RESUMO
BACKGROUND: The optimal treatment approach for hormone receptor-positive/HER2-negative metastatic breast cancer (HR+/HER2-negative MBC) with aggressive characteristics remains controversial, with lack of randomized trials comparing cyclin-dependent kinase (CDK)4/6-inhibitors (CDK4/6i)â +â endocrine therapy (ET) with chemotherapyâ +â ET. MATERIALS AND METHODS: We conducted an open-label randomized phase II trial (NCT03227328) to investigate whether chemotherapyâ +â ET is superior to CDK4/6iâ +â ET for HR+/HER2-negative MBC with aggressive features. PAM50 intrinsic subtypes (IS), immunological features, and gene expression were assessed on baseline samples. RESULTS: Among 49 randomized patients (median follow-up: 35.2 months), median progression-free survival (mPFS) with chemotherapyâ +â ET (11.2 months, 95% confidence interval [CI]: 7.7-15.4) was numerically shorter than mPFS (19.9 months, 95% CI: 9.0-30.6) with CDK4/6iâ +â ET (hazard ratio: 1.41, 95% CI: 0.75-2.64). Basal-like tumors under CDK4/6iâ +â ET exhibited worse PFS (mPFS: 11.4 months, 95% CI: 3.00-not reached [NR]) and overall survival (OS; mOS: 18.8 months, 95% CI: 18.8-NR) compared to other subtypes (mPFS: 20.7 months, 95% CI: 9.00-33.4; mOS: NR, 95% CI: 24.4-NR). In the chemotherapy arm, luminal A tumors showed poorer PFS (mPFS: 5.1 months, 95% CI: 2.7-NR) than other IS (mPFS: 13.2 months, 95% CI: 10.6-28.1). Genes/pathways involved in BC cell survival and proliferation were associated with worse outcomes, as opposite to most immune-related genes/signatures, especially in the CDK4/6i arm. CD24 was the only gene significantly associated with worse PFS in both arms. Tertiary lymphoid structures and higher tumor-infiltrating lymphocytes also showed favorable survival trends in the CDK4/6i arm. CONCLUSIONS: The KENDO trial, although closed prematurely, adds further evidence supporting CDK4/6iâ +â ET use in aggressive HR+/HER2-negative MBC instead of chemotherapy. PAM50 IS, genomic, and immunological features are promising biomarkers to personalize therapeutic choices.
Assuntos
Biomarcadores Tumorais , Neoplasias da Mama , Quinase 4 Dependente de Ciclina , Quinase 6 Dependente de Ciclina , Receptor ErbB-2 , Humanos , Feminino , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Quinase 4 Dependente de Ciclina/antagonistas & inibidores , Pessoa de Meia-Idade , Quinase 6 Dependente de Ciclina/antagonistas & inibidores , Biomarcadores Tumorais/metabolismo , Receptor ErbB-2/metabolismo , Idoso , Adulto , Inibidores de Proteínas Quinases/uso terapêutico , Inibidores de Proteínas Quinases/farmacologia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Receptores de Estrogênio/metabolismo , Receptores de Progesterona/metabolismoRESUMO
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.
Assuntos
Neoplasias da Mama , Camptotecina/análogos & derivados , Imunoconjugados , Neutropenia , Masculino , Humanos , Idoso , Neoplasias da Mama/tratamento farmacológico , Estudos Retrospectivos , Trastuzumab/efeitos adversos , Náusea , Receptor ErbB-2/genéticaRESUMO
Identifying novel circulating biomarkers predictive of response and informative about the mechanisms of resistance, is the new challenge for breast cancer (BC) management. The integration of omics information will gradually revolutionize the clinical approach. Liquid biopsy is being incorporated into the diagnostic and decision-making process for the treatment of BC, in particular with the analysis of circulating tumor DNA, although with some relevant limitations, including costs. Circulating cell-free DNA (cfDNA) fragmentomics and its integrity index may become a cheaper, noninvasive biomarker that could provide significant additional information for monitoring response to systemic treatments in BC. The purpose of our review is to focus on the available research on cfDNA integrity and its features as a biomarker of diagnosis, prognosis and response to treatments in BC, highlighting new perspectives and critical issues for future applications.
Assuntos
Neoplasias da Mama , Ácidos Nucleicos Livres , DNA Tumoral Circulante , Humanos , Feminino , Ácidos Nucleicos Livres/genética , Neoplasias da Mama/diagnóstico , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Biomarcadores Tumorais/genética , Biópsia LíquidaRESUMO
BACKGROUND: To date, a consensus has not yet been reached about the therapy sequence after disease progression (PD) on CDK4/6 inhibitors in patients with HR+/HER2- metastatic breast cancer (MBC). OBJECTIVES: The present study assesses, in a real-world setting, the activity of different subsequent therapies in patients who experienced a PD on palbociclib (P) + endocrine therapy (ET), to evaluate the best therapy sequence. METHODS: This is a multicenter retrospective observational study. Records of consecutive HR+/HER2- MBC patients from January 2017 to May 2019 were reviewed. The primary endpoint was the evaluation of progression-free survival (PFS) according to subsequent treatment lines after progression on P+ET. Toxicity data were also collected. RESULTS: The outcomes were analyzed in 89 MBC patients that had progressed on previous P+ET: 17 patients were on hormone therapy (HT) and 31 patients on chemotherapy (CT) as second-line treatments; seven patients were on HT and 34 on CT as third-line therapies. PFS of patients treated with HT as second-line therapy is significantly improved when compared with patients treated with CT (p=0.01). Considering third-line settings, the difference in PFS was not statistically different between HT and CT. A better outcome in terms of toxicity is observed among HT patients for both second- and third-line therapies. CONCLUSIONS: patients who were progressive on P+ET could still benefit from a subsequent ET. In patients who experienced a good efficacy from prior ET, without visceral metastatic sites, HT seems the most suitable option, when compared to CT, also in terms of safety.
RESUMO
Background: Eribulin shows some activity in controlling brain metastasis in breast cancer. Methods: This observational, multicenter study evaluated brain disease control rates, survival and safety in patients with brain metastatic breast cancer treated with eribulin in clinical practice. Results: A total of 34 patients were enrolled (mean age 49 years, 91% with visceral metastases) and 29 were evaluable for brain disease. Fourteen achieved disease control and showed a longer time without progression: 10 months (95% CI: 2.3-17.7) versus 4 months (95% CI: 3.3-4.7) in the control group (p = 0.029). Patients with clinical benefits at 6 months had longer survival. Leukopenia and neutropenia were the most frequent grade 3-4 toxicities. Conclusion: Eribulin confirms its effectiveness in patients with brain metastatic breast cancer. Further studies on larger cohorts are needed to confirm the results.
Assuntos
Neoplasias Encefálicas/mortalidade , Neoplasias da Mama/mortalidade , Furanos/uso terapêutico , Cetonas/uso terapêutico , Adulto , Idoso , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/secundário , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Feminino , Seguimentos , Humanos , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Taxa de SobrevidaRESUMO
Breast cancer is the most frequent and lethal tumor in women and finding the best therapeutic strategy for each patient is an important challenge. PARP inhibitors (PARPis) are the first, clinically approved drugs designed to exploit synthetic lethality in tumors harboring BRCA1/2 mutations. Recent evidence indicates that PARPis have the potential to be used both in monotherapy and combination strategies in breast cancer treatment. In this review, we show the mechanism of action of PARPis and discuss the latest clinical applications in different breast cancer treatment settings, including the use as neoadjuvant and adjuvant approaches. Furthermore, as a class, PARPis show many similarities but also certain critical differences which can have essential clinical implications. Finally, we report the current knowledge about the resistance mechanisms to PARPis. A systematic PubMed search, using the entry terms "PARP inhibitors" and "breast cancer", was performed to identify all published clinical trials (Phase I-II-III) and ongoing trials (ClinicalTrials.gov), that have been reported and discussed in this review.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Terapia Neoadjuvante/métodos , Inibidores de Poli(ADP-Ribose) Polimerases/uso terapêutico , Animais , Neoplasias da Mama/enzimologia , Neoplasias da Mama/patologia , Feminino , HumanosRESUMO
We discussed the potentialities of tumor mutation burden (TMB) as a predictive marker for immunotherapy in breast cancer, also highlighting the limits that have hindered its introduction in the clinical practice. Although some studies have demonstrated the possibility to select patients more responsive to immune-checkpoint inhibitors by evaluating TMB, some issues emerged regarding the complexity of the methodologies for its determination, the costs of the analysis, and the necessity to improve the TMB determination with that of neoantigen identification.
Assuntos
Antineoplásicos/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/genética , Terapia de Alvo Molecular , Mutação , Biomarcadores Tumorais/antagonistas & inibidores , Neoplasias da Mama/imunologia , Neoplasias da Mama/patologia , Análise Mutacional de DNA , Feminino , Humanos , PrognósticoRESUMO
The lack of effective therapies for metastatic triple-negative breast cancer (mTNBC) highlights the need for the development of novel treatment strategies. The cornerstone of treatment has long been represented by chemotherapy. Relevant evidence has recently emerged regarding the efficacy of immune checkpoint inhibitors, with the demonstration of a statistically significant improvement of progression-free survival with the addition of atezolizumab to nab-paclitaxel in the first-line treatment of mTNBC, accompanied by a substantial overall survival benefit in the PD-L1-positive subgroup. Despite this, it is necessary to identify the biomarkers that could allow a better selection of patients and combination regimens.
Assuntos
Neoplasias de Mama Triplo Negativas , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Humanos , Imunoterapia , Intervalo Livre de Progressão , Neoplasias de Mama Triplo Negativas/tratamento farmacológicoRESUMO
Bevacizumab in combination with taxanes in HER2-negative metastatic breast cancer (MBC) patients has shown improved progression-free survival (PFS), despite the lack of clear overall survival (OS) benefit. We performed a retrospective analysis to evaluate the impact of paclitaxel-bevacizumab and of maintenance therapy with bevacizumab (BM) and endocrine therapy (ET) in the real-world practice. We identified 314 HER2-negative MBC patients treated in 12 cancer centers. Overall, the median PFS and OS were 14 and 40 months, respectively. Among the 254 patients potentially eligible for BM, 183 received BM after paclitaxel discontinuation until progression/toxicity. PFS and OS were improved in patients who had received BM in comparison with those potentially eligible but who did not receive BM (P< 0.0001 and P = 0.001, respectively). Results were confirmed when adjusting for propensity score. Among the 216 hormone-receptor positive patients eligible for BM, a more favorable PFS and OS were observed when maintenance ET was administered (P < 0.0001). Multivariate analysis showed that PS, BM, number of disease sites and maintenance ET were related to PFS, while response and maintenance ET were related to OS. In hormone-receptor positive patients, BM produced a significant PFS and a trend towards OS benefit only in absence of maintenance ET (P = 0.0007 and P = 0.06, respectively). In the triple-negative subgroup, we observed a trend towards a better OS for patients who received BM (P = 0.06), without differences in PFS (P = 0.21). Our results confirmed the efficacy of first-line paclitaxel-bevacizumab in real-world practice; both BM and maintenance ET significantly improved PFS and OS compared to no maintenance therapies. J. Cell. Physiol. 232: 1571-1578, 2017. © 2016 Wiley Periodicals, Inc.
Assuntos
Bevacizumab/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Neoplasias da Mama/patologia , Quimioterapia de Manutenção , Paclitaxel/uso terapêutico , Receptor ErbB-2/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Intervalo Livre de Doença , Feminino , Humanos , Pessoa de Meia-Idade , Análise Multivariada , Metástase Neoplásica , Modelos de Riscos Proporcionais , Estudos Retrospectivos , Resultado do TratamentoAssuntos
Neoplasias da Mama , Anticorpos Monoclonais , Neoplasias da Mama/genética , Feminino , Células Germinativas , Hormônios , Humanos , Ftalazinas , PiperazinasRESUMO
The clinical utility of liquid biopsy in cancer treatment will increase as circulating tumor cells (CTCs) analysis move from the enumeration to the real-time measurement of tumor characteristics. Intratumor heterogeneity is becoming increasingly recognized as a major drawback to the shift to personalized medicine. Spatial and temporal heterogeneity might be reflected by the serial assessment of CTCs. Indeed, the developing technologies for CTCs analysis now allow digital genomic and next-generation sequencing approaches, able to differentiate molecular subtypes of the disease and to monitor genetic variation over time. The liquid biopsy of cancer might offer a real-time assessment of tumor biology, providing the opportunity to serially evaluate patients most likely to benefit from targeted drugs based on a dynamic characterization of the disease at the molecular level. Although hurdles remain before liquid biopsy is seen in routine clinical practice, the information derived from CTCs may facilitate the real-time identification of actionable mutations in cancer leading the way toward personalized medicine.
Assuntos
Neoplasias da Mama/tratamento farmacológico , Classe I de Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Inibidores de Fosfoinositídeo-3 Quinase/uso terapêutico , Tiazóis/uso terapêutico , Biomarcadores Tumorais/genética , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Classe I de Fosfatidilinositol 3-Quinases/genética , Feminino , Fulvestranto/uso terapêutico , Humanos , Terapia de Alvo Molecular , Mutação , PTEN Fosfo-Hidrolase/genética , Medicina de PrecisãoRESUMO
Background: Cyclin-dependent kinase 4 and 6 (CDK4 and CDK6) inhibitors have changed the therapeutic management of hormone receptor-positive (HR+) metastatic breast cancer (mBC) by targeting the cell cycle machinery and overcoming endocrine resistance. However, a large number of patients present disease progression due to cancer cells resisting CDK4/6 inhibitors. Our research considers which clinicopathological characteristics could be useful in identifying patients who might respond to CDK4/6 inhibitors by analyzing a retrospective case series of patients with HR+ mBC who were treated with hormone therapy plus CDK4/6 inhibitors. Methods: Approximately 177 mBC patients were enrolled, of whom 66 were treated with CD4/6 inhibitors plus letrozole and 111 were treated with CDK4/6 inhibitors and fulvestrant. A multistate model was used. Results: A low body surface area and older age were associated with an increased risk of developing neutropenia. A high Ki67 index, the presence of visceral metastases, and not having previously undergone adjuvant chemotherapy were prognostic factors of disease progression/death. As expected, some of the neutropenic patients who had previously undergone multiple lines of treatment were at a higher risk of disease progression/death. Furthermore, neutropenia status was associated with a more than doubled risk of progression/death compared to patients without neutropenia (HR = 2.311; p = 0.025). Conclusions: Having identified certain factors that could be associated with the development of neutropenia and considering that neutropenia itself is associated with an increased risk of progression, we believe that the baseline characteristics should be taken into account to reduce cases of neutropenia and disease progression.
RESUMO
We present a case of breast cancer metastases superimposed on epidural lipomatosis and although none of these findings are considered rare, their coexistence leads to unique image findings, and as far as we know there are no other cases like this in literature.
RESUMO
Abemaciclib demonstrated clinical benefit in women affected by HR+/HER2- advanced breast cancer (aBC). Drug-drug interactions (DDIs) can lead to reduced treatment efficacy or increased toxicity. This retro-prospective study aimed to evaluate outcomes, DDIs' impact, and toxicities of abemaciclib combined with endocrine therapy in a real-world setting. Patients from 12 referral Italian hospitals with HR+/HER2- aBC who received abemaciclib were included. Clinical data about comorbidities, concurrent medications, outcomes, and adverse events (AE) were collected. Drug-PIN® (Personalized Interactions Network) is a tool recognizing the role of multiple interactions between active and/or pro-drug forms combined with biochemical and demographic patient data. The software was used to define the Drug-PIN score and Drug-PIN tier (green, yellow, dark yellow, and red) for each patient. Univariate and multivariate analyses were performed to identify predictors of patients' PFS or toxicity. One hundred seventy-three patients were included. 13% of patients had >75years. The overall response rate (ORR) was 63%. The general population's median PFS (mPFS) was 22 months (mo), while mOS were not reached. Patients treated with abemaciclib in combination with AI and fulvestrant had a mPFS of 36 and 19 mo, respectively. The most common toxicities were diarrhea, asthenia, and neutropenia detected in 63%,49%, and 49% of patients. The number of concomitant medications and comorbidities were not associated with survival outcomes (22 vs 17 mo, p = 0.068, p = 0.99). Drug-PIN tier from dark yellow to red and Drug-PIN score >12 were associated with shorter PFS compared to no/low-risk DDIs and score <12 (15 vs 23, p = 0.005, p = 0.0017). Drug interaction was confirmed as an independent biomarker in a multivariate model (p = 0.02). No difference in any grade AE, severe toxicities, and diarrhea were detected among different age subgroups. No association was found between Drug-PIN score or Drug-PIN tier and overall toxicity (p = 0.44), severe AEs (p = 0.11), or drug reduction (p = 0.27). The efficacy and safety of abemaciclib plus ET were confirmed in a real-world setting, even in the elderly population and patients with comorbidities. Evaluation of DDIs with Drug-PIN appears to be an independent predictor of PFS.
RESUMO
Breast cancer represents one of the most common tumor histologies. To date, based on the specific histotype, different therapeutic strategies, including immunotherapies, capable of prolonging survival are used. More recently, the astonishing results that were obtained from CAR-T cell therapy in haematological neoplasms led to the application of this new therapeutic strategy in solid tumors as well. Our article will deal with chimeric antigen receptor-based immunotherapy (CAR-T cell and CAR-M therapy) in breast cancer.
RESUMO
Neoadjuvant endocrine treatment (NET) associates to satisfactory rates of breast conservative surgery and conversions from inoperable to operable hormone receptor-positive (HR+)/HER2-negative breast cancer (BC), with less toxicities than neoadjuvant chemotherapy (NACT) and similar outcomes. Hence, it has been proposed as a logical alternative to NACT in patients with HR+/HER2- BC candidate to a neoadjuvant approach. Nevertheless, potential barriers to the widespread use of NET include the heterogeneous nature of patient response coupled with the long duration needed to achieve a clinical response. However, interest in NET has significantly increased in the last decade, owing to more in-depth investigation of several biomarkers for a more adequate patient selection and on-treatment benefit monitoring, such as PEPI score, Ki67 and genomic assays. This review is intended to describe the state-of-the-art regarding NET, its future perspectives and potential integration with molecular biomarkers for the optimal selection of patients, regimen and duration of (neo)adjuvant treatments.
Assuntos
Neoplasias da Mama , Terapia Neoadjuvante , Humanos , Feminino , Neoplasias da Mama/genética , Mastectomia , Quimioterapia Adjuvante , Receptor ErbB-2 , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Approximately 6% of metastatic breast cancers arise de novo. While systemic therapy (ST) remains the treatment backbone as for patients with metachronous metastases, locoregional treatment (LRT) of the primary tumor remains a controversial method. The removal of the primary has an established role for palliative purposes, but it is unclear if it could also determine a survival benefit. Retrospective evidence and pre-clinical studies seem to support the removal of the primary as an effective approach to improve survival. On the other hand, most randomized evidence suggests avoiding LRT. Both retrospective and prospective studies suffer several limitations, ranging from selection bias and outdated ST to a small sample of patients. In this review we discuss available data and try to identify subgroups of patients which could benefit the most from LRT of the primary, to facilitate clinical practice decisions, and to hypothesize future studies design on this topic.