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Background: Oncoplastic surgery (OPS) reliability in the post-neoadjuvant chemotherapy (NACT) setting is still debated due to weak scientific evidences in such scenarios. Methods: Our analysis aims to report results obtained in a retrospective series of 111 patients consecutively treated with level II OPS after NACT at the Multidisciplinary Breast Center of the Fondazione Policlinico Universitario Agostino Gemelli IRCCS between 1998 and 2018. The surgical endpoints were the mean specimen volume, rates of positive margins (PMR), re-excision (RR), conversion to mastectomy (CMR), and complications (CR). The oncological endpoints were overall survival (OS), disease-free survival (DFS), and local recurrence (LR). To evaluate the impact of NACT on surgical and oncological outcomes at 302 months, we conducted a propensity score matching, pairing patients in post-NACT and upfront surgery groups. Results: The mean sample volume was 390,796 mm3. We registered a 3.6% of PMR, 1.8% RR, 0.9% CMR, 5% CR. The 10-year OS and 10-year DFS with a median follow-up of 88 months (6-302) were 79% and 76%, respectively, with an LR recurrence rate of 5%. The post-NACT group received significantly larger excised volumes and lower PMR. NACT did not affect surgical and oncological outcomes. Conclusions: Level II OPS can be considered a reliable alternative to mastectomy even in the post-NACT setting.
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BACKGROUND: Breast Cancer (BC) can be classified, due to its heterogeneity, into multiple subtypes that differ for prognosis and clinical management. Notably, triple negative breast cancer (TNBC) - the most aggressive BC form - is refractory to endocrine and most of the target therapies. In this view, taxane-based therapy still represents the elective strategy for the treatment of this tumor. However, due variability in patients' response, management of TNBC still represents an unmet medical need. Telomeric Binding Factor 2 (TRF2), a key regulator of telomere integrity that is over-expressed in several tumors, including TNBC, has been recently found to plays a role in regulating autophagy, a degradative process that is involved in drug detoxification. Based on these considerations, we pointed, here, at investigating if TRF2, regulating autophagy, can affect tumor sensitivity to therapy. METHODS: Human TNBC cell lines, over-expressing or not TRF2, were subjected to treatment with different taxanes and drug efficacy was tested in terms of autophagic response and cell proliferation. Autophagy was evaluated first biochemically, by measuring the levels of LC3, and then by immunofluorescence analysis of LC3-puncta positive cells. Concerning the proliferation, cells were subjected to colony formation assays associated with western blot and FACS analyses. The obtained results were then confirmed also in mouse models. Finally, the clinical relevance of our findings was established by retrospective analysis on a cohort of TNBC patients subjected to taxane-based neoadjuvant chemotherapy. RESULTS: This study demonstrated that TRF2, inhibiting autophagy, is able to increase the sensitivity of TNBC cells to taxanes. The data, first obtained in in vitro models, were then recapitulated in preclinical mouse models and in a cohort of TNBC patients, definitively demonstrating that TRF2 over-expression enhances the efficacy of taxane-based neoadjuvant therapy in reducing tumor growth and its recurrence upon surgical intervention. CONCLUSIONS: Based on our finding it is possible to conclude that TRF2, already known for its role in promoting tumor formation and progression, might represents an Achilles' heel for cancer. In this view, TRF2 might be exploited as a putative biomarker to predict the response of TNBC patients to taxane-based neoadjuvant chemotherapy.
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Neoplasias de la Mama Triple Negativas , Humanos , Animales , Ratones , Neoplasias de la Mama Triple Negativas/tratamiento farmacológico , Neoplasias de la Mama Triple Negativas/genética , Neoplasias de la Mama Triple Negativas/patología , Estudios Retrospectivos , Taxoides/farmacología , Taxoides/uso terapéutico , Hidrocarburos Aromáticos con Puentes/farmacología , Hidrocarburos Aromáticos con Puentes/uso terapéutico , Línea Celular TumoralRESUMEN
BACKGROUND: Trastuzumab deruxtecan (T-DXd) demonstrated unprecedented efficacy in patients with pretreated HER2+ metastatic breast cancer (mBC). However, few data are available about its efficacy in routine clinical practice. In this multicenter retrospective study, we examined effectiveness and safety of T-DXd in a real-world population. METHODS: Clinico-pathological information about patients with HER2+ mBC who received T-DXd were collected from 12 Italian hospitals. HER2 status was determined locally. Patients who received at least one administration of T-DXd, as any therapy line for advanced disease were included in the analysis. The primary endpoint was real-word PFS (rwPFS). RESULTS: One hundred and forty-three patients were included. Median age was 66 (range: 37-90), and 4 men were included. Hormone receptor (HR) status was positive in 108 (75%) patients and negative in 35(25%). T-DXd was administered as first, second, third, or subsequent lines in 4 (3%), 16 (11%), 42 (29%), and 81 (57%) patients, respectively. Among 123 patients with measurable disease, the ORR was 68%, and the DCR was 93% (9 CRs, 74 PRs, and 30 SD). Nine (7%) patients had a primary resistance to T-DXd. With a median follow-up of 12 months, the median rwPFS was 16 months. RwPFS was 84%, 59%, and 39% at 6, 12, and 18 months, respectively. A favorable trend in rwPFS was reported in patients receiving T-DXd as I/II line versus further lines (17 vs. 15 months; Pâ =â .098). Any-grade toxicity was registered in 84 patients (59%). Most common adverse events (AEs) reported were nausea (33%), neutropenia (21%), and asthenia (21%). Liver toxicity and diarrhea were uncommon (5% and 1%). Severe toxicities was registered in 18% of patients, and the most frequent were neutropenia, nausea/vomiting, and ILD observed in 15, 2, and 3 patients. AEs led to dose reduction in 37 patients (26%). Dose reduction and AEs do not affect patients' response and survival outcomes. CONCLUSIONS: Efficacy and safety of T-DXd were confirmed in an unselected real-world population of HER2+ mBC. These results are consistent with the results of known findings, and no new safety concerns were reported.
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Neoplasias de la Mama , Camptotecina/análogos & derivados , Inmunoconjugados , Neutropenia , Masculino , Humanos , Anciano , Neoplasias de la Mama/tratamiento farmacológico , Estudios Retrospectivos , Trastuzumab/efectos adversos , Náusea , Receptor ErbB-2/genéticaRESUMEN
We explored the outcomes of germline BRCA1/2 pathogenic/likely pathogenic variants (PVs/LPVs) in the endocrine-sensitive disease treated with first-line standard of care cyclin-dependent kinase 4/6 (CDK4/6) inhibitors. Three studies retrospectively showed a reduction in the overall survival (OS) and progression-free survival (PFS) in gBRCA1/2m patients compared to both the germinal BRCA1/2 wild type (gBRCA1/2wt) and the untested population. Regarding the efficacy of PI3Kα inhibitors, there are no subgroups or biomarker analyses in which germinal BRCA status was explored. However, the biological interactions between the PIK3CA/AKT/mTOR pathway and BRCA1/2 at a molecular level could help us to understand the activity of these drugs when used to treat BC in BRCA1/2 PVs/LPVs carriers. The efficacy of trastuzumab deruxtecan (T-DXd), an antibody-drug conjugate (ADC) targeting HER2 for HER2-low and HER2-positive (HER2+) BC, has been increasingly described. Unfortunately, data on T-DXd in HER2+ or HER2-low metastatic BC harboring germinal BRCA1/2 PVs/LPVs is lacking. Including germinal BRCA1/2 status in the subgroup analysis of the registration trials of this ADC would be of great interest, especially in the phase III trial DESTINY-breast04. This trial enrolled patients with HER2-negative (HER2-) and both HR+ and HR- metastatic disease, which can now be categorized as HER2-low. The HER2-low subgroup includes tumors that were previously classified as triple negative, so it is highly likely that some women were germline BRCA1/2 PVs/LPVs carriers and this data was not reported. Germline BRCA1/2 status will be available for a higher number of individuals with BC in the near future, and data on the prognostic and predictive role of these PVs/LPVs is needed in order to choose the best treatment options.
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Background: In early breast cancer (BC) the impact of denosumab on survival outcomes is still unclear. We undertook a systematic review and meta-analysis to assess efficacy and safety of adjuvant denosumab in addition to standard anticancer therapy. Methods: PubMed, CENTRAL, Scopus, Embase, and oncological meetings websites were screened to identify potentially eligible randomized controlled trials (RCTs). Survival outcomes were disease-free survival (DFS), bone-metastasis-free survival (BMFS), and overall survival (OS). Fracture incidence and time to first fracture were bone-health outcomes. Osteonecrosis of the jaw (ONJ), atypical femur fractures (AFF), and other adverse events were also evaluated. Pooled hazard ratios (HRs) and risk ratios (RR) with respective 95% confidence interval (95% CI) were computed using a random-effects model. Exploratory subgroup analyses were performed. Results: Two phase III RCTs were included, the Austrian Breast & Colorectal Cancer Study Group-18 (ABCSG-18) and the D-CARE trials, for a total of 7929 patients. In the ABCSG-18 trial, denosumab was administered every 6 months during endocrine therapy (for a median of seven cycles) while the D-CARE trial used an intensive schedule for a total treatment duration of 5 years. Adjuvant denosumab showed no difference in DFS (HR: 0.932; 95% CI: 0.748-1.162), BMFS (HR: 0.9896; 95% CI: 0.751-1.070), and OS (HR: 0.917; 95% CI: 0.718-1.171) compared to placebo in the overall population. In hormone receptor positive/human epidermal growth factor receptor 2 (HER2) negative BC patients, a DFS (HR: 0.883; 95% CI: 0.782-0.996) and BMFS (HR: 0.832; 95% CI: 0.714-0.970) benefit was observed and BMFS was prolonged in all hormone receptor positive patients (HR: 0.850; 95% CI: 0.735-0.983). Fracture incidence (RR: 0.787; 95% CI: 0.696-0.890) and time to first fracture (HR: 0.760; 95% CI: 0.665-0.869) were also improved. No increase in overall toxicity was seen with denosumab and no differences were observed for ONJ and AFF between the 60-mg every 6-month schedule and placebo. Conclusion: Denosumab addition to anticancer treatment does not improve DFS, BMFS, or OS in the overall population, although a DFS improvement was observed in hormone receptor positive/HER2 negative BC patients and a BMFS improvement in all hormone receptor positive patients. Bone-health outcomes were improved with no added toxicity with the 60-mg schedule. Registration: PROSPERO identifier: CRD42022332787.
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BACKGROUND: The diffusion of screening programs has resulted in a decrease of cT4 breast cancer diagnosis. The standard care for cT4 was neoadjuvant chemotherapy (NA), surgery, and locoregional or adjuvant systemic therapies. NA allows two outcomes: 1. improve survival rates, and 2. de-escalation of surgery. This de-escalation has allowed the introduction of conservative breast surgery (CBS). We evaluate the possibility of submitting cT4 patients to CBS instead of radical breast surgery (RBS) by assessing the risk of locoregional disease-free survival, (LR-DFS) distant disease-free survival (DDFS), and overall survival (OS). METHODS: This monocentric, retrospective study evaluated cT4 patients submitted to NA and surgery between January 2014 and July 2021. The study population included patients undergoing CBS or RBS without immediate reconstruction. Survival curves were obtained using the Kaplan-Meyer method and compared using a Log Rank test. RESULTS: At a follow-up of 43.7 months, LR-DFS was 70% and 75.9%, respectively, in CBS and RBS (p = 0.420). DDFS was 67.8% and 29.7%, respectively, (p = 0.122). OS was 69.8% and 59.8%, respectively, (p = 0.311). CONCLUSIONS: In patients with major or complete response to NA, CBS can be considered a safe alternative to RBS in the treatment of cT4a-d stage. In patients with poor response to NA, RBS remained the best surgical choice.
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Background: Given the low chance of response to neoadjuvant chemotherapy (NACT) in luminal breast cancer (LBC), the identification of predictive factors of pathological complete response (pCR) represents a challenge. A multicenter retrospective analysis was performed to develop and validate a predictive nomogram for pCR, based on pre-treatment clinicopathological features. Methods: Clinicopathological data from stage I-III LBC patients undergone NACT and surgery were retrospectively collected. Descriptive statistics was adopted. A multivariate model was used to identify independent predictors of pCR. The obtained log-odds ratios (ORs) were adopted to derive weighting factors for the predictive nomogram. The receiver operating characteristic analysis was applied to determine the nomogram accuracy. The model was internally and externally validated. Results: In the training set, data from 539 patients were gathered: pCR rate was 11.3% [95% confidence interval (CI): 8.6-13.9] (luminal A-like: 5.3%, 95% CI: 1.5-9.1, and luminal B-like: 13.1%, 95% CI: 9.8-13.4). The optimal Ki67 cutoff to predict pCR was 44% (area under the curve (AUC): 0.69; p < 0.001). Clinical stage I-II (OR: 3.67, 95% CI: 1.75-7.71, p = 0.001), Ki67 ⩾44% (OR: 3.00, 95% CI: 1.59-5.65, p = 0.001), and progesterone receptor (PR) <1% (OR: 2.49, 95% CI: 1.15-5.38, p = 0.019) were independent predictors of pCR, with high replication rates at internal validation (100%, 98%, and 87%, respectively). According to the nomogram, the probability of pCR ranged from 3.4% for clinical stage III, PR > 1%, and Ki67 <44% to 53.3% for clinical stage I-II, PR < 1%, and Ki67 ⩾44% (accuracy: AUC, 0.73; p < 0.0001). In the validation set (248 patients), the predictive performance of the model was confirmed (AUC: 0.7; p < 0.0001). Conclusion: The combination of commonly available clinicopathological pre-NACT factors allows to develop a nomogram which appears to reliably predict pCR in LBC.
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Cancer treatment-related adverse events (AEs) are sometimes associated with outcomes for cancer patients, especially with the newest therapies such as target therapy and immunotherapy. A few years ago, the first-line therapy for hormone-receptor-positive metastatic breast cancer (mBC) patients has been deeply changed by the introduction of cyclin-dependent kinase (CDK) 4/6 inhibitors, and now, we are improving our knowledge about their AEs and significance in clinical practice. Here, we report our experience with two cases of vitiligo-like lesions that occur early during treatment with ribociclib. We tried to change the CDK4/6 inhibitor for one patient, but the skin reaction persisted. Both patients retained only the endocrine therapy alone and had an unexpected durable progression-free survival (PFS). Some data on skin toxicities, including vitiligo-like lesions by CDK4/6 inhibitors, have recently been reported in the literature, but for the first time, we highlight a possible correlation with improved survival outcomes of patients. Uncovering the etiology of this toxicity, verifying the involvement of the immune system, and demonstrating a possible positive impact in survival represent an intriguing research objective for the near future.
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Background: In hormone-receptor positive/HER2-negative metastatic breast cancer (mBC) no randomized comparisons are available between CDK4/6 inhibitors. We undertook this systematic review and meta-analysis to assess the reliability of the likelihood of being helped or harmed (LHH). Methods: PubMed, CENTRAL, Embase and oncological meetings websites were searched to September 13th, 2022. We included phase III randomized controlled trials (RCTs) investigating palbociclib, ribociclib and abemaciclib in addition to endocrine therapy (ET) compared to placebo in hormone-receptor positive/HER2-negative advanced or mBC. Outcomes were progression-free survival (PFS), overall survival (OS), adverse events (AEs), dose reductions and discontinuations. Hazard ratios (HRs) and risk differences were computed with a random effect model to estimate the number needed to treat/harm (NNT/NNH). LHH was computed as (1/NNT)/(1/NNH). PROSPERO registration number: CRD42022362417. Findings: 2204 records were screened and seven RCTs (4415 patients) were included. A significant PFS benefit was observed in patients treated with a CDK4/6 inhibitor compared to placebo (HR 0.549; 0.508-0.594, I 2 = 0). Palbociclib, ribociclib and abemaciclib had similar NNTs (4.4, 5.0 and 4.4). Palbociclib and ribociclib showed lower LHHs for grade 3-4 neutropenia (0.33 and 0.35) and febrile neutropenia ([FN], 14.27 and 15.52), while abemaciclib the lowest LHH for any grade diarrhea (0.42). Abemaciclib had a lower LHH for grade 3-4 fatigue (9.92) and the highest LHH for all grade 3-4 AEs (0.62), while ribociclib the lowest LHH (1.75) for grade 3-4 hepatotoxicity. Palbociclib had the highest LHH for dose reductions and discontinuations (0.65 and 6.17). Considering OS, an overall benefit was observed (HR 0.788, 0.727-0.856, I 2 = 0%); ribociclib and abemaciclib had lower NNTs (9.7 and 10.0). Ribociclib showed the highest LHH for diarrhea (1.29), fatigue (7.37), dose reductions (0.28) and discontinuations (2.40), while abemaciclib the highest LHHs for neutropenia (0.40), FN (12.53) and hepatotoxicity (2.23). Interpretation: Palbociclib and ribociclib showed lower LHHs for haematological toxicities and abemaciclib for diarrhea. Palbociclib confirmed to be a manageable drug. The LHH appears to be a reliable synthesis tool for balancing risks and benefits of experimental drugs when head-to-head comparisons are missing. Funding: None.
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Neoadjuvant chemotherapy (NACT) for breast cancer (BC) increases surgical and conservative surgery chances. However, a significant proportion of patients will not be eligible for conservative surgery following NACT because of large tumor size and/or low chemosensitivity, especially for hormone receptor (HR)-positive/ human epidermal growth factor receptor 2 (HER2)-negative tumors, for which pathological complete response rates are lower than for other BC subtypes. On the other hand, for luminal BC neoadjuvant endocrine therapy could represent a valid alternative. Several gene expression assays have been introduced into clinical practice in last decades, in order to define prognosis more accurately than clinico-pathological features alone and to predict the benefit of adjuvant treatments. A series of studies have demonstrated the feasibility of using core needle biopsy for gene expression risk testing, finding a high concordance rate in the risk result between biopsy sample and surgical samples. Based on these premises, recent efforts have focused on the utility of gene expression signatures to guide therapeutic decisions even in the neoadjuvant setting. Several prospective and retrospective studies have investigated the correlation between gene expression risk score from core needle biopsy before neoadjuvant therapy and the likelihood of 1) clinical and pathological response to neoadjuvant chemotherapy and endocrine therapy, 2) conservative surgery after neoadjuvant chemotherapy and endocrine therapy, and 3) survival following neoadjuvant chemotherapy and endocrine therapy. The purpose of this review is to provide an overview of the potential clinical utility of the main commercially available gene expression panels (Oncotype DX, MammaPrint, EndoPredict, Prosigna/PAM50 and Breast Cancer Index) in the neoadjuvant setting, in order to better inform decision making for luminal BC beyond the exclusive contribution of clinico-pathological features.
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Neoplasias de la Mama , Terapia Neoadyuvante , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Neoplasias de la Mama/tratamiento farmacológico , Neoplasias de la Mama/genética , Neoplasias de la Mama/patología , Quimioterapia Adyuvante , Femenino , Expresión Génica , Hormonas/uso terapéutico , Humanos , Estudios Prospectivos , Receptor ErbB-2/genética , Receptor ErbB-2/metabolismo , Estudios RetrospectivosRESUMEN
Oncoplastic surgery level II techniques (OPSII) are used in patients with operable breast cancer. There is no evidence regarding their safety and efficacy after neoadjuvant chemotherapy (NAC). The aim of this study was to compare the oncological and aesthetic outcomes of this technique compared with those observed in mastectomy with immediate breast reconstruction (MIBR), in post-NAC patients undergoing surgery between January 2016 and March 2021. Local disease-free survival (L-DFS), regional disease-free survival (R-DFS), distant disease-free survival (D-DFS), and overall survival (OS) were compared; the aesthetic results and quality of life (QoL) were evaluated using BREAST-Q. A total of 297 patients were included, 87 of whom underwent OPSII and 210 of whom underwent MIBR. After a median follow-up of 39.5 months, local recurrence had occurred in 3 patients in the OPSII group (3.4%), and in 13 patients in the MIBR group (6.1%) (p = 0.408). The three-year L-DFS rates were 95.1% for OPSII and 96.2% for MIBR (p = 0.286). The three-year R-DFS rates were 100% and 96.4%, respectively (p = 0.559). The three-year D-DFS rate were 90.7% and 89.7% (p = 0.849). The three-year OS rates were 95.7% and 95% (p = 0.394). BREAST-Q highlighted significant advantages in physical well-being for OPSII. No difference was shown for satisfaction with breasts (p = 0.656) or psychosocial well-being (p = 0.444). OPSII is safe and effective after NAC. It allows oncological and aesthetic outcomes with a high QoL, and is a safe alternative for locally advanced tumors which are partial responders to NAC.
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The efficacy and safety of the combination of endocrine therapy (ET) and CDK4/6 inhibitors for patients with hormone receptor (HR)-positive HER2-negative metastatic breast cancer (BC) presenting with visceral crisis or life-threatening conditions represent a challenge for daily clinical practice. Indeed, the peculiarity of this clinical presentation (signs and symptoms of rapidly progressive disease) does not allow to include such patients in a trial aiming for drug approval. On the basis of the scientific evidence available so far, chemotherapy represents the standard of care according to guidelines, on the basis of the more rapid activity in comparison with ET alone. Besides, the combination of ET and CDK4/6 inhibitors have demonstrated in clinical trials to have clinically impactful activity in a short time, thus suggesting a potential role in advanced tumors that require rapid response. Herein, we report the clinical history of a young woman with HR-positive HER2-negative metastatic BC and a pancytopenia due to carcinomatosis of the bone marrow receiving letrozole and leuprorelin plus the CDK4/6 inhibitor palbociclib, who significantly derived clinical benefit from treatment. Considering that these peculiar cases are excluded from clinical trials, the estimation of the magnitude of the benefit of the newer ET combination may potentially represent a practical question for large case series and real-world studies.
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Breast cancer represents the first cause of cancer worldwide and the leading cause of cancer mortality for women. Therefore, new therapies are needed to improve the prognosis of women diagnosed with this disease. In this review, we summarize the new drug indications for the treatment of breast cancer approved by European Medicines Agency between January 2015 and June 2021. In particular, we analyzed the clinical trials results leading to approvals and their update (when available), according to setting (localized and locally advanced or metastatic) and clinical features (hormone receptor positive, HER2 positive, triple negative, BRCA 1/2 mutation). The aim of this paper is to describe the clinical benefit obtained with the new indications.
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BACKGROUND: Treatment of de-novo metastatic breast cancer is usually centered around systemic therapy, with local therapy (surgery and radiation therapy) largely reserved for palliation in patients with significant symptoms from primary tumor. The efficacy of locoregional treatment like surgery and/or radiotherapy is still controversial and the debate about surgical resection of primary tumor (PT) in de novo metastatic breast cancer (MBC) patients persists. METHODS: All patients with de-novo MBC undergone surgical treatment between January 2015 and January 2020 at the Multidisciplinary Breast Center of the IRCCS A. Gemelli University Polyclinic Foundation in Rome were included in this study. The primary endpoint was overall survival (OS) after PT resection, the secondary endpoint was progression free survival (PFS). The survival analyses were done using Kaplan-Meier method. Patients and tumor characteristics were analyzed in an exploratory modality in order to identify prognostic factor. RESULTS: Forty-five patients received resection of the primary breast cancer (26 mastectomy and 19 breast conserving surgery). Median age of diagnosis was 53 years old (range 25-75 years old). Median follow-up was 25.67 months. The median OS was not reached with 75% of patients alive over 2 years from PT resection. The median PFS was not reached with 64% of patients alive over 2 years from PT resection. For both PFS and OS only the triple negative (TN) immunophenotype appears to be a prognostically unfavorable factor in multivariate analysis. CONCLUSIONS: In view of the low number of disease progression events and deaths, although our results are preliminary, surgical treatment of primary breast cancer in metastatic setting seems to be an option after systemic therapies in luminal and HER2 positive breast cancer. Randomized prospective trials for each immunophenotype are necessary in order to confirm this evidence.
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Neoplasias de la Mama , Adulto , Anciano , Neoplasias de la Mama/cirugía , Femenino , Humanos , Mastectomía , Persona de Mediana Edad , Estudios Prospectivos , Receptor ErbB-2 , Estudios RetrospectivosRESUMEN
PURPOSE: Incomplete response to neoadjuvant chemotherapy (NACT) in triple negative breast cancer (TNBC) patients is correlated to high risk of relapse. This study aimed to evaluate the role of adjuvant chemotherapy in TNBC with residual tumor after NACT. METHODS: We retrospectively reviewed the outcome of patients with TNBC with residual tumor at surgery after a neoadjuvant treatment, followed by either adjuvant chemotherapy or observation. Primary endpoints were Disease Free Survival (DFS) and Overall Survival (OS). RESULTS: Between January 2000 and December 2016, 223 patients with early TNBC operated at the European Institute of Oncology were eligible. A total of 83.4 % of patients received adjuvant chemotherapy after surgery. 90 patients received standard dose infusional regimens, while 96 patients (51.6 %) received oral metronomic chemotherapy. Adjusting the analysis by surgical stage and Ki67 value there was a benefit for DFS and OS in favor of the group that received postoperative chemotherapy (DFS-HR 0.58 p = 0.04; OS-HR 0.54, p = 0.02). At a subgroup analysis according to the different adjuvant treatments received, a benefit for metronomic chemotherapy versus no chemotherapy both for DFS (HR 0.46, p = 0.008) and OS (HR 0.45, p = 0.009) was reported. CONCLUSION: Our retrospective analysis in a large cohort of TNBC patients with residual disease after NACT confirms the benefit of adding a postoperative treatment to reduce risk of relapse and death. Based on these results, we suggest that the adjuvant therapy based on metronomic cyclophosphamide and methotrexate deserves further investigation in this patients population.
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Neoplasias de la Mama , Neoplasias de la Mama Triple Negativas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Quimioterapia Adyuvante , Supervivencia sin Enfermedad , Femenino , Humanos , Terapia Neoadyuvante , Recurrencia Local de Neoplasia/tratamiento farmacológico , Neoplasia Residual , Estudios Retrospectivos , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
Neoadjuvant chemotherapy is increasingly being employed in the management of breast cancer patients. Efforts and resources have been devoted over the years to the search for an optimal strategy that can improve outcomes in the neoadjuvant setting. Today, a multidisciplinary approach with the application of evidence-based medicine is considered the gold standard for the improvement of oncological results and patient satisfaction. However, several clinical complications and psychological issues due to various factors can arise during neoadjuvant therapy and undermine outcomes. To ensure that health care needs are adequately addressed, clinicians must consider that women with breast cancer have a high risk of developing "unmet needs" during treatment, and often require a clinical intervention or additional care resources to limit possible complications and psychological issues that can occur during neoadjuvant treatment. This work describes a multidisciplinary model developed at "Fondazione Policlinico Universitario Agostino Gemelli" (FPG) in Rome in an effort to optimize treatment, ease the application of evidence-based medicine, and improve patient quality of life in the neoadjuvant setting. In developing our model, our main goal was to adequately meet patient needs while preventing high levels of distress.
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The liver represents the first metastatic site in 5-12% of metastatic breast cancer (MBC) cases. In absence of reliable evidence, liver metastasectomy (LM) could represent a possible therapeutic option for selected MBC patients (patients) in clinical practice. A retrospective analysis including MBC patients who had undergone an LM after a multidisciplinary Tumor Board discussion at the Hepatobiliary Surgery Unit of Fondazione Policlinico Universitario "Agostino Gemelli" IRCCS in Rome, between January 1994 and December 2019 was conducted. The primary endpoint was overall survival (OS) after a MBC-LM; the secondary endpoint was the disease-free interval (DFI) after surgery. Forty-nine MBC patients underwent LM, but clinical data were only available for 22 patients. After a median follow-up of 71 months, median OS and DFI were 67 months (95% CI 45-103) and 15 months (95% CI 11-46), respectively. At univariate analysis, the presence of a negative resection margin (R0) was the only factor that statistically significantly influenced OS (78 months versus 16 months; HR 0.083, p < 0.0001) and DFI (16 months versus 5 months; HR 0.17, p = 0.0058). A LM for MBC might represent a therapeutic option for selected patients. The radical nature of the surgical procedure performed in a high-flow center and after a multidisciplinary discussion appears essential for this therapeutic option.
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Cyclin-dependent kinase 4/6 inhibitors (CDK4/6i) in combination with endocrine therapy (ET) show meaningful efficacy and tolerability in patients with metastatic breast cancer (MBC), but the optimal sequence of ET has not been established. It is not clear if patients with lobular breast carcinomas (LBC) derive the same benefits when receiving second line CDK4/6i. This retrospective study compared the efficacy of palbociclib plus fulvestrant (PALBO-FUL) with everolimus plus exemestane (EVE-EXE) as second-line ET for hormone-resistant metastatic LBC. From 2013 to 2018, patients with metastatic LBC positivity for estrogen and/or progesterone receptors and HER2/neu negativity, who had relapsed during adjuvant hormonal therapy or first-line hormonal treatment, were enrolled from six centers in Italy in this retrospective study. A total of 74 out of 376 patients (48 treated with PALBO-FUL and 26 with EVE-EXE) with metastatic LBC were eligible for inclusion. Progression-free survival (PFS) was longer in patients receiving EVE-EXE compared with PALBO-FUL (6.1 vs. 4.5 months, univariate HR 0.58, 95% CI 0.35-0.96; p = 0.025). On the propensity score (PS) analysis, PFS was confirmed to be significantly longer for patients treated with EVE-EXE compared to PALBO-FUL (6.0 vs. 4.6 months, p = 0.04). This retrospective analysis suggests that EVE-EXE is more effective than PALBO-FUL for second line ET of metastatic LBC, allowing us to speculate on the optimal therapeutic sequence.
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Limited prospective data about the activity of immune checkpoint inhibitors (ICIs) are available for elderly patients. The aim of our analysis was to determine the relative efficacy of ICIs versus available standard therapies [standard of care (SOC)] in subgroups defined by patients' age. Searching the MEDLINE/PubMed, Cochrane Library, and American Society of Clinical Oncology (ASCO) Meeting abstracts randomized clinical trials were identified. Data extraction was conduced according to the Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) statement. The measured outcome was overall survival (OS). Twenty-nine randomized clinical trials (18,839 patients) were selected. As for the distribution of patients by age, all but 3 of the selected studies considered young the patients younger than 65 years (n=10,832) and elderly those with 65 years and older (n=7723); 7 studies identified a third subgroup of very elderly patients aged 75 years and above (n=421). In elderly and very elderly patients ICIs significantly reduced the risk of death by 23% compared with SOC [hazard ratio (HR), 0.77; P<0.00001)]. On the contrary, a lack of a survival advantage of immunotherapy was observed in the subgroup of very elderly patients (HR, 0.85; P=0.39). When comparing the efficacy of ICIs between the 2 subpopulations (elderly vs. young), no significant difference in OS was observed (HR, 0.76; P=0.66). ICIs prolonged OS compared with SOC in both elderly and young patients affected by lung cancer, melanoma, and renal carcinoma, regardless of the age. In conclusion, ICIs (as monotherapy or combinations) significantly improved OS compared with SOC in both young and elderly patients with advanced cancers, regardless of the tumor type. The magnitude of this benefit is debated in patients aged 75 years and above.
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Inhibidores de Puntos de Control Inmunológico/uso terapéutico , Terapia Molecular Dirigida , Neoplasias/tratamiento farmacológico , Factores de Edad , Biomarcadores de Tumor , Susceptibilidad a Enfermedades , Humanos , Inhibidores de Puntos de Control Inmunológico/farmacología , Proteínas de Punto de Control Inmunitario , Terapia Molecular Dirigida/métodos , Neoplasias/diagnóstico , Neoplasias/etiología , Neoplasias/mortalidad , Pronóstico , Sesgo de Publicación , Resultado del TratamientoRESUMEN
INTRODUCTION: Despite recent advances in the molecular characterization of triple-negative breast cancer (TNBC), the standard treatment for early-stage TNBC is represented by the historically used anthracycline and taxane-based chemotherapy. In this modern era of precision medicine, several new therapeutic strategies and novel agents have been investigated in the neoadjuvant setting of TNBC, in order to individualize treatment. AREAS COVERED: This review provides a comprehensive overview of the currently available evidence regarding the activity and efficacy of platinum agents, PARP- and immune-checkpoint-inhibitors for the neoadjuvant treatment of TNBC, highlighting the available data on potential predictive biomarkers of response or resistance to such treatments. EXPERT OPINION: The genomic and immune landscape of TNBC has encouraged the exploration of drugs that interfere with the DNA repair mechanism and that modulate immune response. Overall, these drugs seem to improve the pCR rate in TNBC, despite preliminary and heterogeneous results. Taking into account the economic issues and the side effects of these drugs, it is crucial to further explore the potential predictive role of BRCA mutational status and homologous recombination deficiency score, for platinum agents and PARP-inhibitors, and tumor infiltrating lymphocytes and other immune biomarkers for checkpoint inhibitors, respectively.