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Aim: There is limited data available regarding the comparison of Sacituzumab govitecan (SG) vs. chemotherapy in metastatic breast cancer patients. Materials & methods: We performed a systematic review and meta-analysis aimed to assess the safety profile of SG vs. chemotherapy for metastatic breast cancer (mBC) clinical trials. Results: The pooled odds ratio for outcomes such as grade 3-4 and all grade neutropenia, leukopenia, anemia and other non-hematological adverse events showed a higher risk for patients receiving SG. No statistically significant differences were reported in terms of grade 3-4 fatigue, all grade nausea, febrile neutropenia and treatment discontinuation due to adverse events. Conclusion: Our data, coupled with a statistically and clinically meaningful survival benefit, support the use of SG for mBC.
[Box: see text].
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Cancer-associated thrombosis (CAT) is the second main cause of cancer death with high related mortality and morbidity, leading to anticancer agent delays and interruptions. The recommended therapy, low-molecular-weight heparin (LMWH), however, is burdensome for patients and costly for society, as treatment should last until cancer is no longer active, even indefinitely. Tinzaparin is a manageable, efficient, safe, and cost-effective option. Compared to the other LMWHs, advantages are single-daily dose and safety in the elderly and those with renal impairment (RI). The purpose of this review is to critically discuss recent data on its efficacy and safety in CAT.
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Neoplasias , Insuficiência Renal , Trombose , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Neoplasias/complicações , Trombose/tratamento farmacológico , TinzaparinaRESUMO
Introduction: Large and consistent evidence supports the use of eribulin mesylate in clinical practice in third or later line treatment of metastatic triple negative breast cancer (mTNBC). Conversely, there is paucity of data on eribulin efficacy in second line treatment. Methods: We investigated outcomes of 44 mTNBC patients treated from 2013 through 2019 with second line eribulin mesylate in a multicentre retrospective study involving 14 Italian oncologic centres. Results: Median age was 51 years, with 11.4% of these patients being metastatic at diagnosis. Median overall survival (OS) and progression free survival (PFS) from eribulin starting were 11.9 (95%CI: 8.4-15.5) and 3.5 months (95%CI: 1.7-5.3), respectively. We observed 8 (18.2%) partial responses and 10 (22.7%) patients had stable disease as best response. A longer PFS on previous first line treatment predicted a better OS (HR=0.87, 95%CI: 0.77-0.99, p= 0.038) and a longer PFS on eribulin treatment (HR=0.92, 95%CI: 0.85-0.98, p=0.018). Progression free survival to eribulin was also favorably influenced by prior adjuvant chemotherapy (HR=0.44, 95%CI: 0.22-0.88, p=0.02). Eribulin was generally well tolerated, with grade 3-4 adverse events being recorded in 15.9% of patients. Conclusions: The outcomes described for our cohort are consistent with those reported in the pivotal Study301 and subsequent observational studies. Further data from adequately-sized, ad hoc trials on eribulin use in second line for mTNBC are warranted to confirm our findings.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Furanos/uso terapêutico , Cetonas/uso terapêutico , Terapia Neoadjuvante/métodos , Neoplasias de Mama Triplo Negativas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Quimioterapia Adjuvante/métodos , Feminino , Humanos , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Intervalo Livre de Progressão , Estudos Retrospectivos , Neoplasias de Mama Triplo Negativas/diagnóstico , Neoplasias de Mama Triplo Negativas/mortalidade , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Body mass index (BMI) is a main indicator of obesity and its association with breast cancer is well established. However, little is known in the metastatic setting, especially in HER2-positive patients. We assessed the influence of BMI on clinical outcomes of patients treated with pertuzumab and/or trastuzumab emtansine (T-DM1) for HER2+ metastatic breast cancer (mBC). BMI was addressed as a categorical variable, being classified on the basis of the following ranges, that is, 18.5-24.9, 25-29.9, and 30.0-34.9, namely, normal weight, overweight, and Class I obesity. The outcomes chosen were progression-free survival to first-line chemotherapy (PFS1) and overall survival (OS). Overall (N = 709), no impact of BMI was observed on PFS1 (p = .15), while BMI ≥ 30 was associated with worse OS (p = .003). In subjects who progressed to first line (N = 575), analyzing data across PFS1 quartiles and strata of disease burden, BMI predicted lower PFS1 in patients within the I PFS1 quartile and with the lowest disease burden (p = .001). Univariate analysis showed a detrimental effect of BMI ≥ 30 on OS for women within the I PFS1 quartile (p = .03). Results were confirmed in multivariate analysis. According to PFS1 quartiles a higher percentage of patients with high BMI and low disease burden progressed within 6 months of therapy. The effect of BMI on prognosis was also confirmed in multivariate analysis of OS for overall population. In our cohort, a BMI ≥ 30 correlated with worse OS in patients with HER2+ mBC who received pertuzumab and/or T-DM1 but had no impact on PFS to first line. BMI predicted worse I PFS1 quartile.
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Ado-Trastuzumab Emtansina/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Obesidade/complicações , Adulto , Idoso , Idoso de 80 Anos ou mais , Índice de Massa Corporal , Neoplasias da Mama/genética , Neoplasias da Mama/mortalidade , Progressão da Doença , Feminino , Humanos , Pessoa de Meia-Idade , Sobrepeso/complicações , Intervalo Livre de Progressão , Receptor ErbB-2/genéticaRESUMO
We analyzed data from 738 HER2-positive metastatic breast cancer (mbc) patients treated with pertuzumab-based regimens and/or T-DM1 at 45 Italian centers. Outcomes were explored in relation to tumor subtype assessed by immunohistochemistry (IHC). The median progression-free survival at first-line (mPFS1) was 12 months. Pertuzumab as first-line conferred longer mPFS1 compared to other first-line treatments (16 vs. 9 months, p = 0.0001), regardless of IHC subtype. Median PFS in second-line (mPFS2) was 7 months, with no difference by IHC subtype, but it was more favorable with T-DM1 compared to other agents (7 vs. 6 months, p = 0.03). There was no PFS2 gain in patients with tumors expressing both hormonal receptors (HRs; p = 0.17), while a trend emerged for tumors with one HR (p = 0.05). Conversely, PFS2 gain was significant in HRs-negative tumors (p = 0.04). Median overall survival (mOS) was 74 months, with no significant differences by IHC subtypes. Survival rates at 2 and 3 years in patients treated with T-DM1 in second-line after pertuzumab were significantly lower compared to pertuzumab-naïve patients (p = 0.01). When analyzed by IHC subtype, the outcome was confirmed if both HRs or no HRs were expressed (p = 0.02 and p = 0.006, respectively). Our results confirm that HRs expression impacts the clinical behavior and novel treatment-related outcomes of HER2-positive tumors when treatment sequences are considered. Moreover, multivariate analysis showed that HRs expression had no effect on PFS and OS. Further studies are warranted to confirm our findings and clarify the interplay between HER2 and estrogen receptor pathways in HER2-positive (mbc) patients.
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Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Regulação Neoplásica da Expressão Gênica , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Biomarcadores Tumorais , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/mortalidade , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Metástase Neoplásica , Estadiamento de Neoplasias , Prognóstico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismoRESUMO
BACKGROUND: The 8th edition of the American Joint Committee on Cancer (AJCC) staging has introduced prognostic stage based on anatomic stage combined with biologic factors. We aimed to validate the prognostic stage in HER2-positive breast cancer patients enrolled in the ShortHER trial. METHODS: The ShortHER trial randomized 1253 HER2-positive patients to 9 weeks or 1 year of adjuvant trastuzumab combined with chemotherapy. Patients were classified according to the anatomic and the prognostic stage. Distant disease-free survival (DDFS) was calculated from randomization to distant relapse or death. RESULTS: A total of 1244 patients were included. Compared to anatomic stage, the prognostic stage downstaged 41.6% (n = 517) of patients to a more favorable stage category. Five-year DDFS based on anatomic stage was as follows: IA 96.6%, IB 94.1%, IIA 92.4%, IIB 87.3%, IIIA 81.3%, IIIC 70.5% (P < 0.001). Five-year DDFS according to prognostic stage was as follows: IA 95.7%, IB 91.4%, IIA 86.9%, IIB 85.0%, IIIA 77.6%, IIIC 67.7% (P < 0.001). The C index was similar (0.69209 and 0.69249, P = 0.975). Within anatomic stage I, the outcome was similar for patients treated with 9 weeks or 1 year trastuzumab (5-year DDFS 96.2% and 96.6%, P = 0.856). Within prognostic stage I, the outcome was numerically worse for patients treated with 9 weeks trastuzumab (5-year DDFS 93.7% and 96.3%, P = 0.080). CONCLUSIONS: The prognostic stage downstaged 41.6% of patients, while maintaining a similar prognostic performance as the anatomic stage. The prognostic stage is valuable in counseling patients and may serve as reference for a clinical trial design. Our data do not support prognostic stage as guidance to de-escalate treatment. TRIAL REGISTRATION: EUDRACT number: 2007-004326-25; NCI ClinicalTrials.gov number: NCT00629278.
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Antineoplásicos Imunológicos/uso terapêutico , Neoplasias da Mama/diagnóstico , Genes erbB-2 , Estadiamento de Neoplasias , Trastuzumab/uso terapêutico , Adulto , Idoso , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , PrognósticoRESUMO
Lenvatinib significantly prolonged progression-free survival versus placebo in patients with radio-iodine refractory differentiated thyroid carcinoma. However, the primary adverse effects of any grade that occurred in >40% of patients in the lenvatinib group of the Phase III SELECT trial was hypertension (67.8%). Therefore, this drug should be used with caution in patients with cardiological morbidity. Here, we describe the case of a 73-year-old man with hypertension, obesity and chronic atrial fibrillation, who received lenvatinib for 6 months in the absence of cardiological symptoms.
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Anormalidades Cardiovasculares/tratamento farmacológico , Hipertensão/tratamento farmacológico , Compostos de Fenilureia/administração & dosagem , Quinolinas/administração & dosagem , Câncer Papilífero da Tireoide/tratamento farmacológico , Idoso , Anormalidades Cardiovasculares/complicações , Anormalidades Cardiovasculares/diagnóstico por imagem , Anormalidades Cardiovasculares/patologia , Terapia Combinada , Humanos , Hipertensão/induzido quimicamente , Hipertensão/diagnóstico por imagem , Hipertensão/patologia , Masculino , Compostos de Fenilureia/efeitos adversos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Quinolinas/efeitos adversos , Ablação por Radiofrequência/métodos , Câncer Papilífero da Tireoide/complicações , Câncer Papilífero da Tireoide/diagnóstico por imagem , Câncer Papilífero da Tireoide/patologiaRESUMO
AIM: This retrospective analysis focused on the effect of treatment with EVE/EXE in a real-world population outside of clinical trials. We examined the efficacy of this combination in terms of PFS and RR related to dose intensity (5 mg daily versus 10 mg daily) and tolerability. METHODS: 163 HER2-negative ER+/PgR+ ABC patients, treated with EVE/EXE from May 2011 to March 2016, were included in the analysis. The primary endpoints were the correlation between the daily dose and RR and PFS, as well as an evaluation of the tolerability of the combination. Secondary endpoints were RR, PFS, and OS according to the line of treatment. Patients were classified into three different groups, each with a different dose intensity of everolimus (A, B, C). RESULTS: RR was 29.8% (A), 27.8% (B) (p = 0.953), and not evaluable (C). PFS was 9 months (95% CI 7-11) (A), 10 months (95% CI 9-11) (B), and 5 months (95% CI 2-8) (C), p = 0.956. OS was 38 months (95% CI 24-38) (A), median not reached (B), and 13 months (95% CI 10-25) (C), p = 0.002. Adverse events were stomatitis 57.7% (11.0% grade 3-4), asthenia 46.0% (6.1% grade 3-4), hypercholesterolemia 46.0% (0.6% grade 3-4), and hyperglycemia 35.6% (5.5% grade 3-4). The main reason for discontinuation/interruption was grade 2-3 stomatitis. CONCLUSIONS: No correlation was found between dose intensity (5 vs. 10 mg labeled dose) and efficacy in terms of RR and PFS. The tolerability of the higher dose was poor in our experience, although this had no impact on efficacy.
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Androstadienos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Everolimo/administração & dosagem , Adulto , Idoso , Idoso de 80 Anos ou mais , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Intervalo Livre de Doença , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/classificação , Efeitos Colaterais e Reações Adversas Relacionados a Medicamentos/patologia , Feminino , Humanos , Itália/epidemiologia , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Estomatite/induzido quimicamente , Estomatite/genética , Estomatite/patologiaRESUMO
BACKGROUND: Evidence on the management and treatment of male breast cancer is scant. We report the analysis of a multicenter Italian series of patients with male breast cancer treated with eribulin. To our knowledge, this is the first report on the use or eribulin in this setting. PATIENTS AND METHODS: Patients were retrospectively identified in 19 reference centers. All patients received eribulin treatment, according to the standard practice of each center. Data on the identified patients were collected using a standardized form and were then centrally reviewed by two experienced oncologists. RESULTS: A total of 23 patients (median age, 64 years; range, 42-80) were considered. The median age at the time of diagnosis of breast cancer was 57 years (range, 42-74). HER2 status was negative in 14 patients (61%), and 2 patients (9%) had triple-negative disease. The most common metastatic sites were the lung (n = 14; 61%) and bone (n = 13; 56%). Eribulin was administered for a median of 6 cycles (range, 3-15). All patients reported at least stable disease; two complete responses (9%) were documented. Eribulin was well-tolerated, with only four patients (17%) reporting grade 3 adverse events and two (9%) with treatment interruptions because of toxicity. Eight subjects (35%) did not report any adverse event during treatment. For patients with a reported fatal event, the median overall survival from the diagnosis of metastatic disease was 65 months (range, 22-228). CONCLUSION: Although hampered by all the limitations of any retrospective case series, the results of the present study suggest, for the first time, the use of eribulin as therapy for male breast cancer. IMPLICATIONS FOR PRACTICE: Evidence on the management and treatment of male breast cancer is eagerly awaited. Although hampered by all the limitations of any retrospective case series, the results of the present study suggest, for the first time, the use of eribulin as therapy for male breast cancer.
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Poly(adenosine diphosphate [ADP]-ribose) polymerase 1 (PARP1) plays important roles in DNA damage response pathways and is often overexpressed in various human tumors. Currently, the use of PARP inhibitors for breast cancer (BC) therapy is the subject of debate, and there is an urgent need to understand much the expression and prognostic role of the PARP1 protein. The aim was to investigate the clinicopathological and prognostic significance of PARP1 in BC patients. The PARP1 and breast cancer susceptibility gene 1 (BRCA1) protein expressions were evaluated in 114 BCs by immunohistochemistry. Disease-free survival (DFS) and overall survival (OS) were determined based on the Kaplan-Meier method. Our results showed that nuclear PARP1 expression was significantly associated with peritumoral vascular invasion (P = 0.046), chemotherapeutic treatment (P = 0.026), oestrogen receptor (ER; P = 0.013), human epidermal growth factor receptor 2 (HER2; P = 0.003) and BRCA1 (P < 0.001) expression. Survival analyses showed a significant association with clinical outcome in the subgroup of ER-negative patients (P = 0.017 for DFS and P = 0.048 for OS) and in the subgroup of patients treated with chemotherapeutic agents (P = 0.042 for DFS and P = 0.046 for OS). A significant correlation was also found for DFS in patients characterized by tumors without peritumoral vascular invasion (P = 0.022). More importantly, multivariate analyses revealed that high nuclear PARP1 expression was associated with decreased DFS (P = 0.012) and OS (P = 0.026). In conclusion, PARP1 expression may be used as an independent prognostic factor in BC patients. In addition, this study demonstrated that high PARP1 expression may represent a marker of poorer prognosis both for patients with worse clinical outcome and in less aggressive clinical conditions.
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Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Núcleo Celular/metabolismo , Poli(ADP-Ribose) Polimerase-1/metabolismo , Adulto , Idoso , Proteína BRCA1/genética , Proteína BRCA1/metabolismo , Biomarcadores Tumorais , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Feminino , Expressão Gênica , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Gradação de Tumores , Metástase Neoplásica , Estadiamento de Neoplasias , Poli(ADP-Ribose) Polimerase-1/genética , Prognóstico , Estudos RetrospectivosRESUMO
Addition of trastuzumab to adjuvant chemotherapy has dramatically reduced the risk of recurrence and has become the standard of care for human epidermal growth factor receptor 2 (HER2)-positive early breast cancer patients. Since most data on trastuzumab benefits come from clinical trials, conducted in selected patient populations, we performed a retrospective analysis of HER2-positive early breast cancer patients treated in the "pre-trastuzumab" and "trastuzumab" eras, with the aim to determine patients' outcomes in real-world practice. 925 consecutive HER2-positive breast cancer patients treated with adjuvant chemotherapy in ten Italian oncologic centers were identified. Patients who had received adjuvant chemotherapy alone (cohort A, 352 patients), and patients who had received adjuvant chemotherapy followed or combined with trastuzumab (cohort B, 573 patients) were analyzed. Relapse rate at 3 years, relapse-free survival, and overall survival were significantly more unfavorable in the cohort A than in the cohort B (p < 0.0001). In multivariate analysis, factors related to relapse were younger age, advanced stage at diagnosis, absence of hormonal and of trastuzumab therapy. The benefit derived from the addition of trastuzumab was independent of nodal status and hormonal receptors expression. A subgroup analysis including 163 "triple positive" tumors with high levels of estrogen and progesterone receptor (TP50) suggested that addition of trastuzumab to adjuvant chemotherapy and hormonal therapy did not translate into better outcomes. In our analysis, trastuzumab benefit was confirmed in all but a small subset of TP50 tumors subgroups. In this subset further investigations are needed.
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Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Monoclonais Humanizados/administração & dosagem , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/metabolismo , Neoplasias da Mama/mortalidade , Neoplasias da Mama/patologia , Quimioterapia Adjuvante , Detecção Precoce de Câncer , Feminino , Humanos , Pessoa de Meia-Idade , Estudos Retrospectivos , Análise de Sobrevida , Trastuzumab , Resultado do Tratamento , Adulto JovemRESUMO
AIMS: Clinical activity of chemotherapy plus trastuzumab in HER2 overexpressing advanced breast cancer has been documented. We report the activity and safety results of biweekly combination of trastuzumab, docetaxel and gemcitabine as first-line therapy in HER2-positive advanced breast cancer. PATIENTS & METHODS: Patients were biweekly treated with trastuzumab (4 mg/kg), gemcitabine (1000 mg/m(2)) and docetaxel (50 mg/m(2)). The primary end point was overall response rate, secondary time to progression, clinical benefit rate (partial response plus complete response plus stable disease for ≥ 24 weeks) and tolerability. RESULTS: A total of 65 patients with HER2-positive advanced breast cancer have been enrolled. In total, 47 patients responded (73%; 95% CI, 60-84), 11 achieved complete response (17%; 95% CI: 8.9-28.7), 36 achieved partial response (56%; 95% CI: 43-68.6). The clinical benefit rate was 87.5% (95% CI: 77-94). Three patients (4.7%) experienced progressive disease. The median time to progression was 14.2 months (95% CI: 10.6-17.8), the median overall survival was 39.3 months and the 36-month survival rate was 55.5% (95% CI: 58-73). The worst toxicities were grade 3 neutropenia (12%), thrombocytopenia (6%) and diarrhea (6%). No cardiac toxicity was reported. CONCLUSION: As first-line therapy, this combination allowed the delivery of polychemotherapy in association to targeted therapy, with clinical activity and mild toxicity. The promising results should be further explored in Phase III randomized clinical trials.
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Anticorpos Monoclonais Humanizados/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/tratamento farmacológico , Desoxicitidina/análogos & derivados , Taxoides/administração & dosagem , Adulto , Idoso , Neoplasias da Mama/patologia , Desoxicitidina/administração & dosagem , Intervalo Livre de Doença , Docetaxel , Feminino , Humanos , Pessoa de Meia-Idade , Metástase Neoplásica , Receptor ErbB-2/biossíntese , Trastuzumab , GencitabinaRESUMO
BACKGROUND: So far, baseline Dynamic Contrast-Enhanced Magnetic Resonance Imaging (DCE-MRI) has played a key role for the application of sophisticated artificial intelligence-based models using Convolutional Neural Networks (CNNs) to extract quantitative imaging information as earlier indicators of pathological Complete Response (pCR) achievement in breast cancer patients treated with neoadjuvant chemotherapy (NAC). However, these models did not exploit the DCE-MRI exams in their full geometry as 3D volume but analysed only few individual slices independently, thus neglecting the depth information. METHOD: This study aimed to develop an explainable 3D CNN, which fulfilled the task of pCR prediction before the beginning of NAC, by leveraging the 3D information of post-contrast baseline breast DCE-MRI exams. Specifically, for each patient, the network took in input a 3D sequence containing the tumor region, which was previously automatically identified along the DCE-MRI exam. A visual explanation of the decision-making process of the network was also provided. RESULTS: To the best of our knowledge, our proposal is competitive than other models in the field, which made use of imaging data alone, reaching a median AUC value of 81.8%, 95%CI [75.3%; 88.3%], a median accuracy value of 78.7%, 95%CI [74.8%; 82.5%], a median sensitivity value of 69.8%, 95%CI [59.6%; 79.9%] and a median specificity value of 83.3%, 95%CI [82.6%; 84.0%], respectively. The median and CIs were computed according to a 10-fold cross-validation scheme for 5 rounds. CONCLUSION: Finally, this proposal holds high potential to support clinicians on non-invasively early pursuing or changing patient-centric NAC pathways.
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Neoplasias da Mama , Terapia Neoadjuvante , Humanos , Feminino , Terapia Neoadjuvante/métodos , Inteligência Artificial , Meios de Contraste/uso terapêutico , Resultado do Tratamento , Imageamento por Ressonância Magnética/métodos , Neoplasias da Mama/diagnóstico por imagem , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologiaRESUMO
We assessed the impact of DNA damage response and repair (DDR) biomarker expressions in 222 node-positive early breast cancer (BC) patients from a previous Phase III GOIM 9902 trial of adjuvant taxanes. At a median follow-up of 64 months, the original study showed no disease-free survival (DFS) or overall survival (OS) differences with the addition of docetaxel (D) to epirubicine-cyclophosphamide (EC). Immunohistochemistry was employed to assess the expression of DDR phosphoproteins (pATM, pATR, pCHK1, γH2AX, pRPA32, and pWEE1) in tumor tissue, and their association with clinical outcomes was evaluated through the Cox elastic net model. Over an extended follow-up of 234 months, we confirmed no significant differences in DFS or OS between patients treated with EC and those receiving D â EC. A DDR risk score, inversely driven by ATM and ATR expression, emerged as an independent prognostic factor for both DFS (HR = 0.41, p < 0.0001) and OS (HR = 0.61, p = 0.046). Further validation in a public adjuvant BC cohort was possible only for ATM, confirming its protective role. Overall, our findings confirm the potential role of the DDR pathway in BC prognostication and in shaping treatment strategies advocating for an integrated approach, combining molecular markers with clinical-pathological factors.
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BACKGROUND: Several GI peptides linked to intestinal barrier function could be involved in the modification of intestinal permeability and the onset of diarrhea during adjuvant chemotherapy. The aim of the study was to evaluate the circulating levels of zonulin, glucagon-like peptide-2 (GLP-2), epidermal growth factor (EGF) and ghrelin and their relationship with intestinal permeability and chemotherapy induced diarrhea (CTD). METHODS: Sixty breast cancer patients undergoing an FEC60 regimen were enrolled, 37 patients completed the study. CTD(+) patients were discriminated by appropriate questionnaire and criteria. During chemotherapy, intestinal permeability was assessed by lactulose/mannitol urinary test on day 0 and day 14. Zonulin, GLP-2, EGF and ghrelin circulating levels were evaluated by ELISA tests at five time-points (days 0, 3, 10, 14, and 21). RESULTS: During FEC60 administration, the lactulose/mannitol ratio was significantly higher on day 14 than at baseline. Zonulin levels were not affected by chemotherapy, whereas GLP-2 and EGF levels decreased significantly. GLP-2 levels on day 14 were significantly lower than those on day 0 and day 3, while EGF values were significantly lower on day 10 than at the baseline. In contrast, the total concentrations of ghrelin increased significantly at day 3 compared to days 0 and 21, respectively. Ten patients (27%) suffered from diarrhea. On day 14 of chemotherapy, a significant increase of the La/Ma ratio occurred in CTD(+) patients compared to CTD(-) patients. With regards to circulating gut peptides, the AUCg of GLP-2 and ghrelin were significantly lower and higher in CTD(+) patients than CTD(-) ones, respectively. Finally in CTD(+) patients a significant and inverse correlation between GLP-2 and La/Ma ratio was found on day 14. CONCLUSIONS: Breast cancer patients undergoing FEC60 showed alterations in the intestinal permeability, which was associated with modifications in the levels of GLP-2, ghrelin and EGF. In CTD(+) patients, a different GI peptide profile and increased intestinal permeability was found in comparison to CTD(-) patients. This evidence deserves further studies for investigating the potentially different intestinal luminal and microbiota conditions. TRIAL REGISTRATION: Clinical trial NCT01382667.
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Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Neoplasias da Mama/tratamento farmacológico , Carcinoma Ductal de Mama/tratamento farmacológico , Diarreia/induzido quimicamente , Absorção Intestinal/efeitos dos fármacos , Mucosa Intestinal/efeitos dos fármacos , Peptídeos/sangue , Protocolos de Quimioterapia Combinada Antineoplásica/administração & dosagem , Neoplasias da Mama/metabolismo , Neoplasias da Mama/cirurgia , Carcinoma Ductal de Mama/metabolismo , Carcinoma Ductal de Mama/cirurgia , Quimioterapia Adjuvante , Toxina da Cólera/sangue , Ciclofosfamida/administração & dosagem , Ciclofosfamida/efeitos adversos , Diarreia/sangue , Diarreia/urina , Ensaio de Imunoadsorção Enzimática , Fator de Crescimento Epidérmico/sangue , Epirubicina/administração & dosagem , Epirubicina/efeitos adversos , Feminino , Fluoruracila/administração & dosagem , Fluoruracila/efeitos adversos , Grelina/sangue , Peptídeo 2 Semelhante ao Glucagon/sangue , Haptoglobinas , Humanos , Mucosa Intestinal/metabolismo , Itália , Lactulose/urina , Manitol/urina , Pessoa de Meia-Idade , Permeabilidade , Estudos Prospectivos , Precursores de Proteínas , Estomatite/induzido quimicamente , Fatores de Tempo , Resultado do TratamentoRESUMO
BACKGROUND/AIM: Abemaciclib is a cyclin-dependent kinase 4/6 inhibitor approved in combination with endocrine therapy for treating hormone receptor-positive and human epidermal growth factor receptor 2-negative early and advanced breast cancer patients. The safety profile of abemaciclib is characterized by frequent gastrointestinal toxicity, especially diarrhea. Therefore, we performed an exploratory analysis of clinical factors that may be potentially associated with diarrhea in patients treated with abemaciclib plus endocrine therapy. PATIENTS AND METHODS: Factors potentially predisposing to diarrhea were selected, such as age ≥70 years, concomitant medications and diseases, diet, and use of laxatives. These variables were correlated with the onset of grade 2/3 diarrhea in a cohort of patients treated with abemaciclib from advanced breast cancer. Univariate and multivariate analysis was performed. Sensitivity and specificity were tested using the ROC curve. RESULTS: Eighty women with advanced breast cancer were included in the study. The univariate analysis found a statistically significant correlation between grade 2/3 diarrhea and age ≥70 years, polypharmacy, and concomitant gastrointestinal diseases (p<0.05). In the multivariate analysis, the number of risk factors significantly correlated with the outcome of interest (p<0.0001). ROC analysis showed our model's 82% sensitivity and 75% specificity. CONCLUSION: Taking into account specific pre-existing factors, it is possible to estimate the risk of diarrhea in hormone receptor-positive and human epidermal growth factor receptor 2-negative - advanced breast cancer patients, candidates for abemaciclib plus endocrine therapy. In these subjects, implementing proactive prevention and adopting a dose-escalation strategy may represent practical approaches to decrease the abemaciclib toxicity burden.
Assuntos
Neoplasias da Mama , Diarreia , Humanos , Feminino , Idoso , Diarreia/induzido quimicamente , Aminopiridinas/efeitos adversos , Benzimidazóis/efeitos adversos , Neoplasias da Mama/tratamento farmacológicoRESUMO
BACKGROUND: About 15%-20% of breast cancer (BC) cases is classified as Human Epidermal growth factor Receptor type 2 (HER2) positive. The Neoadjuvant chemotherapy (NAC) was initially introduced for locally advanced and inflammatory BC patients to allow a less extensive surgical resection, whereas now it represents the current standard for early-stage and operable BC. However, only 20%-40% of patients achieve pathologic complete response (pCR). According to the results of practice-changing clinical trials, the addition of trastuzumab to NAC brings improvements to pCR, and recently, the use of pertuzumab plus trastuzumab has registered further statistically significant and clinically meaningful improvements in terms of pCR. The goal of our work is to propose a machine learning model to predict the pCR to NAC in HER2-positive patients based on a subset of clinical features. METHOD: First, we evaluated the significant association of clinical features with pCR on the retrospectively collected data referred to 67 patients afferent to Istituto Tumori "Giovanni Paolo II." Then, we performed a feature selection procedure to identify a subset of features to be used for training a machine learning-based classification algorithm. As a result, pCR to NAC was associated with ER status, Pgr status, and HER2 score. RESULTS: The machine learning model trained on a subgroup of essential features reached an AUC of 73.27% (72.44%-73.66%) and an accuracy of 71.67% (71.64%-73.13%). According to our results, the clinical features alone are not enough to define a support system useful for clinical pathway. CONCLUSION: Our results seem worthy of further investigation in large validation studies and this work could be the basis of future study that will also involve radiomics analysis of biomedical images.
Assuntos
Neoplasias da Mama , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Prognóstico , Terapia Neoadjuvante/métodos , Estudos Retrospectivos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Trastuzumab/uso terapêutico , Aprendizado de Máquina , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
For endocrine-positive Her2 negative breast cancer patients at an early stage, the benefit of adding chemotherapy to adjuvant endocrine therapy is not still confirmed. Several genomic tests are available on the market but are very expensive. Therefore, there is the urgent need to explore novel reliable and less expensive prognostic tools in this setting. In this paper, we shown a machine learning survival model to estimate Invasive Disease-Free Events trained on clinical and histological data commonly collected in clinical practice. We collected clinical and cytohistological outcomes of 145 patients referred to Istituto Tumori "Giovanni Paolo II". Three machine learning survival models are compared with the Cox proportional hazards regression according to time-dependent performance metrics evaluated in cross-validation. The c-index at 10 years obtained by random survival forest, gradient boosting, and component-wise gradient boosting is stabled with or without feature selection at approximately 0.68 in average respect to 0.57 obtained to Cox model. Moreover, machine learning survival models have accurately discriminated low- and high-risk patients, and so a large group which can be spared additional chemotherapy to hormone therapy. The preliminary results obtained by including only clinical determinants are encouraging. The integrated use of data already collected in clinical practice for routine diagnostic investigations, if properly analyzed, can reduce time and costs of the genomic tests.
Assuntos
Neoplasias da Mama , Feminino , Humanos , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Terapia Combinada , Hormônios , Prognóstico , Modelos de Riscos Proporcionais , Receptor ErbB-2/genética , Aprendizado de MáquinaRESUMO
Introduction: Recently, accurate machine learning and deep learning approaches have been dedicated to the investigation of breast cancer invasive disease events (IDEs), such as recurrence, contralateral and second cancers. However, such approaches are poorly interpretable. Methods: Thus, we designed an Explainable Artificial Intelligence (XAI) framework to investigate IDEs within a cohort of 486 breast cancer patients enrolled at IRCCS Istituto Tumori "Giovanni Paolo II" in Bari, Italy. Using Shapley values, we determined the IDE driving features according to two periods, often adopted in clinical practice, of 5 and 10 years from the first tumor diagnosis. Results: Age, tumor diameter, surgery type, and multiplicity are predominant within the 5-year frame, while therapy-related features, including hormone, chemotherapy schemes and lymphovascular invasion, dominate the 10-year IDE prediction. Estrogen Receptor (ER), proliferation marker Ki67 and metastatic lymph nodes affect both frames. Discussion: Thus, our framework aims at shortening the distance between AI and clinical practice.
RESUMO
Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned coprimary or secondary analyses are not yet available. Clinical trial updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We present the final analysis of the phase III noninferiority, randomized ShortHER trial comparing 9 weeks versus 1 year of adjuvant trastuzumab with chemotherapy in patients with human epidermal growth factor receptor 2-positive (HER2+) early breast cancer (BC). Women with HER2+ BC were randomly assigned to anthracycline-taxane combinations plus 1-year trastuzumab (arm A, long) or 9-week trastuzumab (arm B, short). Here, we report the second coprimary end point overall survival (OS), updated disease-free survival (DFS), and outcomes according to hormone receptor status, age, and nodal status. At a median follow-up of 9 years, 10-year DFS is 77% versus 78% in the long versus short arm, respectively. Ten-year OS is 89% versus 88% in the long versus short arm, respectively. 10-year DFS rates in the long versus short arm according to nodal status are N0 81% versus 85%; N1-3 77% versus 79%; and N4+ 63% versus 53%. Ten-year OS rates in long versus short arm according to nodal status are N0 89% versus 95%%; N1-3 92% versus 89%; and N4+ 84% versus 64%. The updated analysis of the ShortHER trial shows that 1-year trastuzumab is the standard treatment for patients with HER2+ early BC as noninferiority cannot be claimed. However, numerically, the differences for the patients at low or intermediate risk (N0/N1-3) is negligible, while patients with N4+ have a clear benefit with 1-year trastuzumab.