Beyond Microsatellite Instability: Evolving Strategies Integrating Immunotherapy for Microsatellite Stable Colorectal Cancer.

OPINION STATEMENT: Advanced colorectal cancer (CRC) is a heterogeneous disease, characterized by several subtypes with distinctive genetic and epigenetic patterns. During the last years, immune checkpoint inhibitors (ICIs) have revamped the standard of care of several tumors such as non-small cell lung cancer and melanoma, highlighting the role of immune cells in tumor microenvironment (TME) and their impact on cancer progression and treatment efficacy. An "immunoscore," based on the percentage of two lymphocyte populations both at tumor core and invasive margin, has been shown to improve prediction of treatment outcome when added to UICC-TNM classification. To date, pembrolizumab, an anti-programmed death protein 1 (PD1) inhibitor, has gained approval as first-line therapy for mismatch-repair-deficient (dMMR) and microsatellite instability-high (MSI-H) advanced CRC. On the other hand, no reports of efficacy have been presented in mismatch-repair-proficient (pMMR) and microsatellite instability-low (MSI-L) or microsatellite stable (MSS) CRC. This group includes roughly 95% of all advanced CRC, and standard chemotherapy, in addition to anti-EGFR or anti-angiogenesis drugs, still represents first treatment choice. Hopefully, deeper understanding of CRC immune landscape and of the impact of specific genetic and epigenetic alterations on tumor immunogenicity might lead to the development of new drug combination strategies to overcome ICIs resistance in pMMR CRC, thus paving the way for immunotherapy even in this subgroup.

Prospective observational study of taste assay in patients with solid tumors treated with standard chemotherapy (POTATO).

PURPOSE: The aim of our study is to evaluate taste changes in patients affected by solid tumors not involving oral cavity within the first month of standard chemotherapy. METHODS: In this monocentric, prospective, cohort study, we enrolled patients treated at our institution for different types of solid tumors between February and July 2019. Taste cotton swabs assay was used to assess taste changes. RESULTS: Thirty-one patients were enrolled and most of them had at least one change in taste. The taste that changed less was acid (42% of the population) whereas the one that changed the most was the perception of sweet (reduced in 35% of the population and increased in 45% of the population) and sour (reduced in 35% of the population). We did not find any statistical significant difference in terms of changes of taste and type of chemotherapy (emetogenic vs not, p > 0.05 for salty, sweet, bitter, and acid tastes). The type of primary tumor (breast vs GI-related) had a significant impact on perception of both salty (p = 0.0163) and acid (p = 0.0312) flavor. Furthermore, body mass composition assessed by BIA showed that obese patients had different changes in acid flavor vs non-obese patients (p = 0.04). This could not be proven when the assessment was made using BMI calculation. CONCLUSIONS: Our study suggests that type of primary tumor (GI vs breast) more than type of chemotherapy used could be relevant in determining changes in taste during chemotherapy. Individualized dietary strategies based on these reported data are suggested, as to optimize patients' management.

Effects of Eribulin on the RNA Content of Extracellular Vesicles Released by Metastatic Breast Cancer Cells.

Extracellular vesicles (EVs) are small lipid particles secreted by almost all human cells into the extracellular space. They perform the essential function of cell-to-cell communication, and their role in promoting breast cancer progression has been well demonstrated. It is known that EVs released by triple-negative and highly aggressive MDA-MB-231 breast cancer cells treated with paclitaxel, a microtubule-targeting agent (MTA), promoted chemoresistance in EV-recipient cells. Here, we studied the RNA content of EVs produced by the same MDA-MB-231 breast cancer cells treated with another MTA, eribulin mesylate. In particular, we analyzed the expression of different RNA species, including mRNAs, lncRNAs, miRNAs, snoRNAs, piRNAs and tRNA fragments by RNA-seq. Then, we performed differential expression analysis, weighted gene co-expression network analysis (WGCNA), functional enrichment analysis, and miRNA-target identification. Our findings demonstrate the possible involvement of EVs from eribulin-treated cells in the spread of chemoresistance, prompting the design of strategies that selectively target tumor EVs.

Rising incidence of late stage breast cancer after COVID-19 outbreak. Real-world data from the Italian COVID-DELAY study.

PURPOSE: Breast cancer (BC) patients' (pts) management was affected by a global reorganization after Coronavirus disease 2019 (COVID-19). Our multicenter study aimed to assess the impact of COVID-19 on access to diagnosis, staging and treatment for BC pts compared to pre-pandemic. METHODS: Medical records of all consecutive newly diagnosed BC pts referred to 6 Italian Institutions between March and December 2020 were assessed. Monthly access rate and temporal intervals between date of symptoms onset, radiological, cytohistological diagnosis and treatment start were analyzed and compared with 2019. RESULTS: A reduction (25%) in newly diagnosed BC was observed compared to 2019 (666 vs 890). New BC pts in 2020 were less likely to be diagnosed with early stage BC (77% vs 83%, p < 0.01), had a worse performance status according to the Eastern Cooperative Oncology Group (ECOG PS) (19.8% had PS > 0 in 2020 vs 16.5% in 2019, p < 0.01) and fewer pts were asymptomatic at diagnosis in 2020 (54% vs 71%,p < 0.01). COVID-19 did not negatively impact in terms of access to diagnosis, staging and treatment. Time intervals between symptom onset and radiological diagnosis, symptom onset and cytohistological diagnosis, cytohistological diagnosis and treatment start were maintained or improved. However, less cases were discussed in multidisciplinary tumor meetings during 2020 (60% vs 73%, p < 0.01). CONCLUSIONS: Our data proved an alarming reduction of early stage BC associated with the COVID-19 crisis in 2020. Despite the upheaval generated by the pandemic, our study shed light on the effective performance delivered by Italian Oncology Departments to guarantee diagnostic-therapeutic pathways.

Prognostic Impact of Ki-67 Change in Locally Advanced and Early Breast Cancer after Neoadjuvant Chemotherapy: A Single Institution Experience.

Systemic neoadjuvant chemotherapy (NCT) is a standard treatment for locally advanced breast cancer (LABC) and for selected early breast cancer (EBC). In these settings, the prognostic and predictive role of Ki-67 before and after NCT is unclear. The aim of our study was to investigate the prognostic role of Ki-67 change in patients not achieving pathological complete response (pCR). We retrospectively analyzed data of patients who did not achieve pCR assessing Ki-67 expression pre- and post-NCT. We stratified three groups: high reduction (>20%), low reduction (1-20%), and no reduction in Ki-67. These groups were correlated with clinical and pathological data by χ2 test. We estimated disease-free survival (DFS) and overall survival (OS) using Kaplan-Meier method, and we adopted univariate and multivariate Cox proportional hazard models. We selected 82 patients from a database of 143 patients, excluding those who were metastatic at diagnosis, achieved pCR, or lack data regarding Ki-67. Median age at diagnosis was 54 years (range 30-75); 51 patients were Luminal B, 10 human epidermal growth factor receptor 2 (HER-2) enriched, and 21 triple negative. A significant correlation between high Ki-67 reduction and luminal B HER-2-negative subtype was observed (p = 0,0035). The change in Ki-67 was significantly associated with DFS (p = 0,0596) and OS (p = 0,0120), also at multivariate analysis (p = 0,0256 for DFS; p = 0,0093 for OS). In particular, as compared to patients with low/no reduction of Ki-67, those with high Ki-67 reduction (>20%) after NCT showed better survival (60% vs. 56% vs. 83% after 5 years from diagnosis, respectively; p = 0.01). In conclusion, in our study, Ki-67 change showed a significant prognostic role in breast cancer patients treated with NCT who did not achieve pCR. Crucially, Ki-67 < 20% identifies a high-risk population that may be eligible for clinical trials with novel therapeutic interventions in adjuvant setting.

Seminoma Retroperitoneal Relapse 23 Years After Surgery.

Stage I seminoma is the most frequent tumour in young men. It has a very good prognosis thanks to the use of a multidisciplinary therapeutic approach including surgery, radiotherapy and systemic chemotherapy. Late (after 2 years) and very late (after 5 years) relapses are uncommon, but not impossible, even if standardized follow-up for testicular tumours lasts up to 5 years after the diagnosis. We report a case of a 67-year-old Caucasian man with metachronous bilateral testicular seminoma who developed a retroperitoneal relapse of testicular seminoma 23 years after the first orchiectomy. Based on histological confirmation of testicular relapse, the patient underwent four cycles of systemic chemotherapy with bleomycin, etoposide and cisplatin (PEB), with no adverse reactions. He subsequently achieved complete radiological response at restaging computed tomography imaging, confirmed by the absence of glucose metabolism on positron emission tomography. In conclusion, this case report suggests the importance of longer standardized follow-up for patients treated for testicular tumours in order to detect earlier recurrence, which can be successfully treated.

Retrospective Comparative Analysis of KRAS G12C vs. Other KRAS Mutations in mCRC Patients Treated With First-Line Chemotherapy Doublet + Bevacizumab.

BACKGROUND: KRAS mutations in metastatic colorectal cancer (mCRC) define a subset of tumors that have primary resistance to anti-EGFR-based therapy. Data concerning whether different KRAS mutations may also have a prognostic value are lacking. Furthermore, novel KRAS G12C inhibitors are currently in development. The aim of our analysis was to compare response rates in patients treated with first-line chemotherapy doublet + Bevacizumab among different KRAS variants. Secondary end-points were progression free survival (PFS) and overall survival (OS). METHODS: Patients with KRAS mutated mCRC treated with either FOLFIRI/FOLFOX/XELOX + Bevacizumab were eligible for enrollment. Patients whose tumor harbored NRAS mutations or that coexpressed also BRAF mutations were excluded from this retrospective analysis. Patients' individual data were collected from patients' records. Propensity score matching (nearest method, 1:2 ratio) was used to define the two different groups of patients for comparison (KRAS G12C mutated vs other KRAS variants). Eastern Cooperative Oncology Group Performance Status (ECOG PS), sex, metastatic site of involvement, synchronous vs metachronous metastatic disease, tumor sidedness, mucinous histology, primary tumor surgery, more than two lines of treatment for metastatic disease, and radical surgery of metastases were used as matching factors. Response rate (RR) was calculated by RECIST 1.1 criteria. Both progression free-survival and overall survival were calculated by Kaplan-Meier method. Categorical variables were compared by Fisher exact test for binomial variables and by chi-square test for all other instances. The level of statistical significance p was set at 0.05 for all tests. RESULTS: A total of 120 patients were assessed in the final analysis. Out of the 120 patients, 15 (12%) were KRAS G12C mutated. In the whole cohort of patients, 59/120 (49%) had partial response (PR), 42/120 (35%) had stable disease (SD), and 19/120 (16%) had progressive disease (PD) as the best response. In KRAS G12C patients, 4/15 (27%) had PR, 6/15 (40%) had SD, and the remaining 5/15 (33%) had PD as the best response. In patients with other KRAS mutations, 55/105 (52%) had PR, 37/105 (35%) had SD, and the remaining 13/105 (12%) had PD as the best response. The difference in RR between the two groups of patients was statistically significant (p=0.017). On the other hand, no difference in PFS (p=0.76) and OS (p=0.56) was observed. After matching procedures, the difference in response rates between KRAS G12C mutated patients vs the matched cohort of patients with other KRAS mutations remained statistically significant (p=0.016). KRAS G12C mutations were not associated with differences in sites of metastatic involvement, sex, and ECOG PS. On the other hand, synchronous vs metachronous metastatic disease (p=0.039), age > 75 years (p=0.043), and mucinous histology (p=0.008) were more frequent in G12C mutated tumors. CONCLUSIONS: In our cohort of patients, it was observed that KRAS G12C mutations are associated with worse response rates compared to other KRAS variants when treated with standard chemotherapy doublet + Bevacizumab. On the other hand, both PFS and OS were not significantly different. Based on these findings, we believe that new treatment options focused on KRAS G12C inhibition should be tested mainly in first-line setting and in addition to standard chemotherapy doublet + Bevacizumab for mCRC patients, as they might "fill the gap" in response rates that was seen in our study.

Retrospective Cohort Study of Caveolin-1 Expression as Prognostic Factor in Unresectable Locally Advanced or Metastatic Pancreatic Cancer Patients.

Caveolin-1 (Cav-1) plays a key role in various neoplastic diseases and is upregulated in different cancers, including pancreatic ductal adenocarcinoma (PDAC). Furthermore, Cav-1 is critical for the uptake of albumin as well as nab-paclitaxel in PDAC cells. Here, we investigated the prognostic impact of Cav-1 expression in a cohort of 39 metastatic PDAC patients treated with different first-line chemotherapy regimens. We also assessed the predictive value of Cav-1 in patients treated with gemcitabine and nab-paclitaxel. Cav-1 expression was evaluated by immunohistochemistry staining in neoplastic and stromal cells, using metastatic sites or primary tumor tissue specimens. Higher levels of Cav-1 expression were associated with significantly worse overall survival (OS) and progression-free survival (PFS). No differences in OS were found between patients treated with gemcitabine + nab-paclitaxel vs. other chemotherapy options. Multivariate analysis for OS and PFS confirmed the independent prognostic role of Cav-1 expression. Our study evidenced a negative prognostic role of Cav-1 in patients affected by metastatic/locally advanced unresectable PDAC. Moreover, Cav-1 expression seems not to predict different response rates to different types of first-line treatment. Future prospective trials will be necessary to confirm the prognostic role of Cav-1 and explore Cav-1 specific inhibitors as a therapeutic option for advanced PDAC patients.

The Impact of Lifestyle Interventions in High-Risk Early Breast Cancer Patients: A Modeling Approach from a Single Institution Experience.

A healthy lifestyle plays a strategic role in the prevention of BC. The aim of our prospective study is to evaluate the effects of a lifestyle interventions program based on special exercise and nutrition education on weight, psycho-physical well-being, blood lipid and hormonal profile among BC patients who underwent primary surgery. From January 2014 to March 2017, a multidisciplinary group of oncologists, dieticians, physiatrists and an exercise specialist evaluated 98 adult BC female patients at baseline and at different time points. The patients had at least one of the following risk factors: BMI ≥ 25 kg/m2, high testosterone levels, high serum insulin levels or diagnosis of MS. Statistically significant differences are shown in terms of BMI variation with the lifestyle interventions program, as well as in waist circumference and blood glucose, insulin and testosterone levels. Moreover, a statistically significant difference was reported in variations of total Hospital Anxiety and Depression Scale (HADS) score, in the anxiety HADS score and improvement in joint pain. Our results suggested that promoting a healthy lifestyle in clinical practice reduces risk factors involved in BC recurrence and ensures psycho-physical well-being.

Systemic immune-inflammation index: a prognostic tiebreaker among all in advanced pancreatic cancer.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) detains a dismal prognosis and has a limited number of prognostic factors. Inflammation has been demonstrated to play a key role both in PDAC initiation and progression and several inflammation-based prognostic scores have been investigated in a wide range of malignancies. We compared the most analyzed inflammation-based prognostic scores in order to establish their potential impact on prediction of the outcome in advanced PDAC patients. METHODS: A total of 234 advanced PDAC patients undergoing first-line chemotherapy in our institute were retrospectively analyzed. Baseline clinicopathological and pre-treatment laboratory data were collected. Survival was estimated using Kaplan-Meier method and survival differences were evaluated using the log-rank test. Level of statistical significance P was set at 0.05. Only those variables that proved to be associated with statistically significant differences in outcome were compared in multivariate analysis using multiple Cox regression, as to identify their independent role and their relative power against each other. RESULTS: In the whole cohort, median overall survival (OS) was 8.7 months (95% CI: 7.8-9.4 months), median progression-free survival (PFS) was 3.8 months (95% CI: 3.1-4.2 months). At univariate analysis high systemic immune-inflammation index (SII) was related to shorter OS [hazard ratio (HR) =2.04, 95% CI: 1.59-4.19, P=0.0001] and PFS (HR =1.52, 95% CI: 1.11-2.20, P=0.01). This was maintained at multivariate analysis both for OS (HR =2.11, 95% CI: 1.29-3.46, P=0.003) and PFS (HR =1.64, 95% CI: 1.14-2.37, P=0.008), whereas other inflammation-based scores lost their independent role. Elevated SII (≥1,200) was associated with low albumin levels (P=0.03) and with elevated lactate dehydrogenase (LDH) (P=0.01). CONCLUSIONS: Elevated SII represents an independent negative prognostic factor above all others for both OS and PFS in advanced PDAC patients treated with first-line chemotherapy, thus confirming a pivotal role of systemic inflammation on PDAC progression and on patient outcome.

Impact of Polypharmacy for Chronic Ailments in Colon Cancer Patients: A Review Focused on Drug Repurposing.

Colorectal cancer is characterized by high incidence worldwide. Despite increased awareness and early diagnosis thanks to screening programmes, mortality remains high, particularly for patients with metastatic involvement. Immune checkpoint inhibitors or poly (ADP-ribose) polymerase (PARP)-inhibitors have met with disappointing results when used in this setting, opposed to other malignancies. New drugs with different mechanisms of action are needed in this disease. Drug repurposing might offer new therapeutic options, as patients with metastatic colorectal cancer often share risk factors for other chronic diseases and thus frequently are on incidental therapy with these drugs. The aim of this review is to summarise the published results of the activity of drugs used to treat chronic medications in patients affected by colorectal cancer. We focused on antihypertensive drugs, Non-Steroid Anti-inflammatory Drugs (NSAIDs), metformin, antidepressants, statins and antibacterial antibiotics. Our review shows that there are promising results with beta blockers, statins and metformin, whereas data concerning antidepressants and antibacterial antibiotics seem to show a potentially harmful effect. It is hoped that further prospective trials that take into account the role of these drugs as anticancer medications are conducted.