0.50, P < 0.0001). Conclusions: This study failed to show the non-inferiority of a shorter trastuzumab administration. One-year trastuzumab remains the standard. However, a 9-week administration decreases the risk of severe cardiac toxicity and can be an option for patients with cardiac events during treatment and for those with a low risk of relapse. Trial Registration: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.
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Antineoplásicos Inmunológicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/terapia , Cardiotoxicidad/epidemiología , Trastuzumab/administración & dosificación , Adulto , Anciano , Antraciclinas/administración & dosificación , Antraciclinas/efectos adversos , Antineoplásicos Inmunológicos/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/normas , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Hidrocarburos Aromáticos con Puentes/administración & dosificación , Hidrocarburos Aromáticos con Puentes/efectos adversos , Cardiotoxicidad/etiología , Quimioterapia Adyuvante/efectos adversos , Quimioterapia Adyuvante/métodos , Quimioterapia Adyuvante/normas , Supervivencia sin Enfermedad , Esquema de Medicación , Femenino , Humanos , Mastectomía , Persona de Mediana Edad , Recurrencia Local de Neoplasia , Estadificación de Neoplasias , Receptor ErbB-2/metabolismo , Taxoides/administración & dosificación , Taxoides/efectos adversos , Factores de Tiempo , Trastuzumab/efectos adversosRESUMEN
BACKGROUND: Although human epidermal growth factor receptor 2 (HER2) overexpression is associated with poor prognosis, patients (pts) with pT1a N0M0 breast cancers (BCs) have an excellent outcome across all subtypes. Interval cancers (ICs) have poorer survival than screen-detected (SD) tumours, and an association has been reported between ICs and HER2 overexpression. We aimed to determine, in a general population of pT1a N0M0 BCs with known screening status, whether HER2-positive ICs have a poorer outcome than HER2-positive SD cancers. METHODS: We evaluated all incident pT1a N0M0 BCs (n = 874) collected in the Emilia-Romagna region (Italy) from 2003 to 2009 and diagnosed in women aged 50-69. Pts unexposed to screening, with unknown HER2 status and/or treated with adjuvant trastuzumab were excluded from analysis. RESULTS: Sixty-one percent of the BCs were SD, whereas 19% were ICs. BCs with high histologic grade, hormone receptor-negative or HER2-positive status (odds ratio=1.7; 95% confidence interval [CI]: 1.1-2.7) were more likely ICs. Median follow-up was 115 months. The 10-year invasive disease-free survival (iDFS) for HER2-positive ICs was lower than that for HER2-positive SD cancers: 75.0% (95% CI: 55.5%-94.5%) versus 93.8% (95% CI: 86.5%-100%). An interaction between ICs and HER2-positive status was found for poorer iDFS after adjusting for prognostic variables (HR = 5.3; 95% CI: 1.6-16.7). CONCLUSIONS: IC detection may identify pts with HER2-positive pT1a N0M0 tumours in whom the rate of recurrence justifies consideration for conventional, anti-HER2, adjuvant treatment.
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Neoplasias de la Mama/diagnóstico , Detección Precoz del Cáncer , Vigilancia de la Población/métodos , Receptor ErbB-2/metabolismo , Sistema de Registros/estadística & datos numéricos , Anciano , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/terapia , Supervivencia sin Enfermedad , Femenino , Humanos , Italia , Persona de Mediana Edad , Estadificación de Neoplasias , Evaluación de Resultado en la Atención de Salud/métodos , Evaluación de Resultado en la Atención de Salud/estadística & datos numéricos , PronósticoRESUMEN
PURPOSE: The new ASCO/CAP guidelines published in 2013 (AC2013) significantly modified the scoring criteria for HER2-FISH, introducing the most controversial change to the HER2-equivocal category. We retrospectively evaluated the impact of AC2013 in a cohort of consecutive invasive breast cancers (IBCs) analyzed with frontline dual-color FISH. METHODS: 2788 consecutive IBCs were reclassified based on the AC2013 guidelines. Clinico-pathological features of equivocal IBCs were compared with HER2-negative and HER2-positive IBCs. FISH HER2-equivocal cases underwent reflex tests: HER2-IHC, RARA-FISH, and SMS-FISH. Overall and disease-free survivals were evaluated in AC2007 HER2-positive patients treated with trastuzumab and in patients that became eligible for target-therapy according to AC2013. RESULTS: Two-hundred HER2-negative cases (7.2%) were classified differently, following AC2013: 0.3% (8/2788) became HER2-positive and 6.9% (192/2788) HER2-equivocal. AC2013, compared with AC2007, significantly increased initial HER2-equivocal cases (6.9%vs1.6%, p < 0.001). AC2013 equivocal-IBCs affected older patients and showed pathological features between HER2-negative and HER2-positive IBCs. After reflex tests, 102 of the 190 equivocal cases (53.7%) were reclassified as HER2-positive, 51 (26.8%) as negative and 37 (19.5%) as equivocal. IHC tested negative in 44.7% of cases, whereas SMS-FISH showed the highest percentage of positive results (45.8%). Clinical outcomes showed no statistically significant differences. CONCLUSION: Overall, 80.5% of FISH-equivocal cases were solved with at least one reflex test and 3.6% of patients became AC2013 HER2-positive, therefore eligible for target-therapy, but showed clinical outcomes similar to HER2-positive patients treated with trastuzumab. Our data belittle the clinical impact of AC2013 HER2-equivocal reclassification; further prospective randomized clinical studies are necessary to support these findings.
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Neoplasias de la Mama/genética , Carcinoma Ductal de Mama/genética , Receptor ErbB-2/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos Inmunológicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama Masculina/genética , Neoplasias de la Mama Masculina/metabolismo , Carcinoma Ductal de Mama/tratamiento farmacológico , Carcinoma Ductal de Mama/metabolismo , Aberraciones Cromosómicas , Cromosomas Humanos Par 17 , Supervivencia sin Enfermedad , Femenino , Dosificación de Gen , Pruebas Genéticas/normas , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ/métodos , Masculino , Persona de Mediana Edad , Guías de Práctica Clínica como Asunto , Receptor ErbB-2/metabolismo , Receptor alfa de Ácido Retinoico/genética , Estudios Retrospectivos , Síndrome de Smith-Magenis/genética , Tasa de Supervivencia , Trastuzumab/uso terapéutico , Adulto JovenRESUMEN
PURPOSE: The aim was to evaluate the role of tumor-infiltrating lymphocytes (TIL) in predicting molecular response after preoperative endocrine or cytotoxic treatment for HR+/HER2- patients who do not achieve a pathological complete response. METHODS: Stromal (Str) TIL were centrally evaluated on samples from diagnostic core-biopsies of HR+/HER2- patients included in two prospective randomized trials: the LETLOB trial (neoadjuvant endocrine-based treatment) and the GIOB trial (neoadjuvant chemotherapy-based treatment). Pre- and post-treatment Ki67 was centrally assessed. RESULTS: StrTIL were evaluable in 111 cases (n = 73 from the LETLOB trial and n = 38 from the GIOB trial). Median StrTIL was 2%. Patients with high StrTIL (StrTIL ≥10%, n = 28) had more frequently breast cancer of ductal histology (p = 0.02), high grade (p = 0.049), and high Ki67 (p = 0.02). After neoadjuvant endocrine treatment (LETLOB cohort), a significant Ki67 suppression (p < 0.01) from pre- to post-treatment was observed in both the low and high StrTIL groups. High StrTIL patients achieve more frequently a relative Ki67 suppression ≥50% from baseline as compared to low StrTIL patients (55 vs. 35%, p non significant). After neoadjuvant chemotherapy (GIOB cohort), a significant Ki67 suppression was observed only for low StrTIL patients (Wilcoxon p = 0.001) and not in the high StrTIL group (p = 0.612). In this cohort, the rate of patients achieving a relative Ki67 suppression ≥50% from baseline was significantly higher in the low vs high StrTIL group (64% vs 10%, p = 0.003). Geometric mean Ki67 suppression was evaluated in each cohort according to StrTIL: the lowest value (-41%) was observed for high StrTIL cases treated with chemotherapy. CONCLUSIONS: This hypothesis-generating study suggests that in HR+/HER2- breast cancer StrTIL at baseline may influence the achievement of a molecular response after neoadjuvant treatment. Further evaluation in large studies is needed, and interaction with the type of treatment warrants to be explored.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Linfocitos Infiltrantes de Tumor/patología , Adulto , Anciano , Anciano de 80 o más Años , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Femenino , Humanos , Lapatinib , Letrozol , Persona de Mediana Edad , Terapia Neoadyuvante , Nitrilos/administración & dosificación , Estudios Prospectivos , Quinazolinas/administración & dosificación , Receptor ErbB-2/metabolismo , Receptores de Superficie Celular/metabolismo , Resultado del Tratamiento , Triazoles/administración & dosificaciónRESUMEN
BACKGROUND: The aim of this work was to evaluate the impact of (and relative contribution of) tumor-related and immune-related diversity of HER2-positive disease on the response to neoadjuvant chemotherapy plus anti-HER2 agents. PATIENTS AND METHODS: The CherLOB phase II study randomized 121 HER2-positive breast cancer patients to neoadjuvant chemotherapy plus trastuzumab, lapatinib or both. Tumor samples from diagnostic core biopsy were centralized. Tumor-infiltrating lymphocytes (TILs) were evaluated on H&E slides. Intrinsic subtyping was carried out using the research-based 50-gene prediction analysis of a microarray (PAM50) subtype predictor. Immune-related gene signatures were also evaluated. RESULTS: Continuous Str-TILs and It-TILs were significantly associated with pCR [OR 1.03, 95% CI 1.02-1.05 (P < 0.001) and OR 1.09, 95% CI 1.04-1.15 (P < 0.001) for Str-TILs and It-TILs, respectively]. According to PAM50, the subtype distribution was as follows: HER2-enriched 26.7%, Luminal A 25.6%, Luminal B 16.3%, Basal-like 14% and Normal-like 17.4%. The highest rate of pCR was observed for the HER2-enriched subtype (50%), followed by Basal-like, Luminal B and Luminal A (χ(2) test, P = 0.026). Immune gene signatures significantly associated with pCR in univariate analyses were identified: most of them maintained a significant association with pCR in multivariate analyses corrected for PAM50 subtypes, whereas TILs did not. CONCLUSIONS: In this study, both tumor-related and immune-related features contribute to the modulation of pCR after neoadjuvant chemotherapy plus anti-HER2 agents. Immune signatures rather than TILs added significant prediction of pCR beyond PAM50 intrinsic subtypes.
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Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/inmunología , Receptor ErbB-2/inmunología , Adulto , Anciano , Biopsia con Aguja Gruesa , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Femenino , Humanos , Lapatinib , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Análisis por Micromatrices , Persona de Mediana Edad , Terapia Neoadyuvante , Pronóstico , Quinazolinas/administración & dosificación , Receptor ErbB-2/antagonistas & inhibidores , Receptor ErbB-2/genética , Receptores de Estrógenos/genética , Trastuzumab/administración & dosificaciónRESUMEN
Lapatinib enhances antibody-dependent cell-mediated cytotoxicity (ADCC) activity of trastuzumab. FcγR polymorphisms have been associated with both ADCC and clinical activity of trastuzumab in HER2+ breast cancer (BC) patients (pts). We analyzed FcγRIIa-H131R and FcγRIIIa-V158F polymorphisms in the CHER-LOB trial population of HER2+ BCs treated with preoperative chemotherapy plus trastuzumab (arm A), lapatinib (arm B) or both (arm C). Genotyping was successfully performed in 73/121 (60%) pts. A significant improvement in pathological complete response (pCR) rate was observed for the combination arm C, but only in FcγRIIIa V allele carriers (C vs A, 67 vs 27%, P=0.043; C vs B, 67 vs 22%, P=0.012). An independent interaction between arm C and FcγRIIIa V allele was found for pCR (odds ratio=9.4; 95% confidence interval, 2.3-39.6; P=0.003). No significant associations were observed between pCR and FcγRIIa polymorphism, and between pre-treatment tumor-infiltrating lymphocytes and FcγR polymorphisms. Our study provides evidence for a FcγRIIIa V allele-restricted pCR benefit from neoadjuvant trastuzumab plus lapatinib in HER2+ BC.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor , Neoplasias de la Mama/tratamiento farmacológico , Terapia Neoadyuvante , Variantes Farmacogenómicas , Polimorfismo de Nucleótido Simple , Inhibidores de Proteínas Quinasas/uso terapéutico , Quinazolinas/uso terapéutico , Receptor ErbB-2/análisis , Receptores de IgG/genética , Trastuzumab/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Biomarcadores de Tumor/análisis , Biomarcadores de Tumor/genética , Neoplasias de la Mama/enzimología , Neoplasias de la Mama/genética , Neoplasias de la Mama/inmunología , Quimioterapia Adyuvante , Ensayos Clínicos Fase II como Asunto , Supervivencia sin Enfermedad , Femenino , Frecuencia de los Genes , Genotipo , Humanos , Lapatinib , Mastectomía , Persona de Mediana Edad , Farmacogenética , Pruebas de Farmacogenómica , Fenotipo , Inhibidores de Proteínas Quinasas/efectos adversos , Quinazolinas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Estudios Retrospectivos , Factores de Tiempo , Trastuzumab/efectos adversos , Resultado del TratamientoRESUMEN
BACKGROUND: Obesity is an independent adverse prognostic factor in early breast cancer patients, but it is still controversial whether obesity may affect adjuvant endocrine therapy efficacy. The aim of our study (ancillary to the two clinical trials Gruppo Italiano Mammella (GIM)4 and GIM5) was to investigate whether the circulating oestrogen levels during treatment with the aromatase inhibitor letrozole are related to body mass index (BMI) in postmenopausal women with breast cancer. METHODS: Plasma concentration of oestrone sulphate (ES) was evaluated by radioimmunoassay in 370 patients. Plasma samples were obtained after at least 6 weeks of letrozole therapy (steady-state time). Patients were divided into four groups according to BMI. Differences among the geometric means (by ANOVA and ANCOVA) and correlation (by Spearman's rho) between the ES levels and BMI were assessed. RESULTS: Picomolar geometric mean values (95% confidence interval, n=patients) of circulating ES during letrozole were 58.6 (51.0-67.2, n=150) when BMI was <25.0 kg m(-2); 65.6 (57.8-74.6, n=154) when 25.0-29.9 kg m(-2); 59.3 (47.1-74.6, n=50) when 30.0-34.9 kg m(-2); and 43.3 (23.0-81.7, n=16) when ≥35.0 kg m(-2). No statistically significant difference in terms of ES levels among groups and no correlation with BMI were observed. CONCLUSIONS: Body mass index does not seem to affect circulating oestrogen levels in letrozole-treated patients.
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Antineoplásicos/uso terapéutico , Índice de Masa Corporal , Neoplasias de la Mama/sangre , Neoplasias de la Mama/tratamiento farmacológico , Estrona/análogos & derivados , Nitrilos/uso terapéutico , Triazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/patología , Quimioterapia Adyuvante/métodos , Estrona/sangre , Femenino , Humanos , Letrozol , Persona de Mediana Edad , Posmenopausia/sangreRESUMEN
Antibody-dependent cellular cytotoxicity (ADCC), which is activated by effector cells via immunoglobulin G (IgG) fragment C receptors (FcRs), was proposed as a mechanism of cetuximab efficacy. Peripheral blood mononuclear cells (PBMCs) from 23 healthy donors and 13 patients with metastatic colorectal cancer (mCRC) treated with cetuximab were tested for FcγR polymorphisms and cetuximab-mediated ADCC. ADCC was measured by chromium-51 release on a epidermal growth factor receptor (EGFR)-positive human colon cancer cell line. Overall, 86 mCRC patients were genotyped for study purposes. PBMCs harbouring the FcγRIIIa 158 V/V genotype had a significantly higher cetuximab-mediated ADCC. No correlation was found between FcγR polymorphisms and response rate or time to progression after cetuximab-based therapy. Despite the in vitro analysis showing that the FcγRIIIa 158 V/V genotype is associated with higher ADCC, clinical data do not support a predictive role of FcγRIIIa polymorphisms in mCRC treated with cetuximab.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Citotoxicidad Celular Dependiente de Anticuerpos/genética , Antineoplásicos/uso terapéutico , Neoplasias Colorrectales/tratamiento farmacológico , Polimorfismo Genético , Receptores de IgG/genética , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos Monoclonales Humanizados/administración & dosificación , Antineoplásicos/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Cetuximab , Neoplasias Colorrectales/genética , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Supervivencia sin Enfermedad , Femenino , Genotipo , Humanos , Leucocitos Mononucleares , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Resultado del TratamientoRESUMEN
BACKGROUND: Therapeutic approach for patients with metastatic breast cancer (MBC) is still controversial. This study was conducted to assess the efficacy and safety of bevacizumab in combination with docetaxel plus capecitabine as first-line treatment for MBC. The feasibility of bevacizumab maintenance therapy in this setting was also evaluated. PATIENTS AND METHODS: In this single-arm, multicenter phase II study, patients received bevacizumab 15 mg/kg and docetaxel 60 mg/m(2) on day 1, plus capecitabine 900 mg/m(2) twice daily on days 1-14 every 21 days. Treatment was administered for up to 6 cycles, then bevacizumab continued until progressive disease. The primary end point was progression-free survival (PFS); secondary end points were tumor response rate, overall survival, and toxicity. RESULTS: Seventy-nine eligible patients were treated with bevacizumab in combination with docetaxel plus capecitabine. The overall response rate was 61 %, with a complete response rate of 8 % and a median duration of response of 10 months. At a median follow-up of 28 months, the median PFS was 11 months. Fifty-two (65 %) patients received bevacizumab maintenance therapy for a median duration of 7 months (range 1 to 33+). Neutropenia was the most common grade 3-4 toxicity (28.1 % of patients), and two fatal adverse events occurred (septic shock and gastrointestinal perforation). CONCLUSIONS: Bevacizumab in combination with docetaxel and capecitabine demonstrates significant activity and quite acceptable toxicity profile as first-line treatment of MBC. Subsequent maintenance therapy with bevacizumab is feasible for a long period of stable disease. Results deserve confirmation.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Recurrencia Local de Neoplasia/tratamiento farmacológico , Adulto , Anciano , Anticuerpos Monoclonales Humanizados/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Bevacizumab , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Capecitabina , Desoxicitidina/administración & dosificación , Desoxicitidina/análogos & derivados , Docetaxel , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/análogos & derivados , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Recurrencia Local de Neoplasia/patología , Cooperación del Paciente , Taxoides/administración & dosificaciónRESUMEN
Estrogen synthesis suppression induced by aromatase inhibitors in breast cancer (BC) patients may be affected by single nucleotide polymorphisms (SNPs) of the gene encoding aromatase enzyme, CYP19A1. We assessed the association between plasma estrone sulfate (ES), letrozole treatment, and four SNPs of CYP19A1 gene (rs10046 C>T, rs4646 G>T, rs749292 C>T, rs727479 T>G) which seem to be related to circulating estrogen levels. Patients were enrolled into a prospective, Italian multi-center clinical trial (Gruppo Italiano Mammella, GIM-5) testing the association of CYP19A1 SNPs with the efficacy of letrozole adjuvant therapy, in postmenopausal early BC patients. SNPs were identified from peripheral blood cell DNA. Plasma ES concentrations were evaluated by Radio Immuno Assay. Blood samples were obtained immediately before letrozole therapy (N = 204), at 6-weeks (N = 178), 6 (N = 152) and 12-months (N = 136) during treatment. Medians (IQR) of ES were 160 pg/mL (85-274) at baseline, 35 pg/mL (12-64) at 6-weeks, 29 pg/mL (17-48) at 6 months and 25 pg/mL (8-46) after 12 months treatment. No statistically significant association was evident between polymorphisms and ES circulating levels during letrozole therapy. Letrozole suppression of the aromatase enzyme function is not affected by polymorphisms of CYP19A1 gene in postmenopausal BC patients.
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Antineoplásicos/uso terapéutico , Aromatasa/genética , Neoplasias de la Mama/genética , Estrona/análogos & derivados , Nitrilos/uso terapéutico , Polimorfismo de Nucleótido Simple , Posmenopausia , Triazoles/uso terapéutico , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Inhibidores de la Aromatasa/farmacología , Inhibidores de la Aromatasa/uso terapéutico , Neoplasias de la Mama/sangre , Neoplasias de la Mama/tratamiento farmacológico , Ensayos Clínicos como Asunto , Estrona/sangre , Femenino , Estudios de Asociación Genética , Genotipo , Humanos , Letrozol , Persona de Mediana Edad , Nitrilos/farmacología , Estudios Prospectivos , Triazoles/farmacologíaRESUMEN
BACKGROUND: Preclinical data suggest that treatment with lapatinib reinduces sensitivity to trastuzumab in human epidermal growth factor receptor 2(HER2)-positive breast cancer cells. PATIENTS AND METHODS: Between January 2007 and November 2010, 179 HER2-positive metastatic breast cancer patients were treated with lapatinib and capecitabine at nine Italian institutions. We evaluated the clinical outcome of 69 patients (38.5%) retreated with trastuzumab after lapatinib progression. RESULTS: Visceral metastases were identified in 51 (74%) and brain metastases in 16 patients (23%). All patients were pretreated with both trastuzumab- and lapatinib-based therapy. We observed with retreatment with trastuzumab-based therapy: 1 complete remission (2%), 18 partial remission (29%) and 10 stable disease ≥6 months (14%) and 47% of clinical benefit (CB). Median duration of response was 8.1 months [95% confidence interval (CI) 5.5-10.7]. No unexpected toxic effects occurred. At a median follow-up of 13 months, median progression-free survival was 4.9 months (95% CI 4.2-5.6) and overall survival (OS) 19.4 months (95% CI 14.0-25.0). Median OS was longer for patients experiencing CB (not reached versus 13.4 months for patients without CB, P = 0.002). Brain involvement was associated with lower median OS (17.3 versus 23.3 months for patients without brain disease; P = 0.021). CONCLUSION: Retreatment with trastuzumab-based therapy showed CB in 47% of patients progressing during lapatinib-based therapy, leading to a prolonged OS.
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Anticuerpos Monoclonales Humanizados/uso terapéutico , Antineoplásicos/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Quinazolinas/farmacología , Receptor ErbB-2/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Progresión de la Enfermedad , Supervivencia sin Enfermedad , Resistencia a Antineoplásicos , Femenino , Humanos , Estimación de Kaplan-Meier , Lapatinib , Persona de Mediana Edad , Análisis Multivariante , Metástasis de la Neoplasia , Modelos de Riesgos Proporcionales , Quinazolinas/uso terapéutico , Estudios Retrospectivos , Trastuzumab , Insuficiencia del TratamientoAsunto(s)
Antineoplásicos/economía , Carcinoma de Pulmón de Células no Pequeñas/tratamiento farmacológico , Neoplasias Pulmonares/tratamiento farmacológico , Antineoplásicos/uso terapéutico , Carcinoma de Pulmón de Células no Pequeñas/economía , Carcinoma de Pulmón de Células no Pequeñas/mortalidad , Análisis Costo-Beneficio , Economía Farmacéutica , Humanos , Neoplasias Pulmonares/economía , Neoplasias Pulmonares/mortalidad , Oncología Médica , Análisis de SupervivenciaRESUMEN
BACKGROUND: The role of anthracyclines has been extensively studied in adjuvant chemotherapy, but much less in the primary chemotherapy of early breast carcinoma. This study, comparing CMF (cyclophosphamide, methotrexate, 5-fluorouracil) with the rotational anthracycline-containing regimen CMFEV (CMF plus epirubicin and vincristine) administered as primary chemotherapy, demonstrated a significant increase in clinical complete response in premenopausal women. We report the long-term results. PATIENTS AND METHODS: Two hundred and eleven patients with stage I or II palpable breast carcinoma and a tumour diameter of >2.5 cm were randomised to receive CMF or CMFEV for four cycles before surgery. After surgery, the patients in both arms received adjuvant CMF for three cycles. RESULTS: In the study population as a whole, there was a non-significant 20% reduction in mortality and relapse rates in the CMFEV arm. However, the effect of the experimental regimen was only found in premenopausal patients, especially in terms of relapse-free survival (P=0.07) and locoregional relapse-free survival (P=0.0009), thus mirroring the effect on response rates. After 10 years, the proportions of premenopausal patients free from locoregional relapse as a first event in the CMF and CMFEV groups were 68% and 97%, respectively. No relevant differences were found in postmenopausal patients. CONCLUSION: The overall results of this study showed that the greater activity of the experimental anthracycline-containing combination over CMF as primary chemotherapy in premenopausal patients translated into long-term effects in the same subgroup.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Epirrubicina/administración & dosificación , Vincristina/administración & dosificación , Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Ciclofosfamida/administración & dosificación , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Humanos , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Resultado del TratamientoRESUMEN
In this study, we retrospectively evaluated the expression of vascular endothelial growth factor (VEGF) and microvessel density (MVD) in 228 and 213 specimens, respectively, from stages I and II breast cancer patients (pts) enrolled in a randomized phase III adjuvant chemotherapy trial comparing epirubicin to CMF, while tamoxifen was given to all postmenopausal pts. The expression of VEGF and MVD was assessed on tissue sections formalin-fixed and paraffin-embedded by immunohistochemical staining using anti-VEGF antibody of human origin and anti-CD34 monoclonal antibody. Univariate and multivariate analysis were performed using chi squared test, log-rank test and Cox's regression model. Sixty four of 228 pts were classified as VEGF positive (28%) with no significant difference in the two treatment arms. In 213 pts evaluated for CD34, 103 pts (48%) were classified as MVD high. No significant association between VEGF and MVD was found, and neither were they correlated with many known prognostic factors such as age, tumor size, nodal status, and histological grade. The only significant correlations observed were between VEGF and estrogen receptor (ER) status (p = 0.013) and between MVD and HER2 overexpression (p = 0.023). At a median follow up of 96 months VEGF and MVD were not correlated with relapse-free survival (RFS) and overall survival (OS) in all pts and in pts assigned to one of the two treatment arms. In conclusion, VEGF and MVD retrospectively evaluated, cannot be considered prognostic factors in node negative (N-) high risk and node positive (N+) breast cancer pts treated with two different regimens of adjuvant chemotherapy.
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Neoplasias de la Mama/irrigación sanguínea , Neoplasias de la Mama/metabolismo , Carcinoma Ductal de Mama/irrigación sanguínea , Carcinoma Ductal de Mama/metabolismo , Neovascularización Patológica/metabolismo , Factor A de Crecimiento Endotelial Vascular/metabolismo , Adulto , Distribución de Chi-Cuadrado , Femenino , Humanos , Inmunohistoquímica , Persona de Mediana Edad , Estadificación de Neoplasias , Valor Predictivo de las Pruebas , Pronóstico , Modelos de Riesgos Proporcionales , Análisis de SupervivenciaRESUMEN
BACKGROUND: 5-Fluorouracil (5-FU), doxorubicin and methotrexate (FAMTX) and cisplatin, epirubicin, leucovorin and 5-FU (PELF) have both been reported to be superior to the combination 5-FU, doxorubicin and mitomycin C (FAM) in advanced gastric carcinoma. On the basis of the presence and dose intensity of the included agents, we hypothesised that PELF would be superior to FAMTX. PATIENTS AND METHODS: Two hundred patients with untreated advanced gastric carcinoma were randomised to receive PELF or FAMTX for a maximum of six cycles or until disease progression. RESULTS: The complete response (CR) rates to PELF and FAMTX were, respectively, 13% [95% confidence intervals (CI) 6% to 20%] and 2% (95% CI 0% to 5%; P = 0.003), and the objective response rates [CR plus partial response (PR) rates] 39% (95% CI 29% to 49%) and 22% (95% CI 13% to 30%; P = 0.009), thus significantly favouring the PELF combination. The survival rates after 12 months (30.8% versus 22.4%) and 24 months (15.7% versus 9.5%) were also higher among patients receiving PELF, but these differences were not statistically significant. The toxicities were qualitatively different but quantitatively similar. Both regimens seem to be feasible provided that careful patient monitoring is assured. CONCLUSIONS: PELF is significantly more active than FAMTX and deserves further research in the adjuvant setting.