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BACKGROUND: The addition of pertuzumab (P) to trastuzumab (H) and standard chemotherapy (CT) as neoadjuvant treatment (NaT) for patients with HER2 + breast cancer (BC), has shown to increase the pathological complete response (pCR) rate, without main safety concerns. The aim of NeoPowER trial is to evaluate safety and efficacy of P + H + CT in a real-world population. METHODS: We retrospectively reviewed the medical records of stage II-III, HER2 + BC patients treated with NaT: who received P + H + CT (neopower group) in 5 Emilia Romagna institutions were compared with an historical group who received H + CT (control group). The primary endpoint was the safety, secondary endpoints were pCR rate, DRFS and OS and their correlation to NaT and other potential variables. RESULTS: 260 patients were included, 48% received P + H + CT, of whom 44% was given anthraciclynes as part of CT, compared to 83% in the control group. The toxicity profile was similar, excluding diarrhea more frequent in the neopower group (20% vs. 9%). Three patients experienced significant reductions in left ventricular ejection fraction (LVEF), all receiving anthracyclines. The pCR rate was 46% (P + H + CT) and 40% (H + CT) (p = 0.39). The addition of P had statistically correlation with pCR only in the patients receiving anthra-free regimens (OR = 3.05,p = 0.047). Preoperative use of anthracyclines (OR = 1.81,p = 0.03) and duration of NaT (OR = 1.18,p = 0.02) were statistically related to pCR. 12/21 distant-relapse events and 14/17 deaths occurred in the control group. Patients who achieve pCR had a significant increase in DRFS (HR = 0.23,p = 0.009). CONCLUSIONS: Adding neoadjuvant P to H and CT is safe. With the exception of diarrhea, rate of adverse events of grade > 2 did not differ between the two groups. P did not increase the cardiotoxicity when added to H + CT, nevertheless in our population all cardiac events occurred in patients who received anthracycline-containing regimens. Not statistically significant, higher pCR rate is achievable in patients receiving neoadjuvant P + H + CT. The study did not show a statistically significant correlation between the addition of P and long-term outcomes.
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Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica , Neoplasias da Mama , Terapia Neoadjuvante , Receptor ErbB-2 , Trastuzumab , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Neoplasias da Mama/metabolismo , Trastuzumab/administração & dosagem , Trastuzumab/efeitos adversos , Trastuzumab/uso terapêutico , Terapia Neoadjuvante/métodos , Pessoa de Meia-Idade , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/efeitos adversos , Anticorpos Monoclonais Humanizados/efeitos adversos , Anticorpos Monoclonais Humanizados/administração & dosagem , Anticorpos Monoclonais Humanizados/uso terapêutico , Estudos Retrospectivos , Receptor ErbB-2/metabolismo , Adulto , Idoso , Resultado do Tratamento , Estadiamento de NeoplasiasRESUMO
Over the last two decades, the use of Next-Generation Sequencing (NGS) in medical oncology has increased the likelihood of identifying druggable mutations that may be potentially susceptible to targeted treatments. The European Society for Medical Oncology (ESMO) currently does not recommend the use of the NGS test to determine the therapeutic course of patients with metastatic breast cancer (mBC) in daily clinical practice. However, the aim of this work is to evaluate the potential contribution of the NGS test in selecting targeted therapies for patients with mBC. Data were retrospectively collected from 101 patients diagnosed with metastatic breast cancer and treated at the Modena Cancer Center between January 2015 and April 2022. A NGS test was performed on the tumor tissue of each patient at the Laboratory of Molecular Pathology of the University Hospital of Modena. This study analyzed the clinical-pathological characteristics and mutational profile of the population using NGS tests, with a focus on actionable mutations that could be targeted in advanced stages of clinical development. The indicator of this study was to quantify the actionable mutations that resulted in a change of cancer treatment. In total, 101 patients with metastatic breast cancer were analyzed, including 86 with luminal phenotype, 10 who were HER2-positive and 5 who were triple-negative. Median age was 52 years. NGS analysis was conducted on 47 samples of primary breast cancer, 52 on metastatic sites of disease and 2 on liquid biopsies. A total of 85 gene mutations were found. The most common mutations were identified in the PIK3CA (47%), FGFR (19%) and ERBB2 genes (12%), and to a lesser extent in other genes. Of the 61 patients with pathogenic mutations, 46 (75%) had at least one actionable mutation. Of these, nine received treatment with a molecular target drug: eight patients with a mutation of the PIK3CA gene were treated with alpelisib and fulvestrant; one patient with FGFR1/2 amplifications received TAS120. Median PFS for these patients was 3.8 months. The study results show that using the NGS test on cancer tissue of metastatic breast cancer could influence the therapeutic choices, considering the small sample size and limited follow-up. About 9% of the study population had their therapy modified based on the results of NGS. The growing number of detectable mutations and increased accessibility of the test may lead to a greater number of potential therapeutic implications for the NGS assay. Perspectives suggest that NGS analysis can be implemented in daily clinical practice, particularly in contexts where a Molecular Tumor Board (MTB) is active.
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Neoplasias da Mama , Humanos , Pessoa de Meia-Idade , Feminino , Neoplasias da Mama/patologia , Biomarcadores Tumorais/genética , Estudos Retrospectivos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Classe I de Fosfatidilinositol 3-Quinases/genéticaRESUMO
BACKGROUND: Current guidelines consider T-DM1 the standard 2nd line therapy for HER2 positive metastatic breast cancer (MBC) patients following trastuzumab (T) + pertuzumab (P) and taxane 1st line treatment. Despite this, there are no prospective studies supporting this sequence. METHODS: We performed a meta-analysis using real world data to determine the efficacy of T-DM1 after 1st line TP in HER2 positive MBC patients. We used a random-effect model to find differences in the rate of 1-year progression free survival (PFS) between TP pre-treated population and the EMILIA phase III pivotal trial. RESULTS: Seven studies were eligible. The meta-analysis showed a combined 1-year PFS risk difference for T-DM1 efficacy after TP in 2nd or more lines of -0.122, with lower and upper limits of -0.253 and 0.010, respectively (p = 0.07), with low heterogeneity among studies (I2 0.01%, p = 0.836). Considering the four studies on T-DM1 in 2nd line setting, 1-year PFS risk was -0.034 (95% CI -0.207 - 0,139; p = 0.701) (I2 0.01%, p = 0.91). CONCLUSION: Overall, the efficacy of T-DM1 after TP seems to be similar to that previously reported in the EMILIA trial. In the second line setting, data are not mature enough to confirm T-DM1 efficacy in TP pre-treated population.
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Neoplasias da Mama , Maitansina , Segunda Neoplasia Primária , Ado-Trastuzumab Emtansina , Anticorpos Monoclonais Humanizados , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/patologia , Feminino , Humanos , Receptor ErbB-2/uso terapêutico , Estudos Retrospectivos , Trastuzumab/uso terapêuticoRESUMO
Endocrine therapy (ET), associated with CDK 4/6 inhibitors, represents the first choice of treatment for HR+/HER2- metastatic breast cancer (mBC). Primary or secondary endocrine resistance could develop; however validated biomarkers capable of predicting such a conditions are not available. Several studies have shown that HR+/HER2- mBC comprises five intrinsic subtypes. The purpose of this systematic review was to analyze the potential correlations between intrinsic subtype, efficacy of treatment, and patient outcome. Five papers that analyzed the intrinsic subtype with PAM50 assay in patients (pts) with HR+/HER2- mBC treated with ET (alone or in combination) within seven phase III clinical trials (EGF30008, BOLERO-2, PALOMA-2,3, MONALEESA-2,3,7) were identified. Non-luminal subtypes are more frequent in endocrine-resistant pts and in metastatic sites (vs. primary tumors), have less benefit from ET, and worse prognosis. Among these, HER2-enriched subtypes are similar to HER2+ tumors and benefit from the addition of anti-HER2 agents (lapatinib) and, for less clear reasons, of ribociclib (unconfirmed data for palbociclib and everolimus). Basal-like subtypes are similar to triple-negative tumors, making them more sensitive to chemotherapy. The intrinsic subtype is also not static but can vary over time with the evolution of the disease. Currently, the intrinsic subtype does not play a decisive role in the choice of treatment in clinical practice, but has potential prognostic and predictive value that should be further investigated.
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Neoplasias da Mama , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Everolimo/uso terapêutico , Feminino , Hormônios/uso terapêutico , Humanos , Lapatinib/uso terapêutico , Receptor ErbB-2RESUMO
BACKGROUND: Elderly patients are underrepresented in clinical study where combined endocrine strategies were compared to endocrine therapy (ET) in hormone receptors positive, HER2 negative, metastatic breast cancer. The role of the new endocrine approaches in elderly women is still unclear. METHODS: We performed a meta-analysis of first line phase II/III randomized trials on ET versus combined strategies considering clinical benefit and safety profile. Trials with hazard ratio (HR) for PFS in elderly patients were included. RESULTS: Overall, the meta-analysis showed a PFS advantage for the experimental arms [HR 0.77, p 0.016] with a significant high/moderate heterogeneity [I2 65.46%, p 0.005]. For patients on CDK 4/6 inhibitors and ET, HR was 0.57 (p < 0.0001), with low heterogeneity [I2 0.0001%, p 0.96]. Hematological adverse events, as well as diarrhea with Abemaciclib, were significantly higher in elderly population. CONCLUSIONS: The magnitude of PFS benefit due to the combined strategies in elderly patients is similar to those reported in the overall clinical trial population. Adding CDK4/6 inhibitors to ET significantly prolongs PFS, even if toxicity profile have to be carefully considered. Future trials should be designed taking into account patients' age, geriatric assessment and comorbidity.
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Antineoplásicos Hormonais/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Padrões de Prática Médica/estatística & dados numéricos , Inibidores de Proteínas Quinases/uso terapêutico , Receptor ErbB-2/metabolismo , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismo , Neoplasias da Mama/metabolismo , Ensaios Clínicos Fase II como Assunto , Ensaios Clínicos Fase III como Assunto , Feminino , Humanos , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
Breast cancer (BC) is the most common women cancer and cause of cancer death. Despite decades of scientific progress in BC treatments, the clinical benefit of new drugs is modest in several cases. The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) pathway mutations are frequent in BC (20-40%) and are significant causes of aggressive tumor behavior, as well as treatment resistance. Improving knowledge of the PI3K/AKT/mTOR pathway is an urgent need. This review aims to highlight the central role of PI3K-mTORC1/C2 mutations in the different BC subtypes, in terms of clinical outcomes and treatment efficacy. The broad base of knowledge in tumor biology is a key point for personalized BC therapy in the precision medicine era.
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The adjuvant endocrine therapy (AET) of HR+ EBC has been changing in recent years. Aromatase inhibitors (AIs) as an upfront strategy (or as part of a switch strategy) have been added to the choice of Tamoxifen (T) alone. Increased TE risk is well known in T-treated patients, while AIs have shown a reduced TE rate. By adding the cyclin dependent kinase 4/6 inhibitors (CDK4/6) to AIs, an increase in TE rate has been shown. We conducted this meta-analysis to evaluate the impact of the AETs on TE incidence. Twelve randomized phase III trials were included. Four trials evaluated the upfront strategy, 6 assessed the switch and 2 the combination with a CDK4/6 inhibitor. The new AETs did not significantly modify or affect the rate of TE events (OR 0.847, 95% CI, 0.528-1.366, P = .489). The OR for CDK4/6 inhibitor plus ET vs. ET was 3.635 (P = .002). Excluding the CDK4/6 inhibitors, the overall OR for AIs vs. T was 0.628 (P < .001), while it was 0.781 (P = .151) for switching T vs. continuing T for 5 years, and 0.52 (P < .0001) for the upfront strategies with AIs. The AIs alone or plus CDK4/6 inhibitors did not affect the rate of TE events. AIs as an upfront strategy is the safest AET, associated with the lowest TE incidence. The switch strategy increases TE rate, whereas the addition of CDK4/6 to the standard AET was shown to significantly increase TE events. The results of the currently ongoing trials with CDK4/6 inhibitors will help obtain additional data to evaluate any differences among the different CDK4/6 inhibitors and clarify the weight of TE adverse events in the benefit/risk balance of this new adjuvant strategy.
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Neoplasias da Mama , Tromboembolia , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/induzido quimicamente , Incidência , Inibidores da Aromatase/efeitos adversos , Tromboembolia/induzido quimicamente , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de CiclinaRESUMO
BACKGROUND: Ovarian function suppression (OFS) and hormone therapy (HT) represent an adjuvant option in premenopausal hormone receptor-positive early breast cancer (HR+EBC). The SOFT-TEXT trials showed improved outcomes upon receiving aromatase inhibitors (AIs)/OFS. METHODS: In order to estimate the magnitude of absolute improvements, we conducted a retrospective study applying composite risk (CR) to 237 premenopausal HR+EBC patients. RESULTS: Overall, 119 of these received tamoxifen (T)/OFS and 118 received AIs/OFS. The median age was 45 years (ys). After a median follow up of 65 months, recurrence was 6.7% in T patients and 10.2% in AI ones. CR (cutoff: 2.67) and ET duration (five-year cutoff) was found to have a significant impact on DFS. Invasive disease-free survival (IDFS) at 5 ys amounted to 82.9% for a CR>2.67 and 95% with CR=2.67 (p 0.0046). Five-year IDFS was 98.3% in patients who had completed 5-year HT compared to 54.6% of those who had stopped before 5 years (P < .0001). Excluding patients who had discontinued therapy due to disease relapse, IDFS difference at 5 years remained statistically significant (p=0.03) between the two groups, with an iDFS rate of 86.5% at 5 years in the second group. Adverse events of different grades were reported in 116 and 112 patients in the T/OFS group and the AIs/OFS, respectively. Early discontinuation due to toxicity was 3.8%. Seven patients (19.4%) discontinued therapy due to pregnancy desire (6 in the T group, 1 in the AI one); of these, one patient relapsed. CONCLUSION: In a real-world setting, treatment options for premenopausal patients who are candidates for HT and OFS should take risk status into account. Therefore, every effort should be made to maintain patient adherence to treatment in order to manage toxicities and improve outcomes.
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Introduction: Triple-negative breast cancer (TNBC) patients who do not obtain pathological complete response (pCR) after neoadjuvant chemotherapy (NACT) present higher rate of relapse and worse overall survival. Risk factors for relapse in this subset of patients are poorly characterized. This study aimed to identify the predictive factors for relapse in TNBC patients without pCR after NACT. Methods: Women with TNBC treated with NACT from January 2008 to May 2020 at the Modena Cancer Center were included in the analysis. In patients without pCR, univariate and multivariable Cox analyses were used to determine factors predictive of relapse. Results: We identified 142 patients with a median follow-up of 55 months. After NACT, 62 patients obtained pCR (43.9%). Young age at diagnosis (<50 years) and high Ki-67 (20%) were signi!cantly associated with pCR. Lack of pCR after NACT resulted in worse 5-year event-free survival (EFS) and overall survival (OS). Factors independently predicting EFS in patients without pCR were the presence of multifocal disease [hazard ratio (HR), 3.77; 95% CI, 1.45-9.61; p=0.005] and residual cancer burden (RCB) III (HR, 3.04; 95% CI, 1.09-9.9; p=0.04). Neither germline BRCA status nor HER2-low expression were associated with relapse. Discussion: These data can be used to stratify patients and potentially guide treatment decision-making, identifying appropriate candidates for treatment intensi!cation especially in neo-/adjuvant setting.
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Immune checkpoint inhibitors (ICIs) changed management of non-small-cell lung cancer, but resistance usually develops. Today, at ICIs failure, chemotherapy is the treatment of choice, but the chance of immunotherapy rechallenge is appealing. Another challenging issue is whether it is safe to treat HIV-positive patients with ICIs: safety and efficacy of immunotherapy have been marginally considered in this subgroup. We report the case of a non-small-cell lung cancer patient treated by PD-1 inhibitors rechallenge despite his HIV-positivity, achieving good partial response with significant clinical benefit and without toxicities. Our experience underlines that HIV-positive patients can be treated similarly to HIV-negative individuals. HIV-positivity should be considered similar to other comorbidities, and not as a sufficient reason to preclude them the best available treatments.
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Anticorpos Monoclonais Humanizados/uso terapêutico , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Infecções por HIV/complicações , Inibidores de Checkpoint Imunológico/uso terapêutico , Neoplasias Pulmonares/tratamento farmacológico , Adulto , Carcinoma Pulmonar de Células não Pequenas/complicações , Carcinoma Pulmonar de Células não Pequenas/patologia , Humanos , Imunoterapia , Neoplasias Pulmonares/complicações , Neoplasias Pulmonares/patologia , Masculino , Nivolumabe/uso terapêutico , RetratamentoRESUMO
MicroRNAs (miRNA) are small noncoding RNAs that can act as both oncogene and tumor suppressors. Deregulated miRNA expression has been detected in human cancers, including breast cancer (BC). Considering their important roles in tumorigenesis, miRNAs have been investigated as potential prognostic and diagnostic biomarkers. Neoadjuvant setting is an optimal model to investigate in vivo the mechanism of treatment resistance. In the management of human epidermal growth factor receptor-2 (HER2)-positive early BC, the anti-HER2-targeted therapies have drastically changed the survival outcomes. Despite this, growing drug resistance due to the pressure of therapy is relatively frequent. In the present review, we focused on the main miRNAs involved in HER2-positive BC tumorigenesis and discussed the recent evidence on their predictive and prognostic value.
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INTRODUCTION: In early-stage HER2 positive breast cancer (BC) patients, tumor response to neoadjuvant chemotherapy (NACT) predict survival outcomes. Patients achieving less than pathological complete response (pCR) have a worse prognosis, however, this group is heterogeneous. Nowadays limited data on predictive/prognostic biomarkers in patients with residual cancer disease are available. METHODS: Using next-generation sequencing technology, we evaluated a panel of 21 cancer genes in a group of HER2 positive BC patients with residual disease after NACT. A control group of patients who achieved the pCR was selected too. The BC mutational profile was analyzed on both the tumor diagnostic biopsy and matched residual disease. RESULTS: Overall, the detection rate of mutations was 79% in the No-pCR group versus 90% in the pCR cohort and 98% in the residual BC. The most mutated genes were TP53 and PIK3CA. No correlations between single gene mutations and survival outcomes were found. In no-pCR cohort, 52% of patients had different mutational profile after NACT, 69% of them had an increased in the number of mutated genes. Mutational profile changes from diagnostic biopsy to residual BC were a negative prognostic factor in term of relapse free survival: recurrence probability in different gene profile sub-group was 42% vs 0% in the same profile one (P = .019). CONCLUSIONS: Treatment selective pressure on tumor cells due to NACT changed the gene mutational profile in more than half of BC patient with residual tumor disease. Treatment-induced gene mutations significantly increase the risk of relapse. Profiling primary and residual BC is a major step in order to further personalized adjuvant treatment strategy.
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PURPOSE: Hormone receptors (HR) status in HER2 + breast cancer (BC) is a recognized stratification factor with relevant clinical implication. According to HR expression, HER2 + BC show different clinical characteristics, treatment sensitivity and prognosis. The interaction between HR and HER2 pathways remains incompletely understood. METHODS: Thirty-four HER2 + BC were included: 18 tumors with HER2+/HR + and 16 with HER2+/HR-. The expression of 770 genes and 13 molecular pathways were evaluated using Nanostring PanCancer Pathway panel performed on FFPE BC biopsies. RESULTS: Gene expression analysis identified 127 genes with significantly different expression between the two cohorts. 83% of these genes were overexpressed in HER2+/HR- cohort. Globally, 23% of them belonged to PI3K pathway (41 genes), 15% to Trascriptional regulation (26 genes) and 12% to MAPK (22 genes). Regarding pathway expression, PI3K, MAPK and NOTCH were significantly differently expressed between the two groups (p = 0.003, p = 0.0018 and p = 0.02, respectively), all of them were overexpressed in HER2+/HR- tumors. CONCLUSIONS: According to HR status, HER2 + tumors express different pathways profiles: the overexpression of PI3K, MAPK and NOTCH pathways in HER2+/HR- group could justify different survival outcomes and treatment sensitivity. The identification of tumor driver pathways may be a useful instrument for individualized pathway-directed therapies. Further clinical implications are warranted.
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Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Receptor ErbB-2/biossíntese , Receptores de Estrogênio/biossíntese , Receptores de Progesterona/biossíntese , Biópsia , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Estudos de Coortes , Feminino , Perfilação da Expressão Gênica , Humanos , Sistema de Sinalização das MAP Quinases , Proteínas Quinases Ativadas por Mitógeno/biossíntese , Proteínas Quinases Ativadas por Mitógeno/genética , Inclusão em Parafina , Receptor ErbB-2/genética , Receptores de Estrogênio/genética , Receptores de Progesterona/genética , Estudos RetrospectivosRESUMO
BACKGROUND: Fat tissue is strongly involved in BC tumorigenesis inducing insulin resistance, chronic inflammation and hormonal changes. Computed tomography (CT) imaging instead of body mass index (BMI) gives a reliable measure of skeletal muscle mass and body fat distribution. The impact of body composition parameters (BCPs) on chemosensitivity is still debated. We examined the associations between BCPs and tumor response to neoadjuvant chemotherapy (NC) in patients treated for operable breast cancer (BC). METHODS: A retrospective review of BC patients treated with NC in Modena Cancer Center between 2005 and 2017 was performed. BCPs, such as subcutaneous fat area (SFA), visceral fat area (VFA), lumbar skeletal muscle index (LSMI) and liver-to-spleen (L/S) ratio were calculated by Advance workstation (General Electric), software ADW server 3.2 or 4.7. BMI and BCPs were correlated with pathological complete response (pCR) and survival outcomes. RESULTS: 407 patients were included in the study: 55% with BMI < 25 and 45% with BMI ≥ 25. 137 of them had pre-treatment CT scan imagines. Overweight was significantly associated with postmenopausal status and older age. Hormonal receptor positive BC was more frequent in overweight patients (p<0.05). Postmenopausal women had higher VFA, fatty liver disease and obesity compared to premenopausal patients. No association between BMI classes and tumor response was detected. High VFA and liver steatosis were negative predictive factors for pCR (pCR rate: 36% normal VFA vs 20% high VFA, p= 0.048; no steatosis 32% vs steatosis 13%, p=0.056). Neither BMI classes nor BCPs significantly influenced overall survival and relapse-free survival. CONCLUSION: Visceral adiposity as well as steatosis were closely involved in chemosensitivity in BC patients treated with NC. Their measures from clinically acquired CT scans provide significant predictive information that outperform BMI value. More research is required to evaluate the relationship among adiposity site and survival outcomes.
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BACKGROUND: Everolimus has been shown to overcome endocrine resistance in hormone receptor positive advanced breast cancer patients. Predictive biomarkers of everolimus efficacy have been investigated in primary breast cancer tissue without finding univocal results. The goal of this study was to investigate the mutational burden in the metastatic site of endocrine-resistant tumors treated with everolimus plus exemestane. PATIENTS AND METHODS: Mass Array Sequenom platform was used to analyse genetic status of 18 cancer-related genes in 25 archival tumor specimens from metastatic lesions and available primary matched breast cancer tissue of patients treated with everolimus and exemestane for advanced disease. An exploratory analysis of everolimus efficacy in terms of progression free survival benefit and single gene mutation was carried out. RESULTS: The overall detection rate of mutation was 30% and 38% from metastatic and primary breast cancer samples, respectively. AKT1E17K was the most frequent mutated gene. No primary breast cancer and matched relapse maintained the same mutation profile. Considering molecular pathways, the most of the genes belong to PI3K pathway (AKT1E17K, PI3KCAE545K, and KITG565R,S709F). In patients with detected mutations in breast and/or recurrence tissue the median PFS was 5,6 months while in the subgroup of patients with no mutations the median PFS was 7,5 months. CONCLUSIONS: The mutational status of breast cancer recurrence allows the identification of some genes potentially correlating tumor response/resistance to everolimus. The most frequently mutated genes were involved in the PI3K/AKT/mTOR pathway highlighting that the deregulation of this pathway in the relapse plays a crucial role in the mechanisms of everolimus resistance/sensitivity. Owing to the small sample size and the retrospective nature of the study, these correlations need to be validated in a large prospective study.
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Androstadienos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias da Mama/genética , Everolimo/uso terapêutico , Fosfatidilinositol 3-Quinases/metabolismo , Idoso , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Análise Mutacional de DNA , Feminino , Genes Neoplásicos/genética , Humanos , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estudos Prospectivos , Estudos Retrospectivos , SirolimoRESUMO
Breast cancer (BC) is a heterogeneous disease, including different subtypes having diverse incidence, drug-sensitivity and survival rates. In particular, claudin-low and basal-like BC have mesenchymal features with a dismal prognosis. Disialoganglioside GD2 is a typical neuroectodermal antigen expressed in a variety of cancers. Despite its potential relevance in cancer diagnostics and therapeutics, the presence and role of GD2 require further investigation, especially in BC. Therefore, we evaluated GD2 expression in a cohort of BC patients and its correlation with clinical-pathological features.Sixty-three patients with BC who underwent surgery without prior chemo- and/or radiotherapy between 2001 and 2014 were considered. Cancer specimens were analyzed by immunohistochemistry and GD2-staining was expressed according to the percentage of positive cells and by a semi-quantitative scoring system.Patient characteristics were heterogeneous by age at diagnosis, histotype, grading, tumor size, Ki-67 and receptor-status. GD2 staining revealed positive cancer cells in 59% of patients. Among them, 26 cases (41%) were labeled with score 1+ and 11 (18%) with score 2+. Notably, the majority of metaplastic carcinoma specimens stained positive for GD2. The univariate regression logistic analysis revealed a significant association of GD2 with triple-receptor negative phenotype and older age (> 78) at diagnosis.We demonstrate for the first time that GD2 is highly prevalent in a cohort of BC patients clustering on very aggressive BC subtypes, such as triple-negative and metaplastic variants.
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Biomarcadores Tumorais , Neoplasias da Mama/metabolismo , Gangliosídeos/metabolismo , Idoso , Idoso de 80 Anos ou mais , Neoplasias da Mama/patologia , Feminino , Humanos , Imuno-Histoquímica , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Neoplasias de Mama Triplo Negativas/metabolismo , Neoplasias de Mama Triplo Negativas/patologiaRESUMO
Microsatellite instability (MSI) is a molecular marker of a deficient mismatch repair (MMR) system and occurs in approximately 15% of colorectal cancers (CRCs), more frequently in early than late-stage of disease. While in sporadic cases (about two-thirds of MSI-H CRCs) MMR deficiency is caused by an epigenetic inactivation of MLH1 gene, the remainder are associated with Lynch syndrome, that is linked to a germ-line mutation of one of the MMR genes (MLH1, MSH2, MSH6, PMS2). MSI-H colorectal cancers have distinct clinical and pathological features such as proximal location, early-stage (predominantly stage II), poor differentiation, mucinous histology and association with BRAF mutations. In early-stage CRC, MSI can select a group of tumors with a better prognosis, while in metastatic disease it seems to confer a negative prognosis. Although with conflicting results, a large amount of preclinical and clinical evidence suggests a possible resistance to 5-FU in these tumors. The higher mutational load in MSI-H CRC can elicit an endogenous immune anti-tumor response, counterbalanced by the expression of immune inhibitory signals, such as PD-1 or PD-L1, that resist tumor elimination. Based on these considerations, MSI-H CRCs seem to be particularly responsive to immunotherapy, such as anti-PD-1, opening a new era in the treatment landscape for patients with metastatic CRC.