Optimizing abemaciclib-induced diarrhea management in patients with breast cancer: a pragmatic 2-group study using a postbiotic microbiota stabilizer.

BACKGROUND: Abemaciclib-induced diarrhea is a relevant concern in clinical practice. Postbiotics have emerged as a promising option for managing it. MATERIALS AND METHODS: We conducted a retrospective-prospective, 2-group, observational study to assess the impact of the postbiotic PostbiotiX-Restore, derived by Lactobacillus paracasei CNCM I-5220, on abemaciclib-induced diarrhea in patients with hormone receptor-positive HER2-negative breast cancer. The prospective population (Postbio group) received postbiotic during the first cycle of abemaciclib, while the retrospective one received standard care (Standard group). Diarrhea grading was defined according to the National Cancer Institute's Common Terminology Criteria for Adverse Events. RESULTS: During the first cycle, diarrhea occurred in 78.9% of patients in the Standard cohort and 97.1% in the Postbio one, with most cases being G1-G2. Severe (G3) diarrhea was significantly less frequent in the Postbio group (0%) compared to the Standard one (7.9%; P = .029). Over the entire study period, while the grading difference was not statistically significant, G3 events were less frequent in the Postbio population (5.9%) than the Standard one (15.4%). Moreover, Postbio patients required fewer dose reductions due to diarrhea compared to the Standard group (P = .002). Notably, in the Postbio population, G1 and G2 events had short median durations (3 and 1 days, respectively) and, for the 2 patients experiencing G3 events during the second abemaciclib cycle (off postbiotic), diarrhea lasted only 1 day. CONCLUSIONS: Our study demonstrates the effect of PostbiotiX-Restore in mitigating abemaciclib-induced diarrhea, resulting in reduced severity, fewer dose reductions, and shorter duration. Further exploration and validation in larger cohorts are needed.

Cyclin-dependent kinase 2 (CDK2) inhibitors and others novel CDK inhibitors (CDKi) in breast cancer: clinical trials, current impact, and future directions.

Aberrant cyclin-dependent kinase 2 (CDK2) activation has been identified as a main resistance mechanism to CDK4/6 inhibition in hormone-receptor positive (HR+) breast cancer. Additionally, consistent preclinical evidence states its crucial role in MYC and CCNE1 overexpressed cancer survival, such as triple-negative breast cancers (TNBC), thus representing an appealing and relatively unexplored target treatment opportunity. Despite emerging initial results of novel CDK2 inhibitors (CDK2i) activity, a comprehensive outcomes collection is currently absent from the scientific literature. We aim to provide an overview of ongoing clinical trials involving CDK2i in the context of metastatic breast cancer (mBC), either as monotherapy or in combination with other agents. The review extends beyond CDK2i to encompass novel emerging CDK4 inhibitors, combined CDK2/4/6 inhibitors, and the well-known pan-CDK inhibitors including those specifically directed at CDK2. Delving into the results, we critically appraise the observed clinical efficacy and offer valuable insights into their potential impact and future applications.

Ovarian Suppression: Early Menopause and Late Effects.

OPINION STATEMENT: Around 90% of breast tumours are diagnosed in the early stage, with approximately 70% being hormone receptor-positive. The cornerstone of adjuvant therapy for early-stage hormone receptor-positive breast cancer is endocrine therapy, tailored according to disease stage, biological characteristics of the tumour, patient's comorbidities, preferences and age. In premenopausal patients with hormone receptor-positive breast cancer, ovarian function suppression is a key component of the adjuvant endocrine treatment in combination with an aromatase inhibitor or tamoxifen. Moreover, it can be used during chemotherapy as a standard strategy for ovarian function preservation in all breast cancer subtypes. In the metastatic setting, ovarian function suppression should be used in all premenopausal patients with hormone receptor-positive breast cancer to achieve a post-menopausal status. Despite its efficacy, ovarian function suppression may lead to several side effects that can have a major negative impact on patients' quality of life if not properly managed (e.g. hot flashes, depression, cognitive impairment, osteoporosis, sexual dysfunction, weight gain). A deep knowledge of the side effects of ovarian function suppression is necessary for clinicians. A correct counselling in this regard and proactive management should be considered a fundamental part of survivorship care to improve treatment adherence and patients' quality of life.

Charting the Course in Sequencing Antibody-Drug Conjugates in Breast Cancer.

Based on the unprecedented results observed in recent clinical trials, antibody-drug conjugates (ADCs) have revolutionized the treatment algorithm of metastatic breast cancer (mBC). The strategy of sequencing different ADCs in other lines of therapy is highly attractive, but the proportion of patients who have undergone such a strategy in the context of published clinical trials is still limited, especially for modern ADCs. HER2-positive disease is primarily managed with a sequence of different ADCs. Historically, trastuzumab emtansine (T-DM1) has been the most commonly used ADC for both early and metastatic HER2-positive disease. Considering the recent evidence related to trastuzumab deruxtecan (T-DXd), it is expected to assume the role of the main ADC in our clinical practice. Herein, we report a retrospective analysis of the sequence of different ADCs relying on available published data from clinical trials.

The Impact of Initial Tumor Response on Survival Outcomes of Patients With HER2-Positive Advanced Breast Cancer Treated With Docetaxel, Trastuzumab, and Pertuzumab: An Exploratory Analysis of the CLEOPATRA Trial.

INTRODUCTION: The CLEOPATRA trial (NCT00567190) established a dual anti-HER2 blockade in combination with docetaxel as the first-line standard of care for patients with metastatic HER2-positive breast cancer. While this treatment is overall associated with significant improvement in progression-free survival (PFS) and overall survival (OS), not all patients respond equally. We hypothesized that a radiological complete response (CR) at week 9 (i.e., first disease re-evaluation) is associated with prolonged OS and PFS compared to radiological partial response (PR) or stable disease (SD). METHODS: We performed an exploratory analysis of the CLEOPATRA study to address this question. RESULTS: Out of 362 patients treated with docetaxel, trastuzumab, and pertuzumab eligible for our analysis, 46 (12.7%) had radiological CR at week 9, 243 (67.1%) PR, and 73 (20.2%) SD per central RECIST v1.0. Radiological CR at first tumor re-evaluation was associated with a 60% risk reduction for death compared to SD (adjusted HR = 0.40 95% confidence interval (CI) 0.23-0.70), whereas no significant impact on survival was observed for PR (adjusted HR = 0.85 95% CI 0.60-1.20). The same was observed for PFS with adjusted HR = 0.30 (95% CI 0.18-0.48) for the CR subgroup and adjusted HR = 0.81 (95% CI 0.60-1.09) for the PR subgroup. In multivariate analysis, no variables were associated with radiological CR. CONCLUSIONS: Our findings suggest that radiological CR at first disease re-evaluation is associated with more prolonged survival; this might result from stronger dependence on HER2 pathway addiction, supporting the need for further translational research.

Ribociclib-Induced Cutaneous Adverse Events in Metastatic HR+/HER2- Breast Cancer: Incidence, Multidisciplinary Management, and Prognostic Implication.

BACKGROUND: Ribociclib is approved for hormone receptor positive (HR+), human epidermal growth factor receptor 2 negative (HER2-) advanced breast cancer (ABC) treatment, in combination with endocrine therapy. Hematological, hepatic, and cardiac adverse events (AEs) emerged from pivotal trials, but little is known about cutaneous adverse events (CAEs). PATIENTS AND METHODS: We report data from a retrospective cohort study of all patients with HR+/HER2- ABC treated with ribociclib at Humanitas Cancer Center between June 2017 and December 2022. We recorded clinical-pathological data, the incidence, and treatment of ribociclib-related CAEs. These were evaluated according to the NCI-CTCAE v5.0 classification. Progression-free survival (PFS) was estimated by Kaplan-Meier method and the log-rank test was used to analyze differences between groups. RESULTS: Thirteen of 91 patients (14.3%) experienced treatment-related CAEs (mean time to the occurrence: 3.9 months). The most frequent CAEs were eczematous dermatitis (53.8%) and maculo-papular reaction (15.4%). Itch was reported by all 13 patients. The grade was G3 in 8 cases, G2 in 4, and G1 in 1. An integrated approach based on ribociclib dose modulation and dermatological interventions (oral antihistamine, moisturized cream, topical, and/or systemic steroids) could prevent ribociclib discontinuation in most patients. At a median follow-up of 20 months, the median PFS was 13 months (range, 1-66) with a better PFS curves for patients experiencing CAEs (P = .04). CONCLUSION: We mapped frequency and types of ribociclib-induced CAEs. An interdisciplinary management of CAEs incorporated into routine care may reduce the rate of drug discontinuation thus potentially contributing to better long-term outcomes.

The Impact of Different Patterns of Residual Disease on Long-Term Oncological Outcomes in Breast Cancer Patients Treated with Neo-Adjuvant Chemotherapy.

BACKGROUNDS: The majority of breast cancer (BC) patients treated with neo-adjuvant chemotherapy (NAC) achieves a pathologic partial response with different patterns of residual disease. No clear correlation between these patterns and oncological results was described. Our aims were to define the predictive factors for different patterns of residual disease and compare the outcomes between the scattered versus the circumscribed pattern. METHODS: We reviewed 219 postoperative surgical specimens. Patients were divided into two groups: scattered versus circumscribed. Disease-free survival (DFS), distant DFS (DDFS), and overall survival (OS) were analyzed. RESULTS: The scattered and circumscribed patterns were assessed in 111 (50.7%) and 108 (49.3%) patients. Two independent predictive factors for the circumscribed pattern were identified: discontinuation of NAC cycles (p = 0.011), and tumor size post-NAC >18 mm (p = 0.022). No difference was observed in terms of DFS and DDFS. Patients with the scattered pattern exhibited a statistically significant better OS. Discontinuation of NAC cycles, tumor size >18 mm, triple-negative BC, and ypN+ were associated with increased recurrence and poorer survival. CONCLUSIONS: Discontinuation of NAC cycles and tumor size are independent factors associated with patterns of residual disease. The scattered pattern presents better survival. Understanding the relationship between NAC, the residual pattern, and differences in survival outcomes offers the potential to optimize the therapeutic approaches.

Progression-free survival assessment by local investigators versus blinded independent central review in randomized clinical trials in metastatic breast cancer: A systematic review and meta-analysis.

INTRODUCTION: In randomized clinical trials (RCTs), blinded independent central review (BICR) is used to minimize heterogeneity and bias associated with radiological response evaluation by local investigators. However, BICR adds costs and complexity to the trial management. We assessed the discrepancy index between progression-free survival (PFS) assessment by local investigators and by BICR in RCTs conducted in patients with metastatic breast cancer (MBC). METHODS: A systematic search of PubMed, Embase, Cochrane databases and conference proceedings (ASCO, SABCS, ESMO) was performed up to January 4, 2023 (PROSPERO: CRD42021229865). All RCTs published from 2000 to 2022, including MBC patients treated in first- or second-line, and reporting PFS assessed by local investigators and BICR were included. A discrepancy index between BICR-assessed and investigator-assessed HR was calculated for each trial and an overall combined DI was obtained using a fixed-effects model. The agreement between hazard ratios (HR) of PFS assessed by local investigators and BICR was measured using intraclass correlation coefficient (ICC). RESULTS: We analyzed 24 studies including 13,168 patients. Among them, 19 (79%) were in first-line, 18 (75%) were phase III trials and 23 (96%) had PFS as primary endpoint. The overall combined discrepancy index was 0.97 (95%CI 0.85-1.10; ICC 0.831, p < 0.001) suggesting no statistically significant difference in PFS assessment between local investigators and BICR. This result was consistent across all analyzed subgroups. CONCLUSIONS: The good concordance between local investigator and BICR assessments supports the reliability of local investigator-assessed PFS as primary endpoint for RCTs in MBC and questions the practical utility of implementing BICR in all RCTs.

Peripheral blood lymphocytes predict clinical outcomes in hormone receptor-positive HER2-negative advanced breast cancer patients treated with CDK4/6 inhibitors.

Background: Cyclin-Dependent Kinase 4/6 inhibitors (CDK4/6i) combined with Endocrine Therapy (ET) are the standard treatment for patients with Hormone Receptor-positive/HER2-negative advanced breast cancer (HR+/HER2- aBC). Objectives: While CDK4/6i are known to reduce several peripheral blood cells, such as neutrophils, lymphocytes and platelets, the impact of these modulations on clinical outcomes is unknown. Design: A multicenter, retrospective-prospective Italian study. Methods: We investigated the association between baseline peripheral blood cells, or their early modifications (i.e. 2 weeks after treatment initiation), and the progression-free survival (PFS) of HR+/HER2- aBC patients treated with ETs plus CDK4/6i. Random Forest models were used to select covariates associated with patient PFS among a large list of patient- and tumor-related variables. Results: We evaluated 638 HR+/HER2- aBC patients treated with ET plus CDK4/6i at six Italian Institutions between January 2017 and May 2021. High baseline lymphocyte counts were independently associated with longer PFS [median PFS (mPFS) 20.1 versus 13.2 months in high versus low lymphocyte patients, respectively; adjusted Hazard Ratio (aHR): 0.78; 95% confidence interval (CI): 0.66-0.92; p = 0.0144]. Moreover, patients experiencing a lower early reduction of lymphocyte counts had significantly longer PFS when compared to patients undergoing higher lymphocyte decrease (mPFS 18.1 versus 14.5 months; aHR: 0.82; 95% CI: 0.73-0.93; p = 0.0037). Patients with high baseline lymphocytes and undergoing a lower reduction, or even an increase, of lymphocyte counts during CDK4/6i therapy experienced the longest PFS, while patients with lower baseline lymphocytes and undergoing a higher decrease of lymphocytes had the lowest PFS (mPFS 21.4 versus 11 months, respectively). Conclusion: Baseline and on-treatment modifications of peripheral blood lymphocytes have independent prognostic value in HR+/HER2- aBC patients. This study supports the implementation of clinical strategies to boost antitumor immunity in patients with HR+/HER2- aBC treated with ETs plus CDK4/6i.

Opportunities and Challenges of Synthetic Data Generation in Oncology.

Widespread interest in artificial intelligence (AI) in health care has focused mainly on deductive systems that analyze available real-world data to discover patterns not otherwise visible. Generative adversarial network, a new type of inductive AI, has recently evolved to generate high-fidelity virtual synthetic data (SD) trained on relatively limited real-world information. The AI system is fed with a collection of real data, and it learns to generate new augmented data while maintaining the general characteristics of the original data set. The use of SD to enhance clinical research and protect patient privacy has drawn a lot of interest in medicine and in the complex field of oncology. This article summarizes the main characteristics of this innovative technology and critically discusses how it can be used to accelerate data access for secondary purposes, providing an overview of the opportunities and challenges of SD generation for clinical cancer research and health care.

Real-world clinical outcomes of patients with stage I HER2-positive breast cancer treated with adjuvant paclitaxel and trastuzumab.

Up to 20% of breast cancer overexpress HER2 protein, making it a reliable target for antibody-based treatments. In early HER2-positive breast cancer avoiding anthracycline-based chemotherapy is a challenge. Based on the single-arm phase II APT trial results, adjuvant paclitaxel/trastuzumab is an accepted regimen for patients with stage I HER2-positive disease. In our retrospective study of 240 patients, the median tumor size was 12.0 mm (IQR 9 -15), and 204 (85%) had estrogen receptor-positive disease. After a median follow-up of 4.6 years, 3-year real-world disease-free survival, distant DFS, and overall survival were 98.8% (95% confidence interval (CI), 96.2-99.6), 99.2% (95% CI, 96.7-99.8), and 98.3% (95% CI, 96.2-99.6), respectively. In a real-world setting, an adjuvant paclitaxel/trastuzumab regimen was associated with low recurrence rates among women with stage I, HER2-positive breast cancer. Additionally, we reviewed other treatment optimization strategies attempted or ongoing in HER2-positive breast cancer.

Unlocking the Potential of Circulating miRNAs in the Breast Cancer Neoadjuvant Setting: A Systematic Review and Meta-Analysis.

The potential role of circulating microRNAs (miRNAs) as biomarkers in breast cancer (BC) management has been widely reported. However, the numerous discrepancies between studies in this regard hinders the implementation of circulating miRNAs in routine clinical practice. In the context of BC patients undergoing neoadjuvant chemotherapy (NAC), the possibility of predicting NAC response may lead to prognostic improvements by individualizing post-neoadjuvant therapy. In this context, the present meta-analysis aims to clarify circulating miRNAs' predictive role with respect to NAC response among BC patients. We conducted a comprehensive literature search on five medical databases until 16 February 2023. We pooled the effect sizes of each study by applying a random-effects model. Cochran's Q test (p-level of significance set at 0.05) scores and I2 values were assessed to determine between-study heterogeneity. The PROBAST (Prediction Model Risk of Bias Assessment Tool) tool was used to evaluate the selected studies' risk of bias. Overall, our findings support the hypothesis that circulating miRNAs, specifically miR-21-5p and miR-155-5p, may act as predictive biomarkers in the neoadjuvant setting among BC patients. However, due to the limited number of studies included in this meta-analysis and the high degrees of clinical and statistical heterogeneity, further research is required to confirm the predictive power of circulating miR-21-5p and miR-155-5p.

Hope and Hype around Immunotherapy in Triple-Negative Breast Cancer.

Triple-negative breast cancer (TNBC) holds a poor prognosis compared to other breast cancer subtypes, and the development of new effective treatment strategies is an unmet medical need. TNBC has traditionally been considered not amenable to treatment with targeted agents due to a lack of actionable targets. Therefore, chemotherapy has remained the mainstay of systemic treatment for many decades. The advent of immunotherapy raised very hopeful expectations in TNBC, possibly due to higher levels of tumor-infiltrating lymphocytes, PD-L1 expression and tumor mutational burden compared to other breast cancer subtypes, that predict an effective anti-tumor immune-engagement. The results of clinical trials testing immunotherapy in TNBC led to the approval of the combination of immune checkpoint inhibitors and chemotherapy in both early and advanced settings. However, some open questions about the use of immunotherapy in TNBC still exist. These include a deeper understanding of the heterogeneity of the disease, identification of reliable predictive biomarkers of response, determination of the most appropriate chemotherapy backbone and appropriate management of potential long-term immune-related adverse events. In this review we aim to examine the available evidence on the use of immunotherapy strategies in both early and advanced TNBC, to critically discuss some of the limitations encountered in clinical research and to summarize data on novel promising immunotherapeutic strategies beyond PD-(L)1 blockade that have been investigated in the most recent trials.

Clinical Review on the Management of Breast Cancer Visceral Crisis.

Visceral crisis is a life-threatening clinical condition requiring urgent treatment and accounts for 10-15% of new advanced breast cancer diagnoses, mainly hormone receptor-positive/human epidermal growth factor 2 negative. As its clinical definition is an open topic with nebulous criteria and much room for subjective interpretation, it poses a challenge for daily clinical practice. International guidelines recommend combined chemotherapy as first-line treatment for patients with visceral crisis, but with modest results and a very poor prognosis. Visceral crisis has always been a common exclusion criterion in breast cancer trials, and the available evidence mainly comes from limited retrospective studies which are not sufficient to draw solid conclusions. The outstanding efficacy of innovative drugs, such as CDK4/6 inhibitors, questions the role of chemotherapy in this setting. In the lack of clinical reviews, we aim to critically discuss the management of visceral crisis, advocating future treatment perspectives for this challenging condition.

Prognostic significance of HER2-low status in HR-positive/HER2-negative advanced breast cancer treated with CDK4/6 inhibitors.

Whether Human Epidermal growth factor Receptor 2 (HER2)-low status has prognostic significance in HR + /HER2- advanced Breast Cancer (aBC) patients treated with first-line Endocrine Therapy plus CDK 4/6 inhibitors remains unclear. In 428 patients evaluated, HER2-low status was independently associated with significantly worse PFS and OS when compared with HER2-0 status. Based on our findings, HER2-low status could become a new prognostic biomarker in this clinical setting.

HR+/HER2- de novo metastatic breast cancer: a true peculiar entity?

De novo metastatic breast cancer (dnMBC) accounts for ~6-10% of all breast cancers and for ~30% of MBC with increasing incidence over time. Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) tumours are the most frequent subtype with a similar incidence to that observed amongst recurrent MBC (rMBC). Higher frequency of PI3KCA and ARID2 mutations and a lower frequency of ESR1 mutations and of genes involved in DNA damage, as compared with rMBC, have been reported in HR+/HER2- dnMBC; however, these are not correlating with prognosis, whilst tumour mutational burden is inversely correlated with outcome. Bone represents the most frequent metastatic site, being the single site in up to 60% of patients with dnMBC. HR+/HER2- dnMBC has been generally reported to have better outcomes than rMBC, with a median overall survival ranging from 26 months to nearly 5 years in patients with favourable features such as age <40 years and bone-only disease, but not when compared with patients with late recurring disease (≥2-5 years). Analyses of the de novo cohorts within randomized clinical trials and large real-world series report a better outcome after treatment with CDK4/6 inhibitors and endocrine agents as compared to rMBC. Despite the limitations of retrospective studies and controversial results of the randomized trials, locoregional treatment of the primary tumour after response to systemic therapy appears to confer a survival benefit, particularly in patients with favourable prognostic factors. Altogether genomic, biological and clinical findings highlight HR+/HER2- dnMBC as a peculiar entity as compared with rMBC and deserve a dedicated treatment algorithm. This article is part of the Tackling clinical complexity in breast cancer Special Issue: https://www.drugsincontext.com/special_issues/tackling-clinical-complexity-in-breast-cancer/.

Pathologic response and residual tumor cellularity after neo-adjuvant chemotherapy predict prognosis in breast cancer patients.

INTRODUCTION: Residual tumor cellularity (RTC) and pathologic complete response (pCR) after neo-adjuvant chemotherapy (NAC) are prognostic factors associated with improved outcomes in breast cancer (BC). However, the majority of patients achieve partial pathologic response (pPR) and no clear correlation between RTC patterns and outcomes was described. Our aims were to define predictive factors for pCR and compare different outcomes of patients with pCR or pPR and with different RTC patterns. MATERIALS AND METHODS: Baseline and post-NAC demographics, clinicopathological characteristics, post-operative data, survival and recurrence status were recorded from our institutional database. A multivariable analysis was performed using a logistic regression model to identify independent predictors of pCR. Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) analyses were performed using the Kaplan-Meier method. RESULTS: Overall, of the 495 patients analyzed, 148 (29.9%) achieved pCR, 347 (70.1%) had pPR, and the median RTC was 40%. Multivariable analysis identified 3 independent factors predictive of pCR: tumor stage before NAC (cT1-2 84.5% versus cT3-4 15.5%), BC sub-type (HER2-positive 54.7% versus triple-negative 29.8% versus luminal-like 15.5%), and vascular invasion (absence 98.0% versus presence 2.0%). We found statistically significant longer DFS, DDFS, and OS in patients with pCR and with RTC <40%; no difference was observed in terms of OS between RTC <40% and RTC ≥40% groups. CONCLUSIONS: Tumor stage before NAC, BC sub-type, and vascular invasion are significant and independent factors associated with pCR. Patients with pCR and with RTC <40% have longer DFS, DDFS, and OS compared with patients with pPR.

Sticking to the Rules: Outcome and Success Rate of Guideline-Based Diarrhea Management in Metastatic Breast Cancer Patients Treated with Abemaciclib.

In clinical trials testing abemaciclib in patients with hormone-receptor-positive (HR+), HER2-negative (HER2-) advanced breast cancer, diarrhea is a very common adverse event (occurring in approximately 85% of patients, any grade). Nonetheless, this toxicity leads to abemaciclib discontinuation in a small proportion of patients (approximately 2%) thanks to the use of effective loperamide-based supportive therapy. We aimed to determine whether the incidence of abemaciclib-induced diarrhea in real-world trials was higher than the one reported in clinical trials, where patients are highly selected, and to evaluate the success rate of standard supportive care in this setting. We conducted a retrospective, observational, monocentric study including 39 consecutive patients with HR+/HER2- advanced breast cancer treated with abemaciclib and endocrine therapy at our institution from July 2019 to May 2021. Overall, diarrhea of any grade occurred in 36 patients (92%), of whom 6 (17%) had diarrhea of grade ≥3. In 30 patients (77%), diarrhea was associated with other adverse events, including fatigue (33%), neutropenia (33%), emesis (28%), abdominal pain (20%), and hepatotoxicity (13%). Loperamide-based supportive therapy was administered to 26 patients (72%). Abemaciclib dose was reduced in 12 patients (31%) due to diarrhea, and treatment was permanently discontinued in 4 patients (10%). In 58% of patients (15/26), diarrhea was effectively managed with supportive care and did not require abemaciclib dose reduction and/or discontinuation. In our real-world analysis, we observed a higher incidence of diarrhea related to abemaciclib compared to data from clinical trials, and a higher rate of permanent treatment discontinuation due to gastrointestinal toxicity. Better implementation of guideline-based supportive care could help to manage this toxicity.

Potential Role of Circulating miRNAs for Breast Cancer Management in the Neoadjuvant Setting: A Road to Pave.

Recently, circulating microRNAs (miRNAs) have emerged as potential non-invasive biomarkers for breast cancer (BC) management. In the context of BC patients undergoing neoadjuvant chemotherapy (NAC), the possibility of obtaining repeated, non-invasive biological samples from patients before, during, and after treatment is incredibly convenient and provides the opportunity to investigate circulating miRNAs as diagnostic, predictive, and prognostic tools. The present review aims to summarize major findings in this setting, thus highlighting their potential applicability in daily clinical practice and their possible limitations. In all the contexts (diagnostic, predictive, and prognostic), circulating miR-21-5p and miR-34a-5p have emerged as the most promising non-invasive biomarkers for BC patients undergoing NAC. Specifically, their high baseline level could discriminate between BC patients and healthy controls. On the other hand, in predictive and prognostic investigations, low circulating miR-21-5p and miR-34a-5p levels may identify patients with better outcomes, in terms of both treatment response and invasive disease-free survival. However, the findings in this field have been very heterogeneous. Indeed, pre-analytical and analytical variables, as well as factors related to patients, may explain the inconsistency among different study results. Thus, further clinical trials, with more precise patient inclusion criteria and more standardized methodological approaches, are definitely needed to better define the potential role of these promising non-invasive biomarkers.

Sentinel Lymph Node Biopsy in Breast Cancer Patients Undergoing Neo-Adjuvant Chemotherapy: Clinical Experience with Node-Negative and Node-Positive Disease Prior to Systemic Therapy.

BACKGROUND: Sentinel lymph node biopsy (SLNB) has emerged as the standard procedure to replace axillary lymph node dissection (ALND) in breast cancer (BC) patients undergoing neo-adjuvant chemotherapy (NAC). SLNB is accepted in clinically node-negative (cN0) patients; however, its role in clinically node-positive (cN+) patients is debatable. METHODS: We performed a retrospective analysis of BC patients undergoing NAC and SLNB. Our aim was to evaluate the clinical significance of SLNB in the setting of NAC. This was accomplished by comparing the characteristics and oncological outcomes between cN0 and cN+ patients prior to NAC and type of axillary surgery. RESULTS: A total of 291 patients were included in the analysis: 131 were cN0 and 160 were cN+ who became ycN0 after NAC. At a median follow-up of 43 months, axillary recurrence occurred in three cN0 (2.3%) and two cN+ (1.3%) patients. However, there were no statistically significant differences in oncological outcomes (disease-free survival, distant disease-free survival, overall survival, and breast-cancer-specific survival) between cN0 and cN+ patients nor between patients treated with SLNB only or ALND. CONCLUSIONS: SLNB in the setting of NAC is an acceptable procedure with a general good prognosis and low axillary failure rates for both cN0 and cN+ patients.