Immunotherapy emerged as a new treatment modality for breast cancer, and its use is approved in combination with chemotherapy for first-line therapy in metastatic triple-negative breast cancer ...overexpressing PD-L1. As immune checkpoint inhibitors alone have modest clinical activity in advanced breast cancer, there is a growing interest in combinatorial modalities, and particularly for their rapid development in the early disease setting. The plethora of ongoing immunotherapy trials in early breast cancer comes at a time when solid data in advanced disease are still imperfect. This review offers a perspective on the efforts to establish the efficacy and safety of immunotherapeutic agents in early breast cancer.
•The investigation of immunotherapeutic agents for breast cancer has shifted from the metastatic to the early setting.•Different scenarios and designs exist for clinical trials testing immunotherapy in early breast cancer.•Combinatorial strategies may increase the activity of immunotherapy in early breast cancer across different subtypes.•Biomarkers for predicting upfront resistance, treatment response, and immune-related toxicities are needed.•Collaborative research is required for the understanding of the available data and the rational design of future trials.
The landscape of clinical trials testing risk-adapted modulations of cancer treatments is complex. Multiple trial designs, endpoints, and thresholds for non-inferiority have been used; however, no ...consensus or convention has ever been agreed to categorise biomarkers useful to inform the treatment intensity modulation of cancer treatments.
An expert subgroup under the European Society for Medical Oncology (ESMO) Precision Medicine Working Group shaped an international collaborative project to develop a classification system for biomarkers used in the cancer treatment de-intensification, based on a tiered approach. A group of disease-oriented clinical, translational, methodology and public health experts, and patients’ representatives provided an analysis of the status quo, and scanned the horizon of ongoing clinical trials. The classification was developed through multiple rounds of expert revisions and inputs.
The working group agreed on a univocal definition of treatment de-intensification. Evidence of reduction in the dose-density, intensity, or cumulative dose, including intermittent schedules or shorter treatment duration or deletion of segment(s) of the standard regimens, compound(s), or treatment modality must be demonstrated, to define a treatment de-intensification. De-intensified regimens must also portend a positive impact on toxicity, quality of life, health system burden, or financial toxicity. ESMO classification categorises the biomarkers for treatment modulation in three tiers, based on the level of evidence. Tier A includes biomarkers validated in prospective, randomised, non-inferiority clinical trials. The working group agreed that in non-inferiority clinical trials, boundaries are highly dependent upon the disease scenario and endpoint being studied and that the absolute differences in the outcomes are the most relevant measures, rather than relative differences. Biomarkers tested in single-arm studies with a threshold of non-inferiority are classified as Tier B. Tier C is when the validation occurs in prospective-retrospective quality cohort investigations.
ESMO classification for the risk-guided intensity modulation of cancer treatments provides a set of evidence-based criteria to categorise biomarkers deemed to inform de-intensification of cancer treatments, in risk-defined patients. The classification aims at harmonising definitions on this matter, therefore offering a common language for all the relevant stakeholders, including clinicians, patients, decision-makers, and for clinical trials.
•The landscape of clinical trials testing risk-adapted modulations of cancer treatments is complex.•Several trial designs and endpoints are used to evaluate de-intensified cancer therapies.•ESMO has developed a classification to categorise biomarkers to inform risk-guided intensity modulation of cancer treatments.•The classification includes three tiers, based on the clinical trial methodology and results.•The ESMO classification will help harmonise definitions, thereby facilitating communication with all relevant stakeholders.
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•Docetaxel can be measured in dried blood spots by LC–MS/MS.•Docetaxel plasma concentrations can be estimated through DBS measurements.•Area under the curve (AUC) are accurately ...obtained from DBS concentrations.•Docetaxel measurement in DBS can potentially be used to optimize cancer therapy.
In this study, a LC–MS/MS method for the measurement of docetaxel in Dried Blood Spots (DBS) samples was developed and validated. Docetaxel was extracted from 8 mm DBS punch with a mixture of methanol and acetonitrile (9:1, v/v). The chromatographic separation occurred in an Acquity® C18 column (150 × 2.1 mm, 1.7 μm) eluted with a mixture of water and acetonitrile plus 0.1% formic acid (45:55, v/v). Total analytical run time was 7 min. The method was linear from 50 to 3000 ng ml−1. Precision assays showed CV% < 9.8% and accuracy between 99 and 103%, mean recovery was 81%. The method was applied in the determination of the docetaxel in 31 patients, after collection of two paired venous blood and DBS samples, following a limited sampling strategy protocol. The analyte was stable in DBS for 18 days at 25 °C and 9 days at 45 °C. The interval of docetaxel concentrations measured in DBS collected before the end of the infusion was 756–3047 ng ml−1 and 60 ± 10 min after the end of the infusion was 57–331 ng ml−1. AUC values calculated from DBS-derived estimated plasma concentrations (EPC) represented on average 100% of those obtained in plasma samples of 3.1 mgh/l (2.4–4.9 mg h/l). There was a 93% agreement between the classification of patients as within or without the therapeutic range by plasma and EPC AUC. These findings support the clinical use of DBS sampling for routine therapeutic drug monitoring of docetaxel.
Prevalence of survivors of breast cancer has been steadily increasing in the last 20 years. Currently, more than 90% of women diagnosed with early-stage breast cancer are expected to be alive at ...5 years from diagnosis thanks to early detection and breakthrough innovations in multimodal treatment strategies. Alongside this advancement in clinical outcomes, survivors of breast cancer might experience several specific challenges and present with unique needs. Survivorship trajectories after diagnosis and treatment of breast cancer can be significantly impacted by long-lasting and severe treatment-related side effects, including physical problems, psychological distress, fertility issues in young women, and impaired social and work reintegration, which add up to patients’ individual risk of cancer recurrence and second primary malignancies. Alongside cancer-specific
sequelae
, survivors still present with general health needs, including management of chronic preexisting or ensuing conditions. Survivorship care should implement high-quality, evidence-based strategies to promptly screen, identify, and address survivors’ needs in a comprehensive way and minimize the impact of severe treatment
sequelae
, preexisting comorbidities, unhealthy lifestyles, and risk of recurrence on quality of life. This narrative review focuses on core areas of survivorship care and discuss the state of the art and future research perspectives in key domains including selected long-term side effects, surveillance for recurrences and second cancers, well-being promotion, and specific survivors’ needs.
Sexual concerns are a major unaddressed need among survivors of breast cancer (BC) with significant negative effects on quality of life. We longitudinally analyzed sexual health over time, using ...patient-reported outcomes.
Patients with stage I-III BC prospectively included from the CANcer TOxicity cohort (CANTO) provided data at diagnosis, then 1, 2, and 4 years afterward. Sexual concerns outcomes included poor body image (score ≤91/100), poor sexual functioning (≤16/100), poor sexual enjoyment (≤66/100), and sexual inactivity (EORTC QLQ-B23). Multivariate generalized estimating equation models assessed associations with sexual concerns after diagnosis, adjusting for age, sociodemographic, tumor, treatment, and clinical characteristics.
Nearly 78.1% among 7895 patients reported at least one sexual concern between diagnosis and 4 years’ follow-up. Over time, the proportion of patients reporting sexual concerns either increased or remained constant with diagnosis. Less than half (46%, range 11.4-57) of the patients with sexual concerns reported the use of supportive care strategies, including gynecological or psychological consultations (range 11.4-57.4). Factors consistently associated with sexual concerns up to 4 years after diagnosis included already reporting the same concern at diagnosis odds ratio (OR)poor body image 3.48 95% confidence interval (CI) 3.11-3.89; ORsexual inactivity 9.94 (95% CI 8.84-11.18), ORpoor sexual function 9.75 (95% CI 8.67-10.95), ORpoorsexual enjoyment 3.96 (95% CI 3.34-4.69), endocrine therapy use ORpoor body image 1.15 (95% CI 1.01-1.31); ORsexual inactivity 1.19 (95% CI 1.02-1.39), ORpoor sexual function 1.17 (95% CI 1.01-1.37), ORpoor sexual enjoyment 1.23 (95% CI 1.00-1.53), and depression ORpoor body image 2.00 (95% CI 1.72-2.34); ORsexual inactivity 1.66 (95% CI 1.40-1.97), ORpoor sexual function 1.69 (95% CI 1.43-2.00), ORpoor sexual enjoyment 1.94 (95% CI 1.50-2.51). Outcome-specific associations were also identified.
Sexual concerns seem frequent, persistent, and insufficiently addressed. Pretreatment concerns, endocrine therapy, and emotional distress are commonly associated factors. A proactive evaluation of sexual health across the care continuum is needed, to promptly identify patients suitable for multidisciplinary counseling, referral, and supportive interventions.
•Sexual concerns are frequent at BC diagnosis and seem to increase or persist in the after-treatment period.•Less than 50% of patients with reported sexual concerns consulted with proper supportive care specialists.•This large longitudinal cohort study helps identify patients that are more likely to report persistent sexual concerns.•A proactive evaluation and management of sexual health must exist across the BC care continuum.
We prove the first bifurcation result of time quasi-periodic
traveling
wave solutions for space periodic water waves with vorticity. In particular, we prove the existence of small amplitude time ...quasi-periodic solutions of the gravity-capillary water waves equations with
constant vorticity
, for a bidimensional fluid over a flat bottom delimited by a space-periodic free interface. These quasi-periodic solutions exist for all the values of depth, gravity and vorticity, and restrict the surface tension to a Borel set of asymptotically full Lebesgue measure.
Lactose is the main carbohydrate in mammals' milk, and it is responsible for the osmotic equilibrium between blood and alveolar lumen in the mammary gland. It is the major bovine milk solid, and its ...synthesis and concentration in milk are affected mainly by udder health and the cow's energy balance and metabolism. Because this milk compound is related to several biological and physiological factors, information on milk lactose in the literature varies from chemical properties to heritability and genetic associations with health traits that may be exploited for breeding purposes. Moreover, lactose contributes to the energy value of milk and is an important ingredient for the food and pharmaceutical industries. Despite this, lactose has seldom been included in milk payment systems, and it has never been used as an indicator trait in selection indices. The interest in lactose has increased in recent years, and a summary of existing information about lactose in the dairy sector would be beneficial for the scientific community and the dairy industry. The present review collects and summarizes knowledge about lactose by covering and linking several aspects of this trait in bovine milk. Finally, perspectives on the use of milk lactose in dairy cattle, especially for selection purposes, are outlined.
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