The evolving role of microsatellite instability in colorectal cancer: A review

Microsatellite instability (MSI) is a molecular marker of a deficient mismatch repair (MMR) system and occurs in approximately 15% of colorectal cancers (CRCs), more frequently in early than late-stage of disease. While in sporadic cases (about two-thirds of MSI-H CRCs) MMR deficiency is caused by an epigenetic inactivation of MLH1 gene, the remainder are associated with Lynch syndrome, that is linked to a germ-line mutation of one of the MMR genes (MLH1, MSH2, MSH6, PMS2). MSI-H colorectal cancers have distinct clinical and pathological features such as proximal location, early-stage (predominantly stage II), poor differentiation, mucinous histology and association with BRAF mutations. In early-stage CRC, MSI can select a group of tumors with a better prognosis, while in metastatic disease it seems to confer a negative prognosis. Although with conflicting results, a large amount of preclinical and clinical evidence suggests a possible resistance to 5-FU in these tumors. The higher mutational load in MSI-H CRC can elicit an endogenous immune anti-tumor response, counterbalanced by the expression of immune inhibitory signals, such as PD-1 or PD-L1, that resist tumor elimination. Based on these considerations, MSI-H CRCs seem to be particularly responsive to immunotherapy, such as anti-PD-1, opening a new era in the treatment landscape for patients with metastatic CRC

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

Impact of anaemia on tumor response to neoadjuvant chemotherapy in breast cancer patients .

BACKGROUND - Pathological complete response (pCR) to neoadjuvant systemic therapy (NST) in patients with breast cancer (BC) predicts long-term outcomes. Anaemia is one of the most common side effects of cytotoxic drugs. Biologically, anaemia induces adaptive responses due to the low intra-tumoral oxygen levels that may be responsible for increase chemotherapy resistance. In literature, data regarding this issue are lacking. AIM - To evaluate the influence of anaemia throughout treatment course on tumour shrinkage induced by NST. METHODS - Patients - 317 patients diagnosed with stage I-III BC treated with NST and with available blood tests were included. Patients and tumor characteristics and treatments information were collected. We focused on Haemoglobin (Hb) level (at baseline, at the end of NST, drop in Hb throughout treatment and duration of anaemia) and its correlation with pCR rate. Anaemia was defined as a drop of Hb under the local limit of normal in women (12 mg/dl). Statistical analysis - Categorical variables were analyzed using chi-square test or Fisher's exact test, continuous variables using t test. Univariate and multivariate analyses were fit to determinate the association between anaemia and pCR rate. A p-value < 0.05 was considered statistically significant; hazard ratio was estimated with 95% of confidence limits. RESULTS- No difference in Hb levels was observed stratifying patients according to nuclear grade, tumor stage, cancer subtypes and chemotherapy regimens. Median baseline Hb was 13.3 g/dl while median Hb level at the end of NST was 10 g/dl. 31 patients had pre-treatment anaemia. 60% of patients developed anaemia during NST period. In the subgroup of anaemic patients, who had a decrease in Hb ≥ 2 g/dl from baseline or anaemia longer than two months, a lower rate of pCR was observed (16% vs 29%, p=0.03 and 16% vs 25%, p=0.01, respectively). Patients with both these characteristics had the lowest rate of pCR (10%, p=0.01). CONCLUSIONS - Anaemia is a negative predictive factor for tumor response in women treated with NST for BC. This evidence suggests that anaemia should be improved in order to improve response to NST

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

Mutational Profile of Metastatic Breast Cancer Tissue in Patients Treated with Exemestane Plus Everolimus

Background. Everolimus has been shown to overcome endocrine resistance in hormone receptor positive advanced breast cancer patients. Predictive biomarkers of everolimus efficacy have been investigated in primary breast cancer tissue without finding univocal results. The goal of this study was to investigate the mutational burden in the metastatic site of endocrine-resistant tumors treated with everolimus plus exemestane. Patients and Methods. Mass Array Sequenom platform was used to analyse genetic status of 18 cancer-related genes in 25 archival tumor specimens from metastatic lesions and available primary matched breast cancer tissue of patients treated with everolimus and exemestane for advanced disease. An exploratory analysis of everolimus efficacy in terms of progression free survival benefit and single gene mutation was carried out. Results. The overall detection rate of mutation was 30% and 38% from metastatic and primary breast cancer samples, respectively. was the most frequent mutated gene. No primary breast cancer and matched relapse maintained the same mutation profile. Considering molecular pathways, the most of the genes belong to PI3K pathway (, , and ). In patients with detected mutations in breast and/or recurrence tissue the median PFS was 5,6 months while in the subgroup of patients with no mutations the median PFS was 7,5 months. Conclusions. The mutational status of breast cancer recurrence allows the identification of some genes potentially correlating tumor response/resistance to everolimus. The most frequently mutated genes were involved in the PI3K/AKT/mTOR pathway highlighting that the deregulation of this pathway in the relapse plays a crucial role in the mechanisms of everolimus resistance/sensitivity. Owing to the small sample size and the retrospective nature of the study, these correlations need to be validated in a large prospective study

GD2 expression in breast cancer.

Breast cancer (BC) is a heterogeneous disease, including different subtypes having diverse incidence, drug-sensitivity and survival rates. In particular, claudin-low and basal-like BC have mesenchymal features with a dismal prognosis. Disialoganglioside GD2 is a typical neuroectodermal antigen expressed in a variety of cancers. Despite its potential relevance in cancer diagnostics and therapeutics, the presence and role of GD2 require further investigation, especially in BC. Therefore, we evaluated GD2 expression in a cohort of BC patients and its correlation with clinical-pathological features.Sixty-three patients with BC who underwent surgery without prior chemo- and/or radiotherapy between 2001 and 2014 were considered. Cancer specimens were analyzed by immunohistochemistry and GD2-staining was expressed according to the percentage of positive cells and by a semi-quantitative scoring system.Patient characteristics were heterogeneous by age at diagnosis, histotype, grading, tumor size, Ki-67 and receptor-status. GD2 staining revealed positive cancer cells in 59% of patients. Among them, 26 cases (41%) were labeled with score 1+ and 11 (18%) with score 2+. Notably, the majority of metaplastic carcinoma specimens stained positive for GD2. The univariate regression logistic analysis revealed a significant association of GD2 with triple-receptor negative phenotype and older age (> 78) at diagnosis.We demonstrate for the first time that GD2 is highly prevalent in a cohort of BC patients clustering on very aggressive BC subtypes, such as triple-negative and metaplastic variants

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