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1.
J Immunother Cancer ; 11(11)2023 11 28.
Artículo en Inglés | MEDLINE | ID: mdl-38016718

RESUMEN

BACKGROUND: It is possible to induce immunomodulation in HER2-positive breast cancer (BC) by modifying the route of administration of trastuzumab. METHODS: In this multicenter randomized phase II trial, all enrolled patients (pts) with T2-T4d HER2-positive BC received 3 cycles of neoadjuvant treatment (NAT) with fluorouracil, epirubicin and cyclophosphamide every 3 weeks (q21), followed by docetaxel/pertuzumab plus intravenous trastuzumab (arm A) or, docetaxel/pertuzumab plus subcutaneous (SC) trastuzumab (arm B) q21x4 cycles. After surgical operation, each pt was treated with trastuzumab q21x14 cycles using the same SC or intravenous formulation of NAT. Primary endpoint was the proportion of subjects with high stromal tumor-infiltrating lymphocytes (sTILs) in postneoadjuvant residual disease (RD). RESULTS: Sixty-three pts (31 (arm A) and 32 (arm B)) were enrolled. Pathological complete response was obtained by 20/31 pts (64.5%; 95% CI 45.4% to 80.1%) in arm A and 19/32 pts (59.4%; 95% CI 40.1% to 76.3%) in arm B. High sTILs were observed in 27% and 46% of postneoadjuvant residual tumors in arms A and B, respectively. CD8+ T cells increased significantly in RDs of both arms (p=0.014 and 0.002 for arm A and B, respectively), whereas a significant decline in the level of CD4+ FoxP3+ regulatory T cells was observed only in arm B (p=0.016). A significant upregulation of PD-1 on sTILs was found in RD of pts enrolled in arm B (p=0.012), while programmed death-ligand 1 (PD-L1) was significantly overexpressed in residual tumors of arm A (p=0.02). A strong negative correlation was reported in arm B between expression of PD-L1 on pretreatment sTILs and CD3 expression on sTILs in RD (τ: -0.73). Grade≥3 AE incidence rates were similar between the two arms. CONCLUSIONS: SC trastuzumab induced relevant sTILs enrichment, with favorable variations of immune parameters in HER2-positive BC pts with RD after NAT. Novel immunotherapy strategies should be tested to achieve SC-specific, antitumor immune response. TRIAL REGISTRATION NUMBER: NCT03144947, and EudraCT number: 2016-000435-41.


Asunto(s)
Neoplasias de la Mama , Humanos , Femenino , Trastuzumab/farmacología , Trastuzumab/uso terapéutico , Neoplasias de la Mama/patología , Antígeno B7-H1/uso terapéutico , Docetaxel/farmacología , Docetaxel/uso terapéutico , Terapia Neoadyuvante , Neoplasia Residual , Receptor ErbB-2/metabolismo , Resultado del Tratamiento , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico
2.
Cancers (Basel) ; 15(19)2023 Oct 04.
Artículo en Inglés | MEDLINE | ID: mdl-37835546

RESUMEN

To evaluate the rate of early breast cancer (EBC) patients treated with neoadjuvant systemic therapy (NAT) in Italy, criteria of patient selection and types of therapies delivered, an analysis of 1276 patients with stage I-II-III was conducted out of 1633 patients enrolled in the multicenter prospective observational BRIDE study. A total of 177 patients (13.9%) were treated with NAT and 1099 (85.9%) with surgery; in multivariate analysis, menopausal status, cT, cN, grade, HER2-positive and Triple negative (TN) subgroups were significantly associated with the decision to administer NAT. The type of NAT delivered was influenced by EBC subtype. NAT was administered to 53.2% of HER2+/HR-negative, 27.9% of HER2+/HR+, 7.1% of HER2-negative/HR+ and 30.3% of TN EBC patients. The pCR rates were similar to the ones reported in the literature: 74.2% in HER2+/HR-negative, 52.3% in HER2+/HR+, 17.2% in HER2-negative/HR+ and 37.9% in TN. In clinical practice, patient and tumor characteristics influenced oncologists in the decision to administer NAT in EBC and in the choice of the type of systemic therapy, according to ESMO and AIOM Guidelines. Currently, it is recommended always to evaluate the use of NAT in EBC, mainly in HER2+ and TN patients, considering that pCR is associated with significantly better survival of the patient and that effective therapies are now available for residual disease.

3.
Clin Cancer Res ; 29(23): 4908-4919, 2023 12 01.
Artículo en Inglés | MEDLINE | ID: mdl-37733800

RESUMEN

PURPOSE: To explore whether specific triple-negative breast cancer (TNBC) molecular subtypes are predictive for a benefit from maintenance low-dose cyclophosphamide and methotrexate (CM) in the adjuvant IBCSG 22-00 phase III clinical trial. EXPERIMENTAL DESIGN: RNA sequencing was performed on a selection of 347 TNBC formalin-fixed paraffin-embedded (FFPE) tumor samples following a case-cohort-like sampling. TNBC subtypes were computed on gene expression data. The association between TNBC subtypes and treatment outcome was assessed using a Cox proportional-hazards interaction test. RESULTS: Immunomodulatory (IM) and basal-like/immune activated (BLIA) molecular subtypes showed a significant survival benefit when treated with low-dose CM [disease-free survival (DFS): HR, 0.5; 95% confidence interval (CI), 0.28-0.89; Pinteraction = 0.018 and HR, 0.49; 95% CI, 0.27-0.9; Pinteraction = 0.021]. Moreover, a high expression of regulatory T-cell immune signature was associated with a better prognosis in the CM arm, in line with a potential immunomodulating role of cyclophosphamide. In contrast, a worse outcome was observed in tumors with a mesenchymal (M) subtype treated with low-dose CM (DFS: HR, 1.9; 95% CI, 1.2-3; Pinteraction = 0.0044). CONCLUSIONS: Our results show a differential benefit of low-dose CM therapy across different TNBC subtypes. Low-dose CM therapy could be considered as a potential strategy for TNBC tumors with IM subtype in the early-disease setting.


Asunto(s)
Neoplasias de la Mama Triple Negativas , Humanos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Resultado del Tratamiento , Supervivencia sin Enfermedad , Pronóstico , Quimioterapia Adyuvante/métodos , Ciclofosfamida
4.
JAMA Oncol ; 9(9): 1267-1272, 2023 09 01.
Artículo en Inglés | MEDLINE | ID: mdl-37440239

RESUMEN

Importance: In spite of the effectiveness of endocrine therapy plus cyclin-dependent kinase (CDK) 4/6 inhibitors as the first-line treatment for estrogen receptor (ER)-positive, erb-b2 receptor tyrosine kinase 2 (ERBB2 [formerly HER2/neu])-negative (ER+/ERBB2-) metastatic breast cancer (MBC), patients eventually develop resistance, and eventually most will receive chemotherapy. The METEORA-II trial compared a metronomic all-oral treatment with intravenous (IV) chemotherapy. Objective: To compare the efficacy of the oral vinorelbine plus cyclophosphamide plus capecitabine (VEX) regimen vs weekly IV paclitaxel among patients with ER+/ERBB2- MBC who are candidates for chemotherapy. Design, Setting, and Participants: This phase 2 randomized clinical trial including 140 women 18 years and older (randomized 1:1) with ER+/ERBB2- MBC was carried out from September 13, 2017, to January 14, 2021 at 15 centers in Italy. Eligible patients could have received 1 prior line of chemotherapy for MBC and/or 2 lines of endocrine therapy (including CDK4/6 inhibitors). Interventions: In 4-week cycles, patients received either metronomic oral VEX or weekly IV paclitaxel. Main Outcomes and Measures: The primary end point was investigator-assessed time to treatment failure (TTF) defined as the interval between the date of randomization to the end of treatment (because of disease progression or lack of tolerability or because further trial treatment was declined). Secondary end points included progression-free survival (PFS), overall survival (OS), and disease control rate (complete or partial response or stable disease lasting for at least 24 weeks). Results: In total, 133 patients received either VEX (n = 70) or paclitaxel (n = 63) in 4-weekly cycles. The median age was 61 (range, 30-80) years. The VEX treatment significantly prolonged TTF vs paclitaxel (hazard ratio [HR], 0.61; 95% CI, 0.42-0.88; P = .008), median TTF was 8.3 (95% CI, 5.6-11.1) months for VEX vs 5.7 (95% CI, 4.1-6.1) months for paclitaxel, and the 12-month TTF was 34.3% for VEX vs 8.6% for paclitaxel. The median PFS was 11.1 (95% CI, 8.3-13.8) months vs 6.9 (95% CI, 5.4-10.1) months favoring VEX (HR, 0.67; 95% CI, 0.46-0.96, P = .03). The 12-month PFS was 43.5% for VEX vs 21.9% for paclitaxel. No difference in OS was found. The TF event for 55.6% of patients was progression of disease; for 23% it was AEs. More patients assigned to VEX had at least 1 grade 3 or 4 targeted adverse event (VEX, 42.9%; 95% CI, 31.1%-55.3% vs paclitaxel, 28.6%; 95% CI, 17.9%-41.3%), but essentially no alopecia. Conclusion and Relevance: This randomized clinical trial found significantly prolonged TTF and PFS for oral VEX but no improvement in OS compared with intravenous paclitaxel, despite increased but still manageable toxic effects. The VEX regimen may provide more prolonged disease control than weekly paclitaxel for ER+/ERBB2- MBC. Trial Registration: ClinicalTrials.gov Identifier: NCT02954055.


Asunto(s)
Neoplasias de la Mama , Femenino , Humanos , Persona de Mediana Edad , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/patología , Capecitabina , Ciclofosfamida , Paclitaxel , Receptor ErbB-2 , Receptores de Estrógenos , Vinorelbina/efectos adversos , Adulto , Anciano , Anciano de 80 o más Años
5.
Front Oncol ; 13: 1152123, 2023.
Artículo en Inglés | MEDLINE | ID: mdl-37260975

RESUMEN

Background: In triple negative breast cancer patients treated with neoadjuvant chemotherapy, residual disease at surgery is the most relevant unfavorable prognostic factor. Current guidelines consider the use of adjuvant capecitabine, based on the results of the randomized CREATE-X study, carried out in Asian patients and including a small subset of triple negative tumors. Thus far, evidence on Caucasian patients is limited, and no real-world data are available. Methods: We carried out a multicenter, observational study, involving 44 oncologic centres. Triple negative breast cancer patients with residual disease, treated with adjuvant capecitabine from January 2017 through June 2021, were recruited. We primarily focused on treatment tolerability, with toxicity being reported as potential cause of treatment discontinuation. Secondarily, we assessed effectiveness in the overall study population and in a subset having a minimum follow-up of 2 years. Results: Overall, 270 patients were retrospectively identified. The 50.4% of the patients had residual node positive disease, 7.8% and 81.9% had large or G3 residual tumor, respectively, and 80.4% a Ki-67 >20%. Toxicity-related treatment discontinuation was observed only in 10.4% of the patients. In the whole population, at a median follow-up of 15 months, 2-year disease-free survival was 62%, 2 and 3-year overall survival 84.0% and 76.2%, respectively. In 129 patients with a median follow-up of 25 months, 2-year disease-free survival was 43.4%, 2 and 3-year overall survival 78.0% and 70.8%, respectively. Six or more cycles of capecitabine were associated with more favourable outcomes compared with less than six cycles. Conclusion: The CaRe study shows an unexpectedly good tolerance of adjuvant capecitabine in a real-world setting, although effectiveness appears to be lower than that observed in the CREATE-X study. Methodological differences between the two studies impose significant limits to comparability concerning effectiveness, and strongly invite further research.

6.
J Cancer Surviv ; 17(6): 1847-1858, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-35689003

RESUMEN

PURPOSE: Despite extensive research on cancer and work-related outcomes, evidence from longitudinal cohort studies is limited, especially in young women with breast cancer (BC). We aimed to investigate employment trajectories in young BC survivors and to identify potential factors associated with changes in work activity. METHODS: The HOHO European prospective multicenter cohort study enrolled 300 young women (≤ 40 years) with newly diagnosed BC. Women completed surveys at baseline and every 6 months for 3 years, then yearly for up to 10 years to assess, among other variables, employment status, sociodemographic, medical, and treatment data. Symptoms were assessed by the Breast Cancer Prevention Trial symptom scales and single items from the Cancer Rehabilitation Evaluation System. Univariable and multivariable multinomial logistic regression analyses identified factors associated with changes in employment status. RESULTS: Among the 245 women included in this analysis, 85% were employed at the last individual post-baseline assessment (1 to 10 years). At 5 years, women had a 29.4% probability (95% CI: 23.6-35.5) of experiencing any reduction and a 14.9% probability (95% CI: 10.6-19.9) of experiencing any increase in work activities. Being enrolled in Switzerland (vs. Italy) and reporting more trouble in performing daily activities were significantly associated with work reduction. CONCLUSION: Our results suggest that most young BC survivors remain employed in the long-term. IMPLICATIONS FOR CANCER SURVIVORS: Regular evaluation of symptoms which may interfere with daily life and identification of financial discomfort is critical in providing timely and individually tailored interventions and in limiting unwanted reductions in work activities.


Asunto(s)
Neoplasias de la Mama , Supervivientes de Cáncer , Femenino , Humanos , Estudios Longitudinales , Neoplasias de la Mama/terapia , Estudios de Cohortes , Estudios Prospectivos , Suiza/epidemiología , Empleo , Italia
7.
Cancer Discov ; 12(12): 2754-2762, 2022 12 02.
Artículo en Inglés | MEDLINE | ID: mdl-36255231

RESUMEN

DESTINY-Breast01 (NCT03248492) evaluated trastuzumab deruxtecan (T-DXd; DS-8201) in patients with heavily pretreated HER2-positive metastatic breast cancer (mBC). We present a subgroup of 24 patients with a history of treated brain metastases (BM), a population with limited treatment options. In patients with BMs, the confirmed objective response rate (cORR) was 58.3% [95% confidence interval (CI), 36.6%-77.9%], and the median progression-free survival (mPFS) was 18.1 months (95% CI, 6.7-18.1 months). In patients without BMs (n = 160), cORR was 61.3% and mPFS was 16.4 months. Eight patients (47.1%) experienced a best overall intracranial response of partial response or complete response. Seven patients (41.2%) had a best percentage change in brain lesion diameter from baseline consistent with stable disease. Two patients (8.3%) with BMs and two (1.3%) without BMs experienced progression in the brain. The safety profile of T-DXd was consistent with previous studies. The durable clinical activity of T-DXd in this population warrants further investigation. SIGNIFICANCE: Advances in treating HER2-positive metastatic breast cancer have greatly improved patient outcomes, but intracranial progression remains an important risk for which few therapeutic options are currently available. T-DXd demonstrated durable efficacy in patients with stable, treated BMs. This article is highlighted in the In This Issue feature, p. 2711.


Asunto(s)
Neoplasias Encefálicas , Neoplasias de la Mama , Inmunoconjugados , Humanos , Femenino , Neoplasias de la Mama/patología , Receptor ErbB-2 , Trastuzumab/uso terapéutico , Inmunoconjugados/uso terapéutico , Camptotecina/uso terapéutico , Neoplasias Encefálicas/tratamiento farmacológico , Neoplasias Encefálicas/secundario
8.
Eur J Cancer ; 153: 133-141, 2021 08.
Artículo en Inglés | MEDLINE | ID: mdl-34153715

RESUMEN

AIM: The Cher-LOB randomised phase II study showed that the combination of lapatinib-trastuzumab plus chemotherapy increases pathologic complete response (pCR) rate compared with chemotherapy plus either trastuzumab or lapatinib. Here, we report the post hoc survival analysis as per treatment arm, pCR and biomarkers. METHODS: The Cher-LOB study randomised 121 patients with human epidermal growth factor receptor 2-positive, stage II-IIIA breast cancer. A specific protocol to collect recurrence-free survival (RFS) and overall survival (OS) data was designed. Tumour-infiltrating lymphocytes (TILs) and PAM50-intrinsic subtyping were evaluated at baseline. RESULTS: At 9-year median follow-up, a trend towards RFS improvement with lapatinib-trastuzumab over trastuzumab was observed (hazard ratio [HR] 0.44, 95% confidence interval [CI] 0.18-1.05). Combining treatment arms, pCR was significantly associated with both RFS (HR 0.12, 95% CI 0.03-0.49) and OS (HR 0.12, 95% CI 0.03-0.49). TILs were significantly associated with RFS (HR = 0.978 for each 1% increment). Luminal-A subtype was a significant and independent predictor of improved RFS as compared with other PAM50-based intrinsic subtypes at the multivariate analysis including the most relevant clinicopathologic variables (HR 0.29, 95% CI 0.09-0.94, p = 0.040). CONCLUSIONS: Cher-LOB trial survival analysis confirmed the prognostic role of pCR and TILs and showed a signal for a better outcome with lapatinib-trastuzumab over trastuzumab. TRIAL REGISTRATION: NCT00429299.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/tratamiento farmacológico , Lapatinib/uso terapéutico , Terapia Neoadyuvante/métodos , Trastuzumab/uso terapéutico , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología , Neoplasias de la Mama/mortalidad , Femenino , Humanos , Lapatinib/farmacología , Persona de Mediana Edad , Análisis de Supervivencia , Trastuzumab/farmacología
9.
Ther Adv Med Oncol ; 13: 1758835920985632, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-33613693

RESUMEN

BACKGROUND: The aim of this study was to improve activity over single human epidermal growth factor receptor 2 (HER2)-blockade sequential neaodjuvant regimens for HER2-positive breast cancer, by exploiting the concomitant administration of trastuzumab, taxane and anthracycline, while restraining cardiac toxicity with use of liposomal doxorubicin, and by adding metformin, based on preliminary evidence of antitumor activity. PATIENTS AND METHODS: This multi-center, single-arm, two-stage phase II trial, assessed the safety and the activity of a new treatment regimen for HER2-positive, early or locally advanced breast cancer. Patients received six 21-day cycles of non-pegylated liposomal doxorubicin, 50 mg/m2 intravenously (i.v.) on day 1, docetaxel, 30 mg/m2 i.v. on days 2 and 9, trastuzumab, 2 mg/kg/week i.v. on days 2, 9, and 16 (with 4 mg/kg loading dose), in association with metformin 1000 mg orally twice daily. The primary endpoint was the rate of pathological complete response (pCR) in the breast and axilla (ypT0/is ypN0). A subgroup of patients performed a 3-deoxy-3-18F-fluorothymidine positron emission tomography (FLT-PET) at baseline and after one cycle. RESULTS: Among 47 evaluable patients, there were 18 pCR [38.3%, 95% confidence interval (CI) 24.5-53.6%]. A negative estrogen-receptor status, high Ki67, and histological grade 3 were related with pCR, although only grade reached statistical significance. FLT-PET maximum standardized uptake value after one cycle was inversely related to pCR in the breast (odds ratio 0.29, 95% CI 0.06-1.30, p = 0.11). Toxicity included grade 3-4 neutropenia in 70% and febrile neutropenia in 4% of patients, grade 1-2 nausea/vomiting in 60%/38%, and grade 3 in 4%/2%, respectively, grade 1-2 diarrhea in 72%, and grade 3 in 6%. There were two cases of reversible grade 2 left-ventricular ejection-fraction decrease, and one case of sharp troponin-T increase. CONCLUSIONS: The concomitant administration of trastuzumab, liposomal doxorubicin, docetaxel, and metformin is safe and shows good activity, but does not appear to improve activity over conventional sequential regimens.

10.
Breast Care (Basel) ; 15(1): 30-37, 2020 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-32231495

RESUMEN

BACKGROUND: Different studies suggest that fulvestrant 500 mg every 28 days (HD-FUL) could be an active treatment in HR+ advanced breast cancer (ABC) patients even treated with aromatase inhibitors in the adjuvant setting. The aim of this analysis is to describe the outcome of ABC patients treated with HD-FUL as first-line treatment in terms of median duration of treatment and the overall response rate in a real-world setting. METHODS: For the purpose of the present analysis, we considered two data sets of HR+ ABC patients collected in Italy between 2012 and 2015 (EVA and GIM-13 AMBRA studies). RESULTS: Eighty-one and 91 patients have been identified from the two data sets. The median age was 63 years (range 35-82) for the EVA and 57.8 years (range 35.0-82.3) for the AMBRA patients. ORRs were 23.5 and 24.3% in the whole population, 26.9% in the patients with bone only, and 21.8 and 21.4% in those with visceral metastases. The median duration of HD-FUL was 11.6 months (range 1-48) and 12.4 months (range 2.9-70.0) in the two data sets, respectively. CONCLUSION: These data suggest that HD-FUL should still continue to play a significant role as first-line therapy in HR+ ABC patients.

11.
Ther Adv Med Oncol ; 12: 1758835919888999, 2020.
Artículo en Inglés | MEDLINE | ID: mdl-32158505

RESUMEN

BACKGROUND: In the Italian Breast Cancer Intergroup Studies (IBIS) 3 phase III trial, we compared cyclophosphamide, methotrexate, 5-fluorouracil (CMF) alone to sequential epirubicin/CMF regimens in patients with rapidly proliferating early breast cancer (RPEBC). We performed a post hoc analysis in the subgroup of patients with hormone-receptor-positive RPEBC on the prognostic role of progesterone receptor (PgR) status. METHODS: RPEBC was defined by thymidine labeling index (TLI) >3% or grade 3 or S-phase >10% or Ki67 >20%. We analyzed 466 patients with hormone-receptor-positive RPEBC receiving sequential epirubicin/CMF regimens followed by tamoxifen, and for whom the status of ER and PgR was available. RESULTS: Considering both cut-off values of 10% and 20%, PgR expression was significantly associated with age, menopausal status, and ER expression; HER2 status was associated with PgR status only at a cutoff value of 20% PgR. Upon univariate analysis, tumor size, nodal status, and PgR were significantly associated with disease-free survival (DFS) and overall survival (OS), while age class and local treatment type were associated only with DFS. Patients with PgR <20% showed lower 5- and 10-year DFS [hazard ratio (HR) = 1.48; 95%CI: 1.01-2.18; p = 0.044] and OS (HR = 1.85; 95%CI: 1.08-3.19, p = 0.025) rates compared with patients with PgR ⩾20%. Upon multivariate analysis, only tumor size, nodal status, and PgR were independent prognostic factors. CONCLUSIONS: Our results highlight the independent prognostic relevance of PgR expression in patients with hormone-receptor-positive RPEBC treated with adjuvant chemotherapy and endocrine therapy, where the definition of prognostic subgroups is still a major need.

12.
Breast Cancer Res Treat ; 181(1): 61-68, 2020 May.
Artículo en Inglés | MEDLINE | ID: mdl-32200486

RESUMEN

PURPOSE: To evaluate the prognostic value of IGF-1R expression on circulating tumor cells (CTCs) in a prospective randomized clinical trial comparing chemotherapy plus metformin with chemotherapy alone in metastatic breast cancer (MBC) patients. METHODS: CTCs were collected at baseline and at the end of chemotherapy. An automated sample preparation and analysis system (CellSearch) were customized for detecting IGF-1R expression. The prognostic role of CTC count and IGF-1R was assessed for PFS and OS by univariate and multivariate analyses. RESULTS: Seventy-two out of 126 randomized patients were evaluated: 57% had ≥ 1 IGF-1R positive CTC and 37.5% ≥ 4 IGF-1R negative cells; 42% had CTC count ≥ 5/7.5 ml. At univariate analysis, the number of IGF-1R negative CTCs was strongly associated with risk of progression and death: HR 1.93 (P = 0.013) and 3.65 (P = 0.001), respectively; no association was detected between number of IGF-1R positive CTCs and PFS or OS (P = 0.322 and P = 0.840). The prognostic role of CTC count was confirmed: HR 1.69, P = 0.042 for PFS and HR 2.80 for OS, P = 0.002. By multivariate analysis, the prognostic role of the number of IGF-1R negative CTCs was maintained, while no residual prognostic role of CTC count or number of IGF-1R positive cells was found. CONCLUSION: Loss of IGF-1R in CTCs is associated with a significantly worse outcome in MBC patients. This finding supports further evaluation for the role of IGF-1R on CTCs to improve patient stratification and to implement new targeted strategies. CLINICAL TRIAL REGISTRATION: Clinicaltrials.gov (NCT01885013); European Clinical Trials Database (EudraCT No.2009-014,662-26).


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/sangre , Neoplasias de la Mama/tratamiento farmacológico , Células Neoplásicas Circulantes/metabolismo , Receptor IGF Tipo 1/metabolismo , Anciano , Biomarcadores de Tumor/metabolismo , Neoplasias de la Mama/patología , Ensayos Clínicos Fase II como Asunto , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Metástasis de la Neoplasia , Células Neoplásicas Circulantes/patología , Pronóstico , Estudios Prospectivos , Ensayos Clínicos Controlados Aleatorios como Asunto , Tasa de Supervivencia , Resultado del Tratamiento
13.
J Clin Oncol ; 37(2): 105-114, 2019 01 10.
Artículo en Inglés | MEDLINE | ID: mdl-30475668

RESUMEN

PURPOSE: Luminal breast cancer has a long natural history, with recurrences continuing beyond 10 years after diagnosis. We analyzed long-term follow-up (LTFU) of efficacy outcomes and adverse events in the Breast International Group (BIG) 1-98 study reported after a median follow-up of 12.6 years. PATIENTS AND METHODS: BIG 1-98 is a four-arm, phase III, double-blind, randomized trial comparing adjuvant letrozole versus tamoxifen (either treatment received for 5 years) and their sequences (2 years of one treatment plus 3 years of the other) for postmenopausal women with endocrine-responsive early breast cancer. When pharmaceutical company sponsorship ended at 8.4 years of median follow-up, academic partners initiated an observational, LTFU extension collecting annual data on survival, disease status, and adverse events. Information from Denmark was from the Danish Breast Cancer Cooperative Group Registry. Intention-to-treat analyses are reported. RESULTS: Of 8,010 enrolled patients, 4,433 were alive and not withdrawn at an LTFU participating center, and 3,833 (86%) had at least one LTFU report. For the monotherapy comparison of letrozole versus tamoxifen, we found a 9% relative reduction in the hazard of a disease-free survival event with letrozole (hazard ratio [HR], 0.91; 95% CI, 0.81 to 1.01). HRs for other efficacy end points were similar to those for disease-free survival. Efficacy of letrozole versus tamoxifen for contralateral breast cancer varied significantly over time (0- to 5-, 5- to 10-, and > 10-year HRs, 0.62, 0.47, and 1.35, respectively; treatment-by-time interaction P = .005), perhaps reflecting a longer carryover effect of tamoxifen. Reporting of specific long-term adverse events seemed more effective with national registry than with case-record reporting of clinical follow-up. CONCLUSION: Efficacy end points continued to show trends favoring letrozole. Letrozole reduced contralateral breast cancer frequency in the first 10 years, but this reversed beyond 10 years. This study illustrates the value of extended follow-up in trials of luminal breast cancer.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Letrozol/uso terapéutico , Tamoxifeno/uso terapéutico , Anciano , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/metabolismo , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Método Doble Ciego , Esquema de Medicación , Femenino , Humanos , Letrozol/administración & dosificación , Letrozol/efectos adversos , Persona de Mediana Edad , Posmenopausia , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Tamoxifeno/administración & dosificación , Tamoxifeno/efectos adversos
14.
J Clin Oncol ; 37(5): 386-395, 2019 02 10.
Artículo en Inglés | MEDLINE | ID: mdl-30589600

RESUMEN

PURPOSE: To evaluate endocrine activity in terms of ovarian function suppression (OFS) of degarelix (a gonadotropin-releasing hormone [GnRH] antagonist) versus triptorelin (a GnRH agonist) in premenopausal patients receiving letrozole as neoadjuvant endocrine therapy for breast cancer. PATIENTS AND METHODS: Premenopausal women with stage cT2 to 4b, any N, M0; estrogen receptor and progesterone receptor greater than 50%; human epidermal growth factor receptor 2-negative breast cancer were randomly assigned to triptorelin 3.75 mg administered intramuscularly on day 1 of every cycle or degarelix 240 mg administered subcutaneously (SC) on day 1 of cycle 1 then 80 mg SC on day 1 of cycles 2 through 6, both with letrozole 2.5 mg/day for six 28-day cycles. Surgery was performed 2 to 3 weeks after the last injection. Serum was collected at baseline, after 24 and 72 hours, at 7 and 14 days, and then before injections on cycles 2 through 6. The primary end point was time to optimal OFS (time from the first injection to first assessment of centrally assessed estradiol level ≤ 2.72 pg/mL [≤ 10 pmol/L] during neoadjuvant therapy). The trial had 90% power to detect a difference using a log-rank test with a two-sided α of .05. Secondary end points included response, tolerability, and patient-reported endocrine symptoms. RESULTS: Between February 2014 and January 2017, 51 patients were enrolled (n = 26 received triptorelin plus letrozole; n = 25 received degarelix plus letrozole). Time to optimal OFS was three times faster for patients assigned to degarelix and letrozole than to triptorelin and letrozole (median, 3 v 14 days; hazard ratio, 3.05; 95% CI, 1.65 to 5.65; P < .001). Furthermore, OFS was maintained during subsequent cycles for all patients assigned to receive degarelix and letrozole, whereas 15.4% of patients assigned to receive triptorelin and letrozole had suboptimal OFS after cycle 1 (six events during 127 measurements). Adverse events as a result of both degarelix plus letrozole and triptorelin plus letrozole were as expected. CONCLUSION: In premenopausal women receiving letrozole for neoadjuvant endocrine therapy, OFS was achieved more quickly and maintained more effectively with degarelix than with triptorelin.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Antineoplásicos Hormonales/administración & dosificación , Antineoplásicos Hormonales/efectos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Neoplasias de la Mama/sangre , Neoplasias de la Mama/patología , Neoplasias de la Mama/cirugía , Quimioterapia Adyuvante , Estradiol/sangre , Femenino , Hormona Liberadora de Gonadotropina/agonistas , Hormona Liberadora de Gonadotropina/antagonistas & inhibidores , Humanos , Letrozol/administración & dosificación , Letrozol/efectos adversos , Persona de Mediana Edad , Terapia Neoadyuvante , Estadificación de Neoplasias , Neoplasias Hormono-Dependientes/sangre , Neoplasias Hormono-Dependientes/tratamiento farmacológico , Neoplasias Hormono-Dependientes/patología , Neoplasias Hormono-Dependientes/cirugía , Oligopéptidos/administración & dosificación , Oligopéptidos/efectos adversos , Ovario/efectos de los fármacos , Ovario/fisiopatología , Premenopausia , Receptores de Estrógenos/metabolismo , Receptores de Progesterona/metabolismo , Pamoato de Triptorelina/administración & dosificación , Pamoato de Triptorelina/efectos adversos
15.
Oncologist ; 24(6): 743-e205, 2019 06.
Artículo en Inglés | MEDLINE | ID: mdl-30591548

RESUMEN

LESSONS LEARNED: The androgen receptor (AR) is present in most breast cancers (BC), but its exploitation as a therapeutic target has been limited.This study explored the activity of dehydroepiandrosterone (DHEA), a precursor being transformed into androgens within BC cells, in combination with an aromatase inhibitor (to block DHEA conversion into estrogens), in a two-stage phase II study in patients with AR-positive/estrogen receptor-positive/human epidermal growth receptor 2-negative metastatic BC.Although well tolerated, only 1 of 12 patients obtained a prolonged clinical benefit, and the study was closed after its first stage for poor activity. BACKGROUND: Androgen receptors (AR) are expressed in most breast cancers, and AR-agonists have some activity in these neoplasms. We investigated the safety and activity of the androgen precursor dehydroepiandrosterone (DHEA) in combination with an aromatase inhibitor (AI) in patients with AR-positive metastatic breast cancer (MBC). METHODS: A two-stage phase II study was conducted in two patient cohorts, one with estrogen receptor (ER)-positive (resistant to AIs) and the other with triple-negative MBC. DHEA 100 mg/day was administered orally. The combination with an AI aimed to prevent the conversion of DHEA into estrogens. The main endpoint was the clinical benefit rate. The triple-negative cohort was closed early. RESULTS: Twelve patients with ER-positive MBC were enrolled. DHEA-related adverse events, reported in four patients, included grade 2 fatigue, erythema, and transaminitis, and grade 1 drowsiness and musculoskeletal pain. Clinical benefit was observed in one patient with ER-positive disease whose tumor had AR gene amplification. There was wide inter- and intra-patient variation in serum levels of DHEA and its metabolites. CONCLUSION: DHEA showed excellent safety but poor activity in MBC. Although dose and patient selection could be improved, high serum level variability may hamper further DHEA development in this setting.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Deshidroepiandrosterona/administración & dosificación , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/epidemiología , Receptores Androgénicos/metabolismo , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Administración Oral , Anciano , Anciano de 80 o más Años , Protocolos de Quimioterapia Combinada Antineoplásica/efectos adversos , Inhibidores de la Aromatasa/administración & dosificación , Inhibidores de la Aromatasa/efectos adversos , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/patología , Deshidroepiandrosterona/efectos adversos , Progresión de la Enfermedad , Efectos Colaterales y Reacciones Adversas Relacionados con Medicamentos/etiología , Femenino , Humanos , Persona de Mediana Edad , Estudios Prospectivos , Receptores de Estrógenos/metabolismo , Criterios de Evaluación de Respuesta en Tumores Sólidos , Análisis de Supervivencia , Factores de Tiempo , Neoplasias de la Mama Triple Negativas/mortalidad , Neoplasias de la Mama Triple Negativas/patología
16.
Clin Breast Cancer ; 19(2): 137-145.e4, 2019 04.
Artículo en Inglés | MEDLINE | ID: mdl-30584056

RESUMEN

INTRODUCTION: Approximately 50% of locally advanced or metastatic breast cancer (MBC) patients treated with first-line exemestane do not show objective response and currently there are no reliable biomarkers to predict the outcome of patients using this therapy. The constitutive genetic background might be responsible for differences in the outcome of exemestane-treated patients. We designed a prospective study to investigate the role of germ line polymorphisms as biomarkers of survival. PATIENTS AND METHODS: Three hundred two locally advanced or MBC patients treated with first-line exemestane were genotyped for 74 germ line polymorphisms in 39 candidate genes involved in drug activity, hormone balance, DNA replication and repair, and cell signaling pathways. Associations with progression-free survival (PFS) and overall survival (OS) were tested with multivariate Cox regression. Bootstrap resampling was used as an internal assessment of results reproducibility. RESULTS: Cytochrome P450 19A1-rs10046TC/CC, solute carrier organic anion transporter 1B1-rs4149056TT, adenosine triphosphate binding cassette subfamily G member 2-rs2046134GG, fibroblast growth factor receptor-4-rs351855TT, and X-ray repair cross complementing 3-rs861539TT were significantly associated with PFS and then combined into a risk score (0-1, 2, 3, or 4-6 risk points). Patients with the highest risk score (4-6 risk points) compared with ones with the lowest score (0-1 risk points) had a median PFS of 10 months versus 26.3 months (adjusted hazard ratio [AdjHR], 3.12 [95% confidence interval (CI), 2.18-4.48]; P < .001) and a median OS of 38.9 months versus 63.0 months (AdjHR, 2.41 [95% CI, 1.22-4.79], P = .012), respectively. CONCLUSION: In this study we defined a score including 5 polymorphisms to stratify patients for PFS and OS. This score, if validated, might be translated to personalize locally advanced or MBC patient treatment and management.


Asunto(s)
Androstadienos/uso terapéutico , Antineoplásicos Hormonales/uso terapéutico , Inhibidores de la Aromatasa/uso terapéutico , Biomarcadores de Tumor/genética , Neoplasias de la Mama/tratamiento farmacológico , Adulto , Anciano , Anciano de 80 o más Años , Inhibidores de la Aromatasa/metabolismo , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Reparación del ADN/genética , Femenino , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Estudios Prospectivos , Receptores de Estrógenos/metabolismo , Reproducibilidad de los Resultados , Riesgo , Transducción de Señal/genética , Análisis de Supervivencia
17.
Breast Cancer Res Treat ; 170(2): 351-360, 2018 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-29589138

RESUMEN

PURPOSE: We investigated the occurrence and the prognostic and predictive relationship of a selected number of somatic mutations in triple-negative breast cancer (TNBC) patients having known clinical outcomes treated within the IBCSG Trial 22-00. METHODS: A matched case-control sampling selected patients enrolled in the IBCSG Trial 22-00 who had TNBC tumors, based on local assessment. Cases had invasive breast cancer recurrence (at local, regional, or distant site) according to the protocol definition. Matched controls had not recurred. Mutational analysis was performed with OncoCarta panel v1.0 using Mass Array System. The panel includes 19 genes belonging to different functional pathways as PI3K pathway, receptor tyrosine kinase, and cell cycle-metabolic group. Conditional logistic regression assessed the association of mutation status with breast cancer recurrence. RESULTS: Mutation assessment was successful for 135 patients (49 cases, 86 controls). A total of 37 (27.4%) of the 135 patients had at least one mutation in the selected genes. PIK3CA was the most common mutated gene (18/135; 13.3%), followed by BRAF, KIT and PDGFRA (each 4/135, 3.0%) and AKT1 (3/135; 2.2%). TNBC patients with at least one mutation had increased odds of recurrence compared with those with wild-type tumors (odds ratio (OR) 2.28; 95% CI 0.88-5.92), though this difference was not statistically significant (p = 0.09). We found no evidence that these mutations were predictive for the value of maintenance metronomic chemotherapy. CONCLUSIONS: Mutations in the tested oncogenes were not associated with breast cancer recurrence in this TNBC subset of patients. The question of whether any of these mutated genes (e.g., PIK3CA) may represent a useful therapeutic target in TNBC may be answered by ongoing clinical trials and/or larger dataset analysis.


Asunto(s)
Biomarcadores de Tumor , Mutación , Neoplasias de la Mama Triple Negativas/genética , Adulto , Anciano , Anciano de 80 o más Años , Antineoplásicos/farmacología , Antineoplásicos/uso terapéutico , Estudios de Casos y Controles , Análisis Mutacional de ADN , Femenino , Genotipo , Humanos , Persona de Mediana Edad , Clasificación del Tumor , Oportunidad Relativa , Pronóstico , Neoplasias de la Mama Triple Negativas/diagnóstico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Carga Tumoral , Adulto Joven
18.
Breast Cancer Res Treat ; 158(2): 323-31, 2016 07.
Artículo en Inglés | MEDLINE | ID: mdl-27372069

RESUMEN

The purpose of this study was to assess the prognostic and predictive value of tumor-infiltrating lymphocytes (TILs) in the triple-negative breast cancer (TNBC) cohort of the phase III IBCSG trial 22-00, comparing low-dose oral 'metronomic' cyclophosphamide-methotrexate maintenance chemotherapy (CM-maintenance) to no-CM-maintenance in early breast cancer. TILs were evaluated in full-face hematoxylin-and-eosin-stained sections of tumor samples confirmed centrally as TNBC (< 1 % of ER and PgR immunoreactivity and absence of HER2 overexpression or amplification). Mononuclear cells were evaluated in the stromal area within the borders of the invasive tumor. The primary endpoint was breast cancer-free interval (BCFI). Cox proportional hazards regression model assessed the association of BCFI and secondary endpoints with TILs score. In the 647 tumor samples, the median percentage of TILs was 18 % (IQR = 8-40 %), with 18 % having TILs ≥ 50 % (lymphocyte-predominant breast cancer, LPBC). At a median follow-up of 6.9 years, TILs were associated with better prognosis. For every 10 % increase of TILs, BCFI risk reduction was 13 % (HR 0.87, 95 % CI 0.79-0.95,P = 0.003). DFS, DRFI, and OS risk reductions were 11 % (P = 0.005), 16 % (P = 0.003), and 17 % (P < 0.001), respectively. Multivariable analysis confirmed the independent prognostic value of TILs. No significant TILs-by-treatment interaction was observed (P = 0.39) for associations of TILs with BCFI, although patients with LPBC receiving CM-maintenance had a greater breast cancer risk reduction (HR 0.64,95 % CI 0.23-1.78) than those with non-LPBC (TILs < 50 %) (HR 0.96, 95 % CI 0.67-1.40). TILs score is a potent prognostic factor in patients with TNBC. Low-dose chemotherapy confers a greater (not statistically significant) clinical benefit in patients with LPBC.


Asunto(s)
Ciclofosfamida/administración & dosificación , Linfocitos Infiltrantes de Tumor/patología , Metotrexato/administración & dosificación , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Administración Metronómica , Adulto , Anciano , Ciclofosfamida/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Humanos , Quimioterapia de Mantención , Metotrexato/uso terapéutico , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Resultado del Tratamiento , Neoplasias de la Mama Triple Negativas/patología
19.
Breast Cancer Res Treat ; 159(1): 79-86, 2016 08.
Artículo en Inglés | MEDLINE | ID: mdl-27460638

RESUMEN

The association between obesity and prognosis in early breast cancer (EBC) is unclear, especially when aggressive phenotypes are considered. We evaluated the influence of BMI on the prognosis of women with high-risk EBC enrolled in a phase III trial of adjuvant chemotherapy (CT). The association was assessed in 1066 patients with rapidly proliferating tumors, randomized to receive adjuvant CT with or without anthracyclines. Disease-free survival (DFS) and overall survival (OS) were calculated by Kaplan-Meier; multivariate analysis was performed according to age, tumor size, nodal, estrogen receptor (ER), and HER2 status and type of CT. Information on BMI was available for 959 women. Of these, 529 (55.2 %) were overweight or obese. Median age was 52 years. A total of 457 (47.7 %) patients had nodal involvement. Centralized pathology was performed in 850 cases: 522 (61.4 %) were ER positive, and 194 (22.8 %) were HER-2 positive. At a median follow-up of 103 months (range 1-188), 5-year DFS was 81 % (95 % CI 77-85), 82 % (95 % CI 77-86), and 76 % (95 % CI 70-83), in normal, overweight, and obese women, respectively (p = 0.44). Five-year OS was 92 % (95 % CI 89-95), 94 % (95 % CI 91-96), and 89 % (95 % CI 84-93), respectively (p = 0.60). BMI was not associated by multivariate analysis with differences in DFS or OS. Higher BMI had no influence on prognosis in high-risk EBC patients treated with CT. These data are consistent with prior observations and suggest that in aggressive biological subtypes, the impact of host factors on patient prognosis is minor.


Asunto(s)
Protocolos de Quimioterapia Combinada Antineoplásica/administración & dosificación , Neoplasias de la Mama/tratamiento farmacológico , Quimioterapia Adyuvante/métodos , Obesidad/complicaciones , Adulto , Anciano , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Índice de Masa Corporal , Cisplatino/administración & dosificación , Cisplatino/uso terapéutico , Supervivencia sin Enfermedad , Femenino , Fluorouracilo/administración & dosificación , Fluorouracilo/uso terapéutico , Humanos , Metotrexato/administración & dosificación , Metotrexato/uso terapéutico , Persona de Mediana Edad , Pronóstico , Análisis de Supervivencia , Resultado del Tratamiento , Adulto Joven
20.
Rev Recent Clin Trials ; 11(4): 317-323, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-27448518

RESUMEN

BACKGROUND: To assess the role of docetaxel plus androgen deprivation in metastatic, hormone- sensitive prostate cancer. METHODS: A qualitative systematic review of literature was performed. All the randomized phase III trials comparing docetaxel plus androgen deprivation with androgen deprivation alone in patients with metastatic, hormone-sensitive prostate cancer were considered eligible and included into the analysis. RESULTS: Six papers (3 randomized clinical trials, and 3 systematic reviews with meta-analysis) were considered eligible and included into the analysis. A significant improvement in time to progression and OS in the entire population treated with docetaxel plus androgen deprivation was reported in all the trials and meta-analyses, and in two trials and all meta-analyses, respectively. One trial reported improvement of OS only in patients with high volume disease, and the meta-analysis that also analyzed the subgroups of patients with high or low volume disease reported a benefit of docetaxel plus androgen deprivation for either the entire population or the two subgroups of patients. CONCLUSION: The early use of docetaxel combined with androgen deprivation improves the main outcomes in the treatment of metastatic, hormone-sensitive prostate cancer. The available data suggest that docetaxel plus androgen deprivation could be considered the novel standard for fit patients with metastatic, hormone-sensitive prostate cancer.


Asunto(s)
Antagonistas de Andrógenos/uso terapéutico , Neoplasias de la Próstata/tratamiento farmacológico , Taxoides/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica , Docetaxel , Humanos , Masculino , Ensayos Clínicos Controlados Aleatorios como Asunto
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