Francesca Romana Di Pietro

The sexist behaviour of immune checkpoint inhibitors in cancer therapy

Background Immune checkpoint inhibitors, targeting the molecules CTLA-4, PD-1 and PD-L1, showed efficacy against several type of cancers and are currently used in clinical practice. An important biological variable that influences innate and adaptive immunity is the sex, acting through genetic, hormonal and environmental factors. The overall differences between sexes could be crucial to evaluate the response to ICIs. Materials and methods We performed a meta-analysis of Phase II-III Clinical Trials published up to June 2017 in which anti-CTLA-4, anti-PD-1 and anti-PD-L1 were studied. We extracted the OS and PFS HR differentiated by sex from subgroups analysis of each trial. We analyzed the three classes of drugs separately. Results We selected 36 Phase II-III Clinical Trials, 9 of which reported results for OS and 6 for PFS. We analyzed 2 Clinical Trials for OS with anti-CTLA-4, including 1178 patients, observing a benefit for males vs females (HR 0.65, 95% CI 0.55-0.77 vs HR 0.79, 95% CI 0.65-0.96, p 0.078). Not statistically significant results were observed with anti-PD-1 neither for OS (males vs females: HR 0.72, 95% CI 0.64-0.83 vs HR 0.81, 95% CI 0.70-0.94, p 0.285) neither for PFS (males vs females: HR 0.66, 95% CI 0.52-0.82 vs HR 0.85, 95% CI 0.66-1.09, p 0.158). We cannot perform a meta-analysis for anti-PD-L1 due to the lack of data. Conclusions Different mechanisms could be involved in sex differences with regard to immunotherapy. These differences could be relevant to identify immunological targets in order to draw studies exploring novel combinations of immunotherapy agents.

A nomogram to predict 5-fluorouracil toxicity: when pharmacogenomics meets the patient

Fluoropyrimidines combined with other agents are commonly used for gastrointestinal cancer treatment. Considering that severe toxicities occur in 30% of patients, we aimed to structure a nomogram to predict toxicity, based on metabolic parameter and patients’ characteristics. We retrospectively enrolled patients affected by gastrointestinal tract cancers. Pretreatment 5-fluorouracil (5-FU) degradation rate and DPYD, TSER, MTHFR A1298T, and C677T gene polymorphisms were characterized. Data on toxicities were collected according to CTCAE v3.0. Multivariate logistic regression analysis was used to structure a nomogram. 642 patients were enrolled (384 men; 258 female; median age: 67 years, range: 27–87): 449 (69.9%) patients were affected by colorectal cancer; 118 (18.4%) by gastroesophageal cancer; 66 (10.3%) by pancreatic cancer; and nine (1.4%) by other cancers. Grade 3–4 toxicities were observed in 118 (18.4%) patients and were most frequently observed in patients with altered 5-FU degradation rate (43.5 and 26.7% of the patients in the poor metabolizer and in the ultrarapid metabolizer group respectively, vs. 17% in the normal metabolizer group) and in DPYD heterozygous mutated patients (83.3% of the patients). Age, DPYD status, the number of drugs administered, and 5-FU degradation rate value were associated to severe toxicities. On the basis of these findings, we structured a nomogram to assess a score to predict the risk of developing severe toxicity. Compared with the available pharmacogenetic tests, this approach can be applied to the whole population, predicting the risk for severe toxicity, with an easy, low-cost, and not invasive technique.