To date, only few marine natural compounds have been proved to be active in breast cancer (BC). The main marine-derived drugs that have been studied for the treatment of BC are tubulin-binding agents ...(eribulin and plocabulin), DNA-targeting agents (cytarabine and minor groove binders—trabectedin and lurbinectedin) and Antibody-Drug Conjugates (ADCs). Notably, eribulin is the only approved cytotoxic drug for the treatment of advanced BC (ABC), while cytarabine has a limited indication in case of leptomeningeal diffusion of the disease. Also plocabulin showed limited activity in ABC but further research is needed to define its ultimate potential role. The available clinical data for both trabectedin and lurbinectedin are of particular interest in the treatment of BRCA-mutated tumours and HR deficient disease, probably due to a possible immune-mediated mechanism of action. One of the most innovative therapeutic options for the treatment of BC, particularly in TNBC and HER2-positive BC, are ADCs. Some of the ADCs were developed using a specific marine-derived cytotoxic molecule as payload called auristatin. Among these, clinical data are available on ladiratuzumab vedotin and glembatumumab vedotin in TNBC, and on disitamab vedotin and ALT-P7 in HER2-positive patients. A deeper knowledge of the mechanism of action and of the potential predictive factors for response to marine-derived drugs is important for their rational and effective use, alone or in combination. In this narrative review, we discuss the role of marine-derived drugs for the treatment of BC, although most of them are not approved, and the opportunities that could arise from the potential treasure trove of the sea for novel BC therapeutics.
Neoadjuvant chemotherapy (NACT) is widely used in the treatment of triple-negative and HER2-positive breast cancer (BC), but its use in estrogen receptor (ER) and/or progesterone receptor (PR) ...positive/HER2-negative BC is questioned because of the low pathologic complete response (pCR) rates. This retrospective study assessed the mRNA-based MammaTyper® assay's capability of predicting pCR with NACT, and ER, PR, Ki67, and HER2 status at immunohistochemical (IHC) through transcriptomics.
Diagnostic biopsies from 76 BC patients treated at the Cremona Hospital between 2012-2018 were analyzed. Relative mRNA expression levels of ERBB2, ESR1, PGR, and MKI67 were measured using the MammaTyper® kit and integrated into a pCR score. Predicting capability of pCR and standard IHC biomarkers could be assessed with ROC curves in 75 and 76 patients, respectively.
Overall, 68.0% patients obtained a MammaTyper® high-score and 32.0% a MammaTyper® low-score. Among high-score patients, 62.7% achieved pCR, compared to 16.7% in the low-score group (p = 0.0003). The binary MammaTyper® score showed good prediction of pCR in the overall cohort (area under curve AUC = 0.756) and in HR+/HER2-negative cases (AUC = 0.774). In cases with residual disease, the continuous MammaTyper® score correlated moderately with residual tumor size and decrease in tumor size. MammaTyper® showed substantial agreement with IHC for ESR1/ER and ERBB2/HER2, and moderate agreement for PGR/PR and MKI67/Ki67.
Overall, MammaTyper® pCR score may serve as a standardized tool for predicting NACT response in HR+/HER2-negative BC, potentially guiding treatment strategies. Additionally, it could provide a more standardized and reproducible assessment of ER, PR, HER2, and Ki67 status.
•76 neoadjuvant chemotherapy-treated breast cancer (BC) patients at the Cremona Hospital between 2012 and 2018 were included.•MammaTyper classified 68.0 % as high-score and 32.0 % as low-score. In the first, 62.7 % achieved pCR vs. 16.7 % in the latter.•MammaTyper score effectively predicted pCR in all patients (AUC = 0.76) and HR+/HER2- BC (AUC = 0.77), not in HER2+ and TN.•The agreement between mRNA levels and IHC ESR1/ER and ERBB2/HER2 was substantial, and moderate for PGR/PR and MKI67/Ki67.•MammaTyper continuous pCR score correlated moderately with residual tumor size and percentage decrease in tumor size.
Background
Low muscle strength has been pointed out as a key characteristic of sarcopenia, but the prognostic significance of muscle function next to reduced skeletal muscle mass (SMM) in patients ...with cancer has been scantily investigated.
Methods
Data on muscle strength by handgrip (HG) dynamometry and total‐body SMM estimated by bioelectrical impedance analysis (BIA) of Italian and German patients with cancer observed prospectively until death or censoring were analysed (N = 1076). Patients were stratified in four risk categories based on low HG (<10th percentiles of age and gender‐specific normative values) and low total‐body SMM according to SMM index cutoffs (<10.75 and <6.75 kg/m2 in men and women, respectively).
Results
During a median follow‐up of 58 months 25th–75th percentile, 37–60, 566 patients had died. Patients presenting low HG in combination or not with low SMM were characterised by shorter median survival (12.7 vs. 27.2 months, respectively; p < 0.001) compared to those with low SMM/normal HG and normal SMM/normal HG (>60 months for both). After adjusting for sex, age, body mass index and percentage of weight loss, disease's stage, performance status and type of cancer, compared to reference category (normal HG and SMM; N = 210) the hazard ratios were: low SMM/normal HG (N = 342), 0.83 95% confidence interval, CI, 0.67–1.02 (p = 0.073); normal SMM/low HG (N = 158), 1.19 95% CI, 1.07–1.32 (p = 0.002); low SMM/low HG (N = 366), 1.39 95% CI, 1.27–1.53 (p < 0.001).
Conclusions
Muscle weakness was found to be a more powerful predictor of survival than BIA‐estimated SMM and should be considered as an additional key feature of sarcopenia in patients with cancer.
Low muscle strength has been pointed out as a key characteristic of sarcopenia, but the prognostic significance of muscle function next to reduced skeletal muscle mass (SMM) in patients with cancer has been scantily investigated. Muscle weakness was found to be a more powerful predictor of survival than SMM and should be considered as additional key feature of sarcopenia in patients with cancer.
The interactions between aromatase inhibitors (AI) in breast cancer (BC) and gut microbiota (GM) have not been completely established yet. The aim of the study is to evaluate the bio-diversity of GM ...and the relationship between GM, inflammation and tumor-infiltrating lymphocytes (TILs) in postmenopausal women with BC during adjuvant AI treatment compared to women with disease relapse during or after one year of AI therapy ("endocrine-resistant"). We conducted a monocenter observational case-control study. Eighty-four women with BC (8 cases, 76 controls) were enrolled from 2019 to 2021. We observed a significant difference in the mean microbial abundance between the two groups for the taxonomic rank of order (
0.035) and family (
0.029); specifically, the
group showed higher diversity than the
group.
reached its maximum abundance in
(
0.022). Cytokine levels were compared among the groups created considering the TILs levels. We obtained a statistically significant difference (
0.045) in IL-17 levels among the groups, with patients with low TILs levels showing a higher median value for IL-17 (0.15 vs. 0.08 pg/mL). Further studies about the bio-diversity in women with BC may lead to the development of new biomarkers and targeted interventions.
Background:
Nutritional support, including nutritional counseling and oral nutritional supplements (ONSs), has been recommended at the earliest opportunity in head and neck (H&N) cancer patients. The ...limited available evidence on the efficacy of immunonutrition during chemoradiotherapy (CT-RT) in H&N cancer patients is positive with regard to some secondary endpoints, but is still scanty, particularly with regard to toxicity and treatment tolerance. We hypothesize that early systematic provision of ONSs with a high-protein–high-calorie mixture containing immunonutrients (Impact) compared to standard high-calorie–high-protein nutritional blends, in addition to nutritional counseling, may be beneficial to patients with H&N cancer during CT-RT. Hence, we designed the present study to evaluate the efficacy, in terms of treatment tolerance, toxicity and response, body weight, body composition, protein-calorie intake, quality of life (QoL), fatigue, muscle strength and immunological profile of the early systematic provision of ONSs enriched in immunonutrients compared to isonitrogenous standard blends, in H&N cancer patients undergoing CT-RT.
Methods:
This is a pragmatic, bicentric, randomized (1:1), parallel-group, open label, controlled, pilot clinical trial.
Discussion:
Many efforts are still to be taken to improve the efficacy of nutritional support in oncology. Immunonutrition represents a promising approach also in H&N cancer patients, but the evidence on its efficacy in improving clinical outcomes during CT-RT is still inconclusive. The present pilot study, which guarantees the early provision of nutritional assessment and support to all the enrolled patients in accordance with the recent guidelines and recommendations, could represent one of the first proofs of the clinical effectiveness of early oral immunonutrition in cancer patients undergoing CT-RT and could stimulate further large randomized trials, potentially resulting in the improvement of supportive care quality.
Trial registration:
This study is registered on ClinicalTrials.gov Identifier: NCT04611113.
There is growing interest in the endocrine treatment (ET) of premenopausal women with hormone receptor positive (HR+) metastatic breast cancer (MBC). This review summarizes available data on ...endocrine therapy for this patient subset and aims to define the most appropriate treatment approach. The combination of luteinizing hormone‐releasing hormone (LHRH) agonists plus tamoxifen seems effective and safe and is considered as being superior to either approach alone; still, single‐agent therapy remains an acceptable treatment option. Due to their mechanism of action, aromatase inhibitors alone are not suitable for the treatment of premenopausal patients, but the combination with LHRH agonists may result in excellent disease control. Fulvestrant, in conjunction with LHRH agonists, also yields interesting results regarding clinical benefit rate and time to progression; currently, other orally available selective estrogen receptor downregulators are under clinical evaluation. Recently, targeted drugs have been added to ET in order to reverse endocrine resistance, but only limited information regarding their activity in premenopausal patients is available. The cyclin dependent kinase 4 and 6 inhibitor palbociclib when combined with fulvestrant and LHRH agonists was shown to prolong progression‐free survival over endocrine therapy alone in pretreated patients; similar results were obtained with the addition of abemacicilib or ribociclib to endocrine therapy. Currently, activity of the mammalian target of rapamycin inhibitor everolimus in combination with letrozole and goserelin is under assessment in premenopausal patients after progression on tamoxifen (MIRACLE trial).
Implications for Practice
This review provides clinicians with an overview on the available data regarding endocrine treatment of hormone receptor positive (HR+) metastatic breast cancer (MBC) in premenopausal women and summarizes the treatment options available in routine clinical practice. Knowledge of an up‐to‐date therapeutic approach in women with premenopausal HR+ MBC will lead to better disease management, thereby improving disease control and quality of life while minimizing side effects.
摘要
绝经前女性激素受体阳性(HR+)转移性乳腺癌(MBC)内分泌治疗(ET)越来越受到关注。本文总结了有关该患者人群内分泌治疗的现有数据,旨在确定最合适的治疗方法。促黄体生成激素释放激素(LHRH)激动剂与他莫昔芬联合使用似乎安全有效,并且被认为优于任何一种单药治疗,然而,单药疗法仍然是一种可接受的治疗选项。由于芳香化酶抑制剂作用机制的原因,单药治疗不适合绝经前期的患者,但与 LHRH 激动剂联合应用可更好地控制疾病。氟维司群与 LHRH 激动剂联合使用,在临床受益率和至进展时间方面也出现了值得关注的结果。目前,其他现有的口服选择性雌激素受体下调调节剂正在接受临床评估。最近,为了逆转内分泌抵抗,已将靶向药物添加到 ET 中,但有关其在绝经前期患者的作用的信息有限。与单纯内分泌治疗相比,将细胞周期蛋白依赖性激酶4和6抑制剂palbociclib与氟维司群和 LHRH 激动剂联合使用,可以延长经治患者的无进展生存期。在内分泌治疗中加入 abemacicilib 或ribociclib也取得了类似的结果。目前正在他莫昔芬经治后进展的绝经前期患者中,评估雷帕霉素抑制剂依维莫司与来曲唑、戈舍瑞林联合应用对哺乳动物靶点的作用(MIRACLE试验)。
实践意义: 本文为临床医生提供了关于绝经前女性激素受体阳性(HR+)转移性乳腺癌(MBC)内分泌治疗(ET)的现有数据概述,并总结了常规临床实践中的治疗方案。了解绝经前HR+的MBC女性最新治疗方法将有助于更好的管理疾病,从而提高疾病控制率和生活质量,同时最大限度地减少副作用。
This review provides clinicians with an overview of the available data on endocrine treatment in premenopausal women with hormone receptor positive metastatic breast cancer and summarizes the treatment options available in routine clinical practice.
Malnutrition is a frequent comorbidity in people with cancer, associated with poor tolerance of anticancer treatments, prognosis, and quality of life. Despite the abundance of scientific literature ...supporting this evidence and the availability of international guidelines for managing nutritional care in people with cancer, attitudes about this issue still vary considerably among oncologists, to the point that many patients who are malnourished do not receive adequate nutritional support. In view of this, the Italian Association of Medical Oncology, the Italian Society of Artificial Nutrition and Metabolism, and the Italian Federation of Volunteer-based Cancer Organizations implemented in 2016 a collaborative working group and initiated a structured project called Integrating Nutritional Therapy in Oncology, with the aim of increasing oncologists’ awareness of nutritional issues and consequently improving the nutritional care of cancer patients in Italy. In 2019, the Italian Society of Oncological Surgery and the Technical Scientific Association of Food, Nutrition and Dietetics joined the working group. In this article, we present the updated initiatives and the perspectives of this intersociety project.
•Attitudes about malnutrition still vary considerably among Italian oncologists.•Many cancer patients with malnourishment do not receive prompt and adequate nutritional support.•Inadequate nutritional care should be considered ethically unacceptable.•More efforts are still needed to improve the quality of nutritional care in Italy.•The Italian Intersociety Working Group for Nutritional Support in Cancer Patients continues its activity to improve nutritional care in oncology.
The process in which locally confined epithelial malignancies progressively evolve into invasive cancers is often promoted by unjamming, a phase transition from a solid-like to a liquid-like state, ...which occurs in various tissues. Whether this tissue-level mechanical transition impacts phenotypes during carcinoma progression remains unclear. Here we report that the large fluctuations in cell density that accompany unjamming result in repeated mechanical deformations of cells and nuclei. This triggers a cellular mechano-protective mechanism involving an increase in nuclear size and rigidity, heterochromatin redistribution and remodelling of the perinuclear actin architecture into actin rings. The chronic strains and stresses associated with unjamming together with the reduction of Lamin B1 levels eventually result in DNA damage and nuclear envelope ruptures, with the release of cytosolic DNA that activates a cGAS-STING (cyclic GMP-AMP synthase-signalling adaptor stimulator of interferon genes)-dependent cytosolic DNA response gene program. This mechanically driven transcriptional rewiring ultimately alters the cell state, with the emergence of malignant traits, including epithelial-to-mesenchymal plasticity phenotypes and chemoresistance in invasive breast carcinoma.
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