Association Between TP53 Mutations and Platinum Resistance in a Cohort of High-Grade Serous Ovarian Cancer Patients: Novel Implications for Personalized Therapeutics

The integrity of p53 machinery is crucial for platinum activity, while p53 mutation is frequent in high-grade serous ovarian cancer (HGS-OC). This study aimed to evaluate the link between p53 mutations, platinum sensitivity (PS), and the platinum-free interval (PFI) in patients with HGS-OC. We prospectively analyzed 159 consecutive women with ovarian cancer who underwent surgery. The somatic mutational status of BRCA, HRD, and TP53 (according to structural, hotspot, and functional classification) was evaluated. Among enrolled patients, 82.4% of cases were TP53-mutated (MT), and 27.8% were BRCA-MT. The distribution of TP53 mutation categories did not differ significantly between the BRCA-MT and wild-type (WT) cases. In the entire population, the proportion of PS patients was significantly lower in TP53-MT compared to TP53-WT (p = 0.0208), in nonsense/frameshift/splicing compared to missense (p = 0.0319), and in loss-of-function (LOF) compared to GOF (p = 0.0048) MT cases. For the BRCA-MT patients, structural and functional TP53 mutations were not significantly different between the PS and PR patients. Conversely, for the BRCA WT patients, the distribution of structural and functional TP53 mutations significantly differed between PS and PR patients. In a multivariate regression analysis, LOF mutations were found to be independent negative predictors of PS (HR: 0.1717; 95% CI: 0.0661–0.4461; p-value: 0.0003). Kaplan–Meier curves showed a significantly lower PFI in cases with LOF mutations in the overall population (log-rank p = 0.0020) and in BRCA-WT patients (log-rank p = 0.0140). Via multivariate COX testing, it was found that LOF mutations were independently associated with a decreased PFI (p = 0.0036). In conclusion, our data show that HGS-OC harboring p53 LOF mutations is the poorest prognostic subgroup regarding PS and the PFI. Further studies are needed to confirm our findings

Colorectal Cancer Stage at Diagnosis Before vs During the COVID-19 Pandemic in Italy

IMPORTANCE Delays in screening programs and the reluctance of patients to seek medical attention because of the outbreak of SARS-CoV-2 could be associated with the risk of more advanced colorectal cancers at diagnosis. OBJECTIVE To evaluate whether the SARS-CoV-2 pandemic was associated with more advanced oncologic stage and change in clinical presentation for patients with colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS This retrospective, multicenter cohort study included all 17 938 adult patients who underwent surgery for colorectal cancer from March 1, 2020, to December 31, 2021 (pandemic period), and from January 1, 2018, to February 29, 2020 (prepandemic period), in 81 participating centers in Italy, including tertiary centers and community hospitals. Follow-up was 30 days from surgery. EXPOSURES Any type of surgical procedure for colorectal cancer, including explorative surgery, palliative procedures, and atypical or segmental resections. MAIN OUTCOMES AND MEASURES The primary outcome was advanced stage of colorectal cancer at diagnosis. Secondary outcomes were distant metastasis, T4 stage, aggressive biology (defined as cancer with at least 1 of the following characteristics: signet ring cells, mucinous tumor, budding, lymphovascular invasion, perineural invasion, and lymphangitis), stenotic lesion, emergency surgery, and palliative surgery. The independent association between the pandemic period and the outcomes was assessed using multivariate random-effects logistic regression, with hospital as the cluster variable. RESULTS A total of 17 938 patients (10 007 men [55.8%]; mean [SD] age, 70.6 [12.2] years) underwent surgery for colorectal cancer: 7796 (43.5%) during the pandemic period and 10 142 (56.5%) during the prepandemic period. Logistic regression indicated that the pandemic period was significantly associated with an increased rate of advanced-stage colorectal cancer (odds ratio [OR], 1.07; 95%CI, 1.01-1.13; P = .03), aggressive biology (OR, 1.32; 95%CI, 1.15-1.53; P < .001), and stenotic lesions (OR, 1.15; 95%CI, 1.01-1.31; P = .03). CONCLUSIONS AND RELEVANCE This cohort study suggests a significant association between the SARS-CoV-2 pandemic and the risk of a more advanced oncologic stage at diagnosis among patients undergoing surgery for colorectal cancer and might indicate a potential reduction of survival for these patients

Ovarian hyperstimulation in premenopausal women during adjuvant tamoxifen treatment for endocrine-dependent breast cancer: A report of two cases

Adjuvant endocrine therapy is an integral component of care for endocrine-dependent breast cancer. The aim of this type of therapy is to counteract the production and the action of estrogens. The ovary is the primary site of estrogen production in premenopausal women, whereas, in postmenopausal women, the main source of estrogens is adipose tissue. Therefore, ovarian function suppression is an effective adjuvant strategy in premenopausal estrogen-dependent breast cancer. Similarly, the inhibition of estrogen action at the receptor site by tamoxifen has proven to be effective. To date, international consensus statements recommend tamoxifen (20 mg/day) for five years as the standard adjuvant endocrine therapy for premenopausal women. It should be noted that tamoxifen is a potent inducer of ovarian function and consequent hyperestrogenism in premenopausal women. In the present study, we report two cases of ovarian cyst formation with very high estrogen levels and endometrial hyperplasia during the administration of tamoxifen alone as adjuvant treatment for estrogen receptor-positive breast cancer in premenopausal women. These cases suggest that in young premenopausal patients with estrogen-dependent breast cancer, ovarian suppression is an essential prerequisite for an adjuvant endocrine therapy with tamoxifen. In this context, luteinizing hormone-releasing hormone agonist treatment by suppressing effective ovarian function may lead to a hypoestrogenic status that may positively impact breast cancer prognosis and prevent the effects of tamoxifen at the gynecological level. It is important to reconsider the action of tamoxifen on ovarian function and include these specific effects of tamoxifen in the informed consent of premenopausal patients who are candidates for tamoxifen alone as adjuvant endocrine treatment

Muscle wasting as main evidence of energy impairment in cancer cachexia: future therapeutic approaches

The present review aimed at discussing the impact, pathogenesis and therapeutic approaches of muscle wasting, which is a major clinical feature of cancer-related cachexia syndrome. The pathogenesis of muscle wasting in cancer cachexia lies in a discrepancy between anabolic and catabolic pathways mediated by chronic inflammation. Effective interventions specifically aimed at hampering muscle loss and enhancing muscle function are still lacking. Promising agents include anti-inflammatory, orexigenic and anabolic drugs, alongside with nutritional supplements that influence the STAT3 and PI3K/Akt/mTOR pathways involved in muscle wasting. Personalized physical activity combined with pharmacological and nutritional support hold promise. A greater understanding of the pathogenetic processes of cancer cachexia-related muscle wasting will enable the development of an early and effective targeted mechanism-based multimodal approach

Role of M1-polarized tumor-associated macrophages in the prognosis of advanced ovarian cancer patients

AbstractThe identification of prognostic and predictive markers is crucial for choosing the most appropriate management method for ovarian cancer patients. We aimed to assess the prognostic role of tumor-associated macrophage (TAM) polarization in advanced ovarian cancer patients. We carried out a prospective observational study that included 140 consecutive patients with advanced-stage high-grade serous ovarian cancer as well as patients with other histotypes of ovarian cancer and patients with ovarian metastasis from other sites between June 2013 and December 2018. Patients were enrolled at the time of laparoscopic surgery before receiving any antineoplastic treatment. We found that patients with high-grade serous papillary ovarian cancers had a prevalence of M1 TAMs, a higher M1/M2 ratio, and a longer overall survival (OS) and progression-free survival (PFS) than other patients. Regression analysis confirmed that there was a significant positive association between the M1/M2 ratio and an improved OS, PFS and platinum-free interval (PFI), both in the entire population and in patients stratified according to tumor type and initial surgery. Kaplan-Meier analysis was performed after the patients were divided into 2 groups according to the median M1/M2 ratio and revealed that patients with a high M1/M2 ratio had a higher OS, PFS and PFI than those with a low M1/M2 ratio. In conclusion, the prognostic and predictive role of TAM polarization in the tumor microenvironment could be of great clinical relevance and may allow the early identification of patients who are likely to respond to therapy. Further studies in a larger prospective sample are warranted.</jats:p

Correlation of Leptin, Proinflammatory Cytokines and Oxidative Stress with Tumor Size and Disease Stage of Endometrioid (Type I) Endometrial Cancer and Review of the Underlying Mechanisms

Endometrioid endometrial cancer is associated with increased BMI and obesity through multiple pathogenetic mechanisms involving hyperestrogenism, hyperinsulinemia, altered adipokine secretion, inflammation, and oxidative stress. In the present study, we aimed to investigate the correlation between BMI, leptin, the proinflammatory cytokines IL-6 and TNFα, reactive oxygen species (ROS), and the traditional prognostic factors T, G, N and M status among type I endometrioid and type II endometrial cancer patients. We enrolled 305 consecutive endometrial cancer patients prospectively. We found that BMI, leptin, and IL-6 significantly correlated with T status, N status, and M status among endometrioid type I endometrial cancer patients. Among type II endometrial cancer patients, BMI and leptin did not correlate with any of the prognostic parameters, whereas there was a positive correlation between IL-6 and the presence of distant metastases. In the multivariate regression analysis, BMI, leptin, and IL-6 were independent predictive variables of T, N, and M status in endometrioid type I endometrial cancer patients. Our study demonstrates that weight gain, adiposity-related adipokines, inflammation, and oxidative stress correlate with the prognostic factors of endometrioid endometrial cancer. Knowledge of the role of obesity-related biological pathways and mediators in the pathogenesis and prognosis of endometrioid endometrial malignancies may offer new perspectives on combined therapeutic strategies that have not been explored to date, both in the advanced disease and in the adjuvant setting.</jats:p