Clinical Prognosticators in Patients Treated with CDK 4/6 Inhibitors for Hormone Receptors Positive Advanced Breast Cancer

Background: CDK4/6 inhibitors are the new standard of care in hormonal receptors positive (HR+) advanced breast cancer (ABC). Phase III trials demonstrated an improvement in survival outcomes in patients with combined endocrine approach compared to endocrine therapy (ET) alone. The aim of this retrospective study was to assess prognostic factors for clinical response to CDK4/6 inhibitors. Methods: All patients receiving CDK4/6 inhibitors from September 2016 to July 2019 were registered in a database. Data on tumor and patient\u2019s characteristics as well as concomitant medications were collected. Survival data were analyzed by Kaplan Meier curves and log rank test. Treatment toxicities were graded according to CTCAE v5. A drug-drug interactions analysis among CDK 4/6 inhibitors and co-administered medications was performed too. Results: 121 patients were included in the study: 49% of patients treated in 1st -line, 25% in 2nd -line and 26% in 3rd \u2013or further lines. 1st-line objective response rate (ORR) and clinical benefit rate (CBR) was 56% and 68%, compared to 40% and 50% in 2nd-line and 31% and 47% in heavily pre-treated patients, respectively. Median PFS according to line setting was: not reached in 1st-line, 17 months (95% CI 13-21) in 2nd-line and 7 months (95% CI 4-12) in 3rd or further lines. Negative prognostic factors in term of PFS were: previous chemotherapy for metastatic disease (p=0.0001), visceral metastatic sites (p=0.002) and endocrine sensitivity (p=0.001). No association among concomitant drugs administered and survival outcome was found. 94% of patients experienced neutropenia (G3-G4 60%) with 3% of febrile neutropenia. 71% of patients treated with Abemaciclib had diarrhea. Management of AE included 63% of treatment delay, 44% of 1st dose reduction and 15% of 2nd dose reduction, all due to neutropenia. No treatment discontinuation due to any toxicity was observed. Conclusion: Data on efficacy and safety profile of CDK 4/6 inhibitors administered outside the context of a clinical trial are consistent with those reported in Phase III trials. Previous chemotherapy for metastatic disease, visceral metastatic site as well as previous endocrine sensitivity negatively affect CDK 4/6 inhibitors efficacy. Concomitant medications did not affect survival outcome or safety profile

Circulating and Intracellular miRNAs as Prognostic and Predictive Factors in HER2-Positive Early Breast Cancer Treated with Neoadjuvant Chemotherapy: A Review of the Literature

SIMPLE SUMMARY: Breast cancer is a leading cause of female cancer-related death worldwide. Anti-HER2-targeted therapies dramatically improved prognosis for HER2-positive breast cancer patients. Despite that, growing drug resistance due to the pressure of therapy is relatively frequent. For that reason, it is necessary to find biomarkers able to predict treatment sensitivity and survival outcomes. Increasing research has shown how miRNAs, secreted by tumor cells, are strongly involved in cancer development. In this review, we will discuss the recent evidence on the predictive and prognostic value of miRNAs involved in HER2-positive early breast cancer progression. ABSTRACT: MicroRNAs (miRNA) are small noncoding RNAs that can act as both oncogene and tumor suppressors. Deregulated miRNA expression has been detected in human cancers, including breast cancer (BC). Considering their important roles in tumorigenesis, miRNAs have been investigated as potential prognostic and diagnostic biomarkers. Neoadjuvant setting is an optimal model to investigate in vivo the mechanism of treatment resistance. In the management of human epidermal growth factor receptor-2 (HER2)-positive early BC, the anti-HER2-targeted therapies have drastically changed the survival outcomes. Despite this, growing drug resistance due to the pressure of therapy is relatively frequent. In the present review, we focused on the main miRNAs involved in HER2-positive BC tumorigenesis and discussed the recent evidence on their predictive and prognostic value

Clinical and Pathological Features of Breast Cancer in Systemic Sclerosis: Results from the Sclero-Breast Study

Systemic Sclerosis (SSc) is a chronic disease associated with a 1.5-fold increase in cancer risk, including lung cancer, hematological malignancies, and breast cancer (BC). This is a retrospective study aiming to explore the clinical and pathological features of BC developed by SSc patients. A total of 54.5% of patients developed BC before SSc (median interval: 5 years), whereas 45.5% of patients developed BC after SSc (median delay: 8 years). A total of 93.1% of patients were diagnosed with an early stage tumor. Among invasive carcinomas, 70.8% presented with a low Mib1, 8.3% with a tubular histotype, and 42.8% with a Luminal A-like phenotype. A total of 66.6% of patients underwent breast-conserving surgery and 55.5% RT. A total of 40% of patients developed interstitial lung disease after RT and 20% diffuse cutaneous SSc. The cause of death of the six deceased patients was PAH. A significant association was observed between the use of immunosuppressive therapy and diffuse skin extension, negative ACA, positive Anti-Scl-70, and interstitial lung disease, but not BC status. SSc patients developed BC at a good prognosis, suggesting a de-escalation strategy of cancer therapies. In particular, ionizing radiation and chemotherapeuticals should be limited to higher-risk cases. Finally, proper screening is mandatory in order to allow for early cancer detection in SSc patients

CLINICAL AND PATHOLOGICAL FEATURES OF BREAST CANCER IN PATIENTS WITH SYSTEMIC SCLEROSIS: PRELIMINARY DATA FROM THE SCLERO-BREAST STUDY

Systemic Sclerosis (SSc) is a chronic disease associated with a 1.5-fold increase in cancer risk, including lung cancer, hematological malignancies, and breast cancer (BC). This is a retrospective study aiming to explore the clinical and pathological features of BC developed by SSc patients. A total of 54.5% of patients developed BC before SSc (median interval: 5 years), whereas 45.5% of patients developed BC after SSc (median delay: 8 years). A total of 93.1% of patients were diagnosed with an early stage tumor. Among invasive carcinomas, 70.8% presented with a low Mib1, 8.3% with a tubular histotype, and 42.8% with a Luminal A-like phenotype. A total of 66.6% of patients underwent breast-conserving surgery and 55.5% RT. A total of 40% of patients developed interstitial lung disease after RT and 20% diffuse cutaneous SSc. The cause of death of the six deceased patients was PAH. A significant association was observed between the use of immunosuppressive therapy and diffuse skin extension, negative ACA, positive Anti-Scl-70, and interstitial lung disease, but not BC status. SSc patients developed BC at a good prognosis, suggesting a de-escalation strategy of cancer therapies. In particular, ionizing radiation and chemotherapeuticals should be limited to higher-risk cases. Finally, proper screening is mandatory in order to allow for early cancer detection in SSc patients

Endocrine-based targeted combination versus endocrine therapy alone as first-line treatment in elderly patients with hormone receptor-positive advanced breast cancer: Meta-analysis of phase II and III randomized clinical trials.

Background: Combined endocrine approaches have been widely investigated as 1st-line treatment in hormone receptors positive metastatic breast cancer. In particular, multiple randomized trials showed that the addiction of CDK (cyclindependent kinase) 4/6 inhibitors to endocrine therapy (ET) increase progression free survival (PFS). Elderly patients (aged ≥ 65 years) are under represented in most of the clinical studies. Moreover, due to the multi-morbidity and the major toxicity associated with the targeted agents, the combination strategy in that subgroup is widely discussed. The present metaanalysis aimed to understand the role of the new endocrine approaches in women aged ≥65 years. Methods: This metaanalysis included first line phase II/III randomized published trials comparing (ET) to the experimental strategy. Trials with no data about hazard ratios (HR) for PFS in the subgroup of patients aged ≥ 65 years were excluded. The heterogeneity of the data was evaluated by Chi-square Q test and I2 statistic. Results: 8 studies were included in the analysis. 4 trials (Paloma1/TRIO-18, Paloma2, Monaleesa2, Monarch3) investigated the role of CDK 4/6 inhibitors, 2 trials (SWOG and FACT) analysed the combination of Fulvestrant plus Aromatase Inhibitors, while other two trials explored the association of ET with Bevacizumab (LEA) and Temsirolimus (HORIZON), respectively. Overall, the meta-analysis showed a PFS advantage for the experimental arms [HR 0.77, p 0.016] with a significant high/moderate heterogeneity [I2 65.46%, p 0.005]. The 4 studies adding CDK4/6 inhibitors to ET showed a significant improvement in PFS compared to ET alone. No significant advantages for the addition of anti-angiogenic agents or Fulvestrant to ET have been found in elderly population subgroup. Conclusions: The novel experimental combo-strategies in the first line setting showed an improvement in PFS in the subgroup of elderly patients. Adding CDK4/6 inhibitors to ET significantly prolongs PFS as compared to ET alone. The magnitude of PFS benefit due to addition of CDK4/6 inhibitors to ET is age-independent

Molecular Pathways of Breast Cancer in Systemic Sclerosis: Exploratory Immunohistochemical Analysis from the Sclero-Breast Study

Several authors reported an increased risk of cancer in SSc patients, including breast cancer (BC). Nevertheless, the mechanisms underlying this association have not yet been clarified. SSc and BC share several molecular pathways, which seem to play a common etiopathogenetic role. The previously published Sclero-Breast study demonstrated the development of BC with a good prognosis among these patients, which could be explained by an autoimmune background as a possible mechanism for limiting tumor extension. Here, we report the results of an IHC analysis of molecular pathways known to be common drivers for both diseases, with the aim to better define the mechanisms underlying a good prognosis of BC in patients affected by SSc. The analysis demonstrated higher TILs rates in all BC subgroups, with a high rate of PD-L1 expression especially in TNBC and HER2-positive BC, suggesting a less aggressive behavior in these patients compared to the general population. These results support a possible de-escalation strategy of cancer therapies in these fragile patients. These data could represent a starting point for future prospective studies based on the clinical application of these biomarkers with a larger sample size to promote a personalized and targeted oncological treatment for this specific subset of patients

Dissecting Tumor Growth: The Role of Cancer Stem Cells in Drug Resistance and Recurrence

Emerging evidence suggests that a small subpopulation of cancer stem cells (CSCs) is responsible for initiation, progression, and metastasis cascade in tumors. CSCs share characteristics with normal stem cells, i.e., self-renewal and differentiation potential, suggesting that they can drive cancer progression. Consequently, targeting CSCs to prevent tumor growth or regrowth might offer a chance to lead the fight against cancer. CSCs create their niche, a specific area within tissue with a unique microenvironment that sustains their vital functions. Interactions between CSCs and their niches play a critical role in regulating CSCs’ self-renewal and tumorigenesis. Differences observed in the frequency of CSCs, due to the phenotypic plasticity of many cancer cells, remain a challenge in cancer therapeutics, since CSCs can modulate their transcriptional activities into a more stem-like state to protect themselves from destruction. This plasticity represents an essential step for future therapeutic approaches. Regarding self-renewal, CSCs are modulated by the same molecular pathways found in normal stem cells, such as Wnt/β-catenin signaling, Notch signaling, and Hedgehog signaling. Another key characteristic of CSCs is their resistance to standard chemotherapy and radiotherapy treatments, due to their capacity to rest in a quiescent state. This review will analyze the primary mechanisms involved in CSC tumorigenesis, with particular attention to the roles of CSCs in tumor progression in benign and malignant diseases; and will examine future perspectives on the identification of new markers to better control tumorigenesis, as well as dissecting the metastasis process

Impact of body composition parameters on tumor response to neoadjuvant chemotherapy in operable breast cancer patients.

Fat tissue promotes cancer progression by increasing cell proliferation, cell survival and metastatic processes. Adipose tissue determines a dysregulation of several metabolic pathways by a continuous crosstalk between fat tissue and cancer cells. Moreover, influence of adipose tissue on cancer development depend on the type of fat too BMI cannot account for differences in fat distribution and cannot distinguish between adipose tissue and muscles Computed tomography (CT) imaging can be a useful tool for a directly measure of body fat distribution distinguishing among visceral, subcutaneous, internal fat tissue (mostly in the liver) and skeletal muscles mass. Patients treated with neoadjuvant chemotherapy for early BC at the Modena Cancer Center from 2005 to 2017 we collected. According to BMI score, patients were categorized in two main classes: normal weight (BMI < 25) and overweight (BMI ≥ 25) (Table 1) Using Advance workstation (General Electric), software ADW server 3.2 or 4.7. we calculated body composition parameters (BCPs) from pre-treated CT scan images. BCPs considered are: subcutaneous fat area (SFA, cm2), visceral fat area (VFA, cm2), lumbar muscle cross-sectional area (LMCA, m2) and liver steatosis (L/S ratio) BMI score and BCPs value were correlated with pathological complete response (pCR) and survival outcomes. All analyses were performed using STATA 14 (StataCorp. 2015. Stata Statistical Software: Release 14. College Station, TX: StataCorp LP). pre-treatment CT scan imagine available for BCPs analysis 55% of the women had BMI < 25 versus 45% with BMI >25 Overweight was significantly associated with postmenopausal status, older age and hormonal receptor positive BC (Table 1) Menopausal status was associated with higher VFA, presence of fatty liver disease and obesity disease compared to pre-menopausal one (Table 2). No association between BMI classes and pCR was detected. High VFA and liver steatosis were negative predictive factors for pCR (pCR rate: 35% normal VFA vs 20% high VFA, no steatosis 32% vs steatosis 13%; p<0.05) ( Figure 1) Neither BMI classes nor BCPs significantly influenced overall survival and relapse free survival. The evaluation of BCPs is the best way to assess the real body composition Menopausal status is associated with higher VFA, presence of fatty liver disease and obesity disease Visceral adiposity as well as liver steatosis were negative predictive factors for pCR in BC patients treated with neoadijuvant chemotherapy

Molecular Pathways of Breast Cancer in Systemic Sclerosis: Exploratory Immunohistochemical Analysis from the Sclero-Breast Study

Several authors reported an increased risk of cancer in SSc patients, including breast cancer (BC). Nevertheless, the mechanisms underlying this association have not yet been clarified. SSc and BC share several molecular pathways, which seem to play a common etiopathogenetic role. The previously published Sclero-Breast study demonstrated the development of BC with a good prognosis among these patients, which could be explained by an autoimmune background as a possible mechanism for limiting tumor extension. Here, we report the results of an IHC analysis of molecular pathways known to be common drivers for both diseases, with the aim to better define the mechanisms underlying a good prognosis of BC in patients affected by SSc. The analysis demonstrated higher TILs rates in all BC subgroups, with a high rate of PD-L1 expression especially in TNBC and HER2-positive BC, suggesting a less aggressive behavior in these patients compared to the general population. These results support a possible de-escalation strategy of cancer therapies in these fragile patients. These data could represent a starting point for future prospective studies based on the clinical application of these biomarkers with a larger sample size to promote a personalized and targeted oncological treatment for this specific subset of patients