The Predictive Role of Radiomics in Breast Cancer Patients Imaged by [18F]FDG PET: Preliminary Results from a Prospective Cohort.

BACKGROUND: Recently, radiomics has emerged as a possible image-derived biomarker, predominantly stemming from retrospective analyses. We aimed to prospectively assess the predictive role of [18F]FDG-PET radiomics in breast cancer (BC). METHODS: Patients affected by stage I-III BC eligible for neoadjuvant chemotherapy (NAC) staged with [18F]FDG-PET/CT were prospectively enrolled. The pathological response to NAC was assessed on surgical specimens. From each primary breast lesion, we extracted radiomic PET features and their predictive role with respect to pCR was assessed. Uni- and multivariate statistics were used for inference; principal component analysis (PCA) was used for dimensionality reduction. RESULTS: We analysed 93 patients (53 HER2+ and 40 triple-negative (TNBC)). pCR was achieved in 44/93 cases (24/53 HER2+ and 20/40 TNBC). Age, molecular subtype, Ki67 percent, and stage could not predict pCR in multivariate analysis. In univariate analysis, 10 radiomic indices resulted in p < 0.1. We found that 3/22 radiomic principal components were discriminative for pCR. Using a cross-validation approach, radiomic principal components failed to discriminate pCR groups but predicted the stage (mean accuracy = 0.79 ± 0.08). CONCLUSIONS: This study shows the potential of PET radiomics for staging purposes in BC; the possible role of radiomics in predicting the pCR response to NAC in BC needs to be further investigated.

Empowering beyond Pain: Pain Neuroscience Education Interventions in Breast Cancer Survivorship Care.

Chronic pain is a common consequence of breast cancer (BC) and its treatments. Pain neuroscience education (PNE) is a non-pharmacological intervention that adopts a biopsychosocial approach and has already been proven to be effective for different chronic pain syndromes. The present review aims to critically assess clinical trials comparing the efficacy of PNE to traditional biomedical education (BME) in reducing BC-related pain and improving quality of life. We conducted a literature search in scientific databases, including all studies regarding PNE use specifically for BC-related pain. Ongoing randomized controlled and observational studies were identified from ClinicalTrials.gov and congress proceedings. A total of eight clinical trials met the review criteria. The participants were all administered physical therapy and assigned to receive either BME or PNE interventions. Among the completed clinical studies, one reported no statistically relevant differences between the two groups, whereas the other showed lower levels of pain-related indexes in the PNE population compared to the BME one. While the current literature is inconclusive regarding the effectiveness of PNE for managing BC pain, we strongly support the need for further trials, as PNE could empower BC patients in both prevention of and coping with pain, offering the advantage of having no side effects.

Empowerment, Pain Control, and Quality of Life Improvement in Early Triple-Negative Breast Cancer Patients through Pain Neuroscience Education: A Prospective Cohort Pilot Study Protocol (EMPOWER Trial).

The treatment of early triple-negative breast cancer (eTNBC) has improved patients' prognosis but often leads to adverse events and sequelae affecting quality of life (QoL). Pain Neuroscience Education (PNE) is a promising non-pharmacological intervention in this field. Preliminary data have shown the beneficial effect of PNE in BC survivors. However, there are still gaps in knowledge regarding its optimal use in eTNBC. To address this issue, a prospective pilot study will enroll 30 consecutive patients diagnosed with eTNBC at IRCCS Humanitas Research Hospital. The PNE program will consist of 10 weekly sessions to be started within 4 weeks of the onset or worsening of a pain syndrome (PS). QoL, pain, and disability will be assessed before, during, at the end of, and 6 months after PNE using validated questionnaires. Peripheral venous blood samples will be taken before and at the end of PNE to evaluate inflammatory serum biomarker levels. The primary objective is to evaluate whether PNE leads to clinical improvement in QoL and pain. If successful, it will be validated in a larger multi-centric cohort, potentially leading to its widespread implementation as a standard pain management tool for eTNBC patients.

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.

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.

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.

Identification of a Panel of miRNAs Associated with Resistance to Palbociclib and Endocrine Therapy.

We investigated whether we could identify a panel of miRNAs associated with response to treatment in tumor tissues of patients with Hormone Receptor-positive/HER2-negative metastatic breast cancer treated with endocrine therapy (ET) and the CDK4/6 inhibitor (CDK4/6i)i palbociclib. In total, 52 patients were evaluated, with 41 receiving treatment as the first line. The overall median PFS was 20.8 months (range 2.5-66.6). In total, 23% of patients experienced early progression (<6 months). Seven miRNAs (miR-378e, miR-1233, miR-99b-5p, miR-1260b, miR-448, -miR-1252-5p, miR-324-3p, miR-1233-3p) showed a statistically significant negative association with PFS. When we considered PFS < 6 months, miR-378e, miR-99b-5p, miR-877-5p, miR-1297, miR-455-5p, and miR-4536-5p were statistically associated with a poor outcome. In the multivariate analysis, the first three miRNAs confirmed a significant and independent impact on PFS. The literature data and bioinformatic tools provide an underlying molecular rationale for most of these miRNAs, mainly involving the PI3K/AKT/mTOR pathway and cell-cycle machinery as cyclin D1, CDKN1B, and protein p27Kip1 and autophagy. Our findings propose a novel panel of miRNAs associated with a higher likelihood of early progression in patients treated with ET and Palbociclib and may contribute to shed some light on the mechanisms of de novo resistance to CDK4/6i, but this should be considered exploratory and evaluated in larger cohorts.

Real-world use of multigene signatures in early breast cancer: differences to clinical trials.

PURPOSE: In Italy, Lombardy was the first region to reimburse multigene assays (MGAs) for patients otherwise candidates for chemotherapy. This is a real-world experience of MGAs usage in six referral cancer centers in Lombardy. METHODS: Among MGAs, Oncotype DX (RS) was used in 97% of cases. Consecutive patients tested with Oncotype DX from July 2020 to July 2022 were selected. The distribution of clinicopathologic features by RS groups (low RS: 0-25, high RS: 26-100) was assessed using chi-square and compared with those of the TAILORx and RxPONDER trials. RESULTS: Out of 1,098 patients identified, 73% had low RS. Grade and Ki67 were associated with RS (p < 0.001). In patients with both G3 and Ki67 > 30%, 39% had low RS, while in patients with both G1 and Ki67 < 20%, 7% had high RS. The proportion of low RS in node-positive patients was similar to that in RxPONDER (82% vs 83%), while node-negative patients with low RS were significantly less than in TAILORx (66% vs 86%, p < 0.001). The distribution of Grade was different from registration trials, with more G3 and fewer G1 (38% and 3%) than in TAILORx (18% and 27%) and RxPONDER (10% and 24%) (p < 0.001). Patients ≤ 50 years were overrepresented in this series (41%) than in TAILORx and RxPONDER (31% and 24%, respectively) (p < 0.001) and, among them, 42% were node positive. CONCLUSIONS: In this real-world series, Oncotype DX was the test almost exclusively used. Despite reimbursement being linked to pre-test chemotherapy recommendation, almost 3/4 patients resulted in the low-RS group. The significant proportion of node-positive patients ≤ 50 years tested indicates that oncologists considered Oncotype DX informative also in this population.

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.

Common Misconceptions about Diet and Breast Cancer: An Unclear Issue to Dispel.

Breast cancer (BC) constitutes a prevalent health condition among women. Recent years have witnessed the identification of dietary proto-oncogenic factors that deserve attention. Besides the well-known role of alcohol and red and processed meat in BC development, the impact of other dietary components remains unclear. Our narrative review aims to explore the diet-BC relationship, focusing on sugar, dairy, and soy consumption. We conducted a PubMed literature search covering the last decade (2013-2023) and included 35 papers. We found limited evidence on the association between high sugar intake and BC incidence. On the other hand, dairy and soy consumption displayed a protective effect in the majority of the analyzed papers. However, a significant degree of heterogeneity was reported among the results. Menopausal status and the specific BC molecular subtypes were the main factors influencing the interpretation of the results. Exploring dietary factors and BC revealed inconsistencies: high glycemic index post-menopause may be a risk factor, while sugar-sweetened drinks and artificial sweeteners yielded conflicting results; fermented dairy showed potential benefits, non-fermented dairy presented inconsistent findings; soy impact on BC varied according to molecular subtype, with some studies suggesting a positive association in luminal-like BC. Hence, further investigation is crucial to obtain a uniform consensus on the diet-BC relationship.

Extracellular nicotinamide phosphoribosyltransferase (eNAMPT) neutralization counteracts T cell immune evasion in breast cancer.

BACKGROUND: Nicotinamide phosphoribosyltransferase (NAMPT) is a key intracellular enzyme that participates in nicotinamide adenine dinucleotide (NAD) homeostasis as well as a released cytokine (eNAMPT) that is elevated in inflammatory conditions and in cancer. In patients with breast cancer, circulating eNAMPT is elevated and its plasma levels correlate with prognosis and staging. In light of this, we investigated the contribution of eNAMPT in triple negative mammary carcinoma progression by investigating the effect of its neutralization via a specific neutralizing monoclonal antibody (C269). METHODS: We used female BALB/c mice injected with 4T1 clone 5 cells and female C57BL6 injected with EO771 cells, evaluating tumoral size, spleen weight and number of metastases. We injected two times a week the anti-eNAMPT neutralizing antibody and we sacrificed the mice after 28 days. Harvested tumors were analyzed by histopathology, flow cytometry, western blot, immunohistochemistry, immunofluorescence and RNA sequencing to define tumor characteristics (isolating tumor infiltrating lymphocytes and tumoral cells) and to investigate the molecular mechanisms behind the observed phenotype. Moreover, we dissected the functional relationship between T cells and tumoral cells using three-dimensional (3D) co-cultures. RESULTS: The neutralization of eNAMPT with C269 led to decreased tumor size and reduced number of lung metastases. RNA sequencing and functional assays showed that eNAMPT controlled T-cell response via the programmed death-ligand 1/programmed cell death protein 1 (PD-L1/PD-1) axis and its neutralization led to a restoration of antitumoral immune responses. In particular, eNAMPT neutralization was able to activate CD8+IFNγ+GrzB+ T cells, reducing the immunosuppressive phenotype of T regulatory cells. CONCLUSIONS: These studies indicate for the first time eNAMPT as a novel immunotherapeutic target for triple negative breast cancer.

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.

Imaging Correlates between Headache and Breast Cancer: An [18F]FDG PET Study.

This study aimed to examine brain metabolic patterns on [18F]Fluorodeoxyglucose ([18F]FDG) positron emission tomography (PET) in breast cancer (BC), comparing patients with tension-type headache (TTH), migraine (MiG), and those without headache. Further association with BC response to neoadjuvant chemotherapy (NAC) was explored. In this prospective study, BC patients eligible for NAC performed total-body [18F]FDG PET/CT with a dedicated brain scan. A voxel-wise analysis (two-sample t-test) and a multiple regression model were used to compare brain metabolic patterns among TTH, MiG, and no-headache patients and to correlate them with clinical covariates. A single-subject analysis compared each patient's brain uptake before and after NAC with a healthy control group. Primary headache was diagnosed in 39/46 of BC patients (39% TTH and 46% MiG). TTH patients exhibited hypometabolism in specific brain regions before NAC. TTH patients with a pathological complete response (pCR) to NAC showed hypermetabolic brain regions in the anterior medial frontal cortex. The correlation between tumor uptake and brain metabolism varied before and after NAC, suggesting an inverse relationship. Additionally, the single-subject analysis revealed that hypometabolic brain regions were not present after NAC. Primary headache, especially MiG, was associated with a better response to NAC. These findings suggest complex interactions between BC, headache, and hormonal status, warranting further investigation in larger prospective cohorts.

A Prognostic Model Based on Residual Cancer Burden and Tumor-Infiltrating Lymphocytes on Residual Disease after Neoadjuvant Therapy in HER2+ Breast Cancer.

PURPOSE: We aim to evaluate the prognostic significance of tumor-infiltrating lymphocyte on residual disease (RD-TIL) in HER2+ patients with breast cancer who failed to achieve pathologic complete response (pCR) after anti-HER2+ chemotherapy (CT)-based neoadjuvant treatment (NAT). We assessed the feasibility of combining the prognostic information provided by residual cancer burden (RCB) and RD-TILs into a composite score (RCB+TIL). EXPERIMENTAL DESIGN: HER2+ patients with breast cancer treated with CT+anti-HER2-based NAT at three institutions were retrospectively included. RCB and TIL levels were evaluated on hematoxylin and eosin-stained slides from surgical samples according to available recommendations. Overall survival (OS) was used as an outcome measure. RESULTS: A total of 295 patients were included, of whom 195 had RD. RCB was significantly associated with OS. Higher RD-TILs were significantly associated with poorer OS as compared with lower RD-TILs (15% cutoff). In multivariate analysis, both RCB and RD-TIL maintained their independent prognostic value. A combined score, RCB+TIL, was calculated from the estimated coefficient of RD-TILs and the RCB index in a bivariate logistic model for OS. The RCB+TIL score was significantly associated with OS. The C-index for OS of the RCB+TIL score was numerically higher than that of RCB and significantly higher than that of RD-TILs. CONCLUSIONS: We have reported an independent prognostic impact of RD-TILs after anti-HER2+CT NAT, which might underlie an imbalance of the RD microenvironment towards immunosuppressive features. We provided a new composite prognostic score based on RCB+TIL, which was significantly associated with OS and proved to be more informative than the isolated evaluation of RCB and RD-TILs.

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.

The Role of Female Reproductive Hormones in the Association between Migraine and Breast Cancer: An Unanswered Question.

Accumulating epidemiological studies have investigated a possible interconnection between migraine (Mi) and breast cancer (BC) because of the strong link between these diseases and female reproductive hormones. This review aims to consolidate findings from epidemiological studies and explore biologically plausible hypothetical mechanisms related to hormonal pathways. Current evidence suggests a protective role of Mi in BC development, particularly in case-control studies but not in cohort ones. The inconsistency among studies may be due to several reasons, including diagnostic criteria for Mi and the age gap between the development of these two diseases. Furthermore, recent research has challenged the concept of a net beneficial effect of Mi on BC, suggesting a more complex relationship between the two conditions. Many polymorphisms/mutations in hormone-related pathways are involved in at least one of the two conditions. The most promising evidence has emerged for a specific alteration in the estrogen receptor 1 gene (rs2228480). However, the possible specific mutation or polymorphism involved in this association has not yet been identified. Further studies with robust methodologies are needed to validate the protective role of Mi in BC and fully elucidate the precise nature of this causal relationship.

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.

Profiling the Spectrum of Headache Disorders on 440 Breast Cancer Patients: Highlights on Clinical and Pathological Mechanisms.

Although widely studied, the association between migraines (M) and breast cancer (BC) risk remains evasive. In this prospective single-center study, 440 early or locally advanced BC patients were enrolled at IRCCS Humanitas Research Hospital. Clinical and demographical data were collected. Those who suffered from headaches were evaluated with the International Classification of Headache Disorders. M was found to be significantly more prevalent in BC patients: 56.1% versus an expected prevalence of 17% in the global population. M patients showed a higher risk of having stage II or III BC than stage I, which was more frequently found in the non-headache population. Interestingly, the frequency of headache attacks was positively correlated with estrogen (r = 0.11, p = 0.05) and progesterone (r = 0.15, p = 0.007) expression, especially in patients with migraine without aura. The higher the expression of hormone receptors in BC, the higher the headache frequency. Moreover, patients suffering from headaches showed an overall earlier onset of BC. Our findings challenge the idea of a net preventive role of M on BC, suggesting a rather complex interaction in which M mostly influences some BC subtypes and vice versa. Further multi-center studies with extended follow-up are needed.

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.

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.