During out-of-area military operations, the presence of carcinogenic and/or genotoxic agents has been reported, posing potential health risks to deployed soldiers. Military working dogs (MWDs), trained to detect explosives in the same environments as soldiers, could also serve as sentinel animals, providing valuable information on exposure to hazardous agents. These dogs can help identify environmental and potential adverse effects on their health and that of their handlers, possibly before relevant pathologies manifest. This study aims to evaluate the effectiveness of 33 Italian Army MWDs, deployed to the Lebanese theater for six consecutive months from October 2013 to January 2015, as sentinel animals for detecting exposure to genotoxic agents. The Cytokinesis-Block MicroNucleus (CBMN) assay was used to assess DNA damage, cytostasis, and cytotoxicity in the lymphocytes of these dogs. DNA damage events were specifically scored in once-divided binucleated cells (BCs) and included: a) micronuclei (MNi), indicative of chromosome breakage and/or whole chromosome loss; b) nucleoplasmic bridges (NPBs), a marker of DNA misrepair and/or telomere end-fusions; and c) nuclear buds (NBUDs), which signal the elimination of amplified DNA and/or DNA repair complexes. Our findings revealed an increase in chromosomal damage, assessed before and after deployment, with a statistically significant rise in MNi frequency, thus supporting the use of MWDs as sentinels for human exposure to hazardous agents.

In advanced HER2-positive breast cancer, the standard first-line chemotherapy is single-agent taxane, trastuzumab and pertuzumab. In the present CLEOPATRA trial subanalysis, we showed that an early radiological complete response is associated with significantly longer overall and progression-free survival compared to stable disease or partial response. This association remained consistent after adjustment for other baseline patients and tumor-related prognostic factors. Introduction: The CLEOPATRA trial (NCT00567190) established a dual anti-HER2 blockade in combination with docetaxel as the first-line standard of care for patients with metastatic HER2-positive breast cancer. While this treatment is overall associated with significant improvement in progression-free survival (PFS) and overall survival (OS), not all patients respond equally. We hypothesized that a radiological complete response (CR) at week 9 (i.e., first disease reevaluation) is associated with prolonged OS and PFS compared to radiological partial response (PR) or stable disease (SD). Methods: We performed an exploratory analysis of the CLEOPATRA study to address this question. Results: Out of 362 patients treated with docetaxel, trastuzumab, and pertuzumab eligible for our analysis, 46 (12.7%) had radiological CR at week 9, 243 (67.1%) PR, and 73 (20.2%) SD per central RECIST v1.0. Radiological CR at first tumor re-evaluation was associated with a 60% risk reduction for death compared to SD (adjusted HR = 0.40 95% confidence interval (CI) 0.23-0.70), whereas no significant impact on sur vival was obser ved for PR (adjusted HR = 0.85 95% CI 0.60-1.20). The same was observed for PFS with adjusted HR = 0.30 (95% CI 0.18-0.48) for the CR subgroup and adjusted HR = 0.81 (95% CI 0.60-1.09) for the PR subgroup. In multivariate analysis, no variables were associated with radiological CR. Conclusions: Our findings suggest that radiological CR at first disease re-evaluation is associated with more prolonged survival; this might result from stronger dependence on HER2 pathway addiction, supporting the need for further translational research.

BACKGROUND:Recent studies supported the association between occupational exposure to asbestos and risk of cholangiocarcinoma (CC). Aim of the present study is to investigate this association using an update of mortality data from the Italian pooled asbestos cohort study and to test record linkage to Cancer Registries to distinguish between hepatocellular carcinoma (HCC) and intrahepatic/extrahepatic forms of CC. METHODS:The update of a large cohort study pooling 52 Italian industrial cohorts of workers formerly exposed to asbestos was carried out. Causes of death were coded according to ICD. Linkage was carried out for those subjects who died for liver or bile duct cancer with data on histological subtype provided by Cancer Registries. RESULTS:47 cohorts took part in the study (57,227 subjects). We identified 639 causes of death for liver and bile duct cancer in the 44 cohorts covered by Cancer Registry. Of these 639, 240 cases were linked to Cancer Registry, namely 14 CC, 83 HCC, 117 cases with unspecified histology, 25 other carcinomas, and one case of cirrhosis (likely precancerous condition). Of the 14 CC, 12 occurred in 2010-2019, two in 2000-2009, and none before 2000. CONCLUSION:Further studies are needed to explore the association between occupational exposure to asbestos and CC. Record linkage was hampered due to incomplete coverage of the study areas and periods by Cancer Registries. The identification of CC among unspecific histology cases is fundamental to establish more effective and targeted liver cancer screening strategies.

BACKGROUND:Hormone receptor expression is a known positive prognostic and predictive factor in breast cancer; however, limited evidence exists on its prognostic impact on prognosis of young patients harboring a pathogenic variant (PV) in the BRCA1 and/or BRCA2 genes. PATIENTS AND METHODS:This international, multicenter, retrospective cohort study included young patients (aged ≤40 years) diagnosed with invasive breast cancer and harboring germline PVs in BRCA genes. We investigated the impact of hormone receptor status on clinical behavior and outcomes of breast cancer. Outcomes of interest [disease-free survival (DFS), breast cancer-specific survival (BCSS), and overall survival (OS)] were first investigated according to hormone receptor expression (positive versus negative), and then according to breast cancer subtype [luminal A-like versus luminal B-like versus triple-negative versus human epidermal growth factor receptor 2 (HER2)-positive breast cancer]. RESULTS:From 78 centers worldwide, 4709 BRCA carriers were included, of whom 2143 (45.5%) had hormone receptor-positive and 2566 (54.5%) hormone receptor-negative breast cancer. Median follow-up was 7.9 years. The rate of distant recurrences was higher in patients with hormone receptor-positive disease (13.1% versus 9.6%, P < 0.001), while the rate of second primary breast cancer was lower (9.1% versus 14.7%, P < 0.001) compared to patients with hormone receptor-negative disease. The 8-year DFS was 65.8% and 63.4% in patients with hormone receptor-positive and negative disease, respectively. The hazard ratio of hormone receptor-positive versus negative disease changed over time for DFS, BCSS, and OS (P < 0.05 for interaction of hormone receptor status and survival time). Patients with luminal A-like breast cancer had the worst long-term prognosis in terms of DFS compared to all the other subgroups (8-year DFS: 60.8% in luminal A-like versus 63.5% in triple-negative versus 65.5% in HER2-positive and 69.7% in luminal B-like subtype). CONCLUSIONS:In young BRCA carriers, differences in recurrence pattern and second primary breast cancer among hormone receptor-positive versus negative disease warrant consideration in counseling patients on treatment, follow-up, and risk-reducing surgery.

BACKGROUND AND AIM:Surgical gastrojejunostomy (GJJ) and endoscopic stenting (ES) are the two most available treatments for palliation of malignant gastric obstruction (MGOO). The aim of this study is to compare these two techniques regarding efficacy, safety, time of hospitalization and survival.METHODS:We performed a literature search from January 2010 to September 2020 to identify available randomized controlled studies and observational studies that compared ES and GJJ for the treatment of MGOO.RESULTS:A total of 17 studies were found. ES and GJJ showed similar technical and clinical success rate. ES was superior to obtain early oral re-feeding, shorter length of hospitalization and a lower incidence of complications than GJJ. Surgical palliation had a lower recurrence rate of obstructive symptoms and longer overall survival than ES.CONCLUSIONS:Both procedures have advantages and disadvantages. Probably we should not find the best palliation but the best approach based on the patient characteristics and tumor type.

Aim To compare interleukin-2 levels (IL-2) and IL-2 gene site 1 methylation levels between preterm newborns (PN) and full-term newborns (FN) and investigate their association with the environmental exposure of their mothers during pregnancy. Methods IL-2 and IL-2 gene site 1 methylation levels were assessed in 50 PN and 56 FN. Newborns' mothers filled in questionnaires about their living and occupational environments, habits, diets, and hobbies. Results The mothers of PN were significantly more frequently agrarian/rural residents than the mothers of FN. PN had significantly higher IL-2 levels, and significantly lower methylation of IL-2 gene site 1 levels than FN. Conclusion IL-2 levels, hypomethylation of the IL-2 gene site 1, and the mother's rural residence (probably due to pesticide exposure) were predictive biomarkers for preterm birth. For the first time, we present the reference values for the methylation of IL-2 gene site 1 in PN and FN, which can be used in the clinical setting and biomonitoring.

The combination of docetaxel (D) with trastuzumab and pertuzumab (T+P) remains the standard first-line in metastatic HER2-positive breast cancer (BC), based on the results of the CLEOPATRA trial. However, all patients (pts) do not benefit equally from this therapy. We explored the association between survival outcomes and initial tumoral response to D+T+P. We performed an exploratory analysis of CLEOPATRA (NCT00567190) using data extracted from the Vivli database (ID:00007856). The primary objective was to assess the overall survival (OS) of pts treated with D+T+P according to their response at the first tumor assessment at 9 weeks. Secondary objective was progression-free survival (PFS). Response was classified as complete (CR), partial (PR), or stable (SD), according to RECIST1.0 based on central review as per original trial. Pts without first tumor assessment were excluded. We performed a log-rank test to compare Kaplan-Meier curves, and uni- and multivariate analysis. We applied Extended Cox Regression Model to consider a possible guarantee-time bias. In D+T+P arm, 362/402 pts were included: 12.7% (46/62) with CR, 67.1% (243/362) with PR, and 20.2% (73/362) with SD. In CR group, 47.8% of pts had de novo disease (61.3% in PR, 43.8% in SD, Fisher’s exact test p=0.015), 69.6% had visceral disease (83.3% in PR, 67.1% in SD, p=0.005), 60.9% were hormone receptor (HR) negative (51.9% in PR, 49.3% in SD, p=NS). After a median (m) follow-up of 4.1 years, pts in CR group had a significantly longer PFS compared to PR or SD (log-rank p<0.001), and a longer OS compared to PR or SD (mOS not reached (NR), 57.3 mo (interquartile (IQR) 32.1-NR) and 43.4 mo (IQR 22-103.5) in the CR, PR, and SD group, respectively, p=0.002). In multivariate analysis, a high body mass index was associated with better OS in SD group (HR=0.93 95%; confidence interval (CI) (0.88-0.99) p=0.023), ECOG ≥1 with worse OS in PR group (HR=1.66 95% CI (1.17-2.36) p=0.005). The outcome benefit of CR was equal in HR- and HR+ tumors, p=NS. Obtaining an early radiological CR with D+T+P confers significantly longer OS and PFS, whereas no difference is observed once compared with PR and SD.

1104 Background: HER2-Low breast cancer (BC) has been recently identified as a new therapeutic target. However, it is unclear if HER2-Low status has an independent impact on prognosis, both in metastatic and early settings. Methods: A systematic literature research of PubMed, Cochrane and conference proceedings (ASCO meetings, SABCS and ESMO congress) up to December 8, 2022 was performed to identify studies comparing survival outcomes of patients affected by HER2-Low BC vs. HER2-zero BC. HER2-Low status was defined as immunohistochemistry score 1 + or 2+ without in situ hybridization amplification. Pooled hazard ratios (HRs) for survival endpoints in the metastatic [progression-free survival (PFS), overall survival (OS)] and in the early [disease free-survival (DFS) and OS] settings as well as their 95% confidence intervals (95%CI) were calculated using the random-effect model of Der Simonian and Laird. The above-mentioned endpoints were also assessed according to estrogen receptor (ER) status. Results: Among 1,916 identified records, 42 studies including 1,797,377 patients were eligible for this analysis. We show the pooled HRs in the overall population and specific subgroups. In the early setting, HER2-Low status was associated with significant improved DFS (HR 0.86, 95%CI 0.79-0.92, p<0.001) and OS (HR 0.84, 95%CI 0.77-0.92, p<0.001) when compared to HER2-zero status. Improved OS was observed in subgroup analysis for both ER-positive and ER-negative HER2-Low populations, while DFS improvement was observed only in the ER-positive subgroup. Similarly, in the metastatic setting, patients affected by HER2-Low BC showed better OS when compared to those with HER2-zero BC (HR 0.94, 95%CI 0.89-0.98, p=0.008). HER2-Low metastatic BC was associated with significant improvement in OS compared to HER2-zero BC also in ER-positive and ER-negative subgroups. No significant differences were found in terms of PFS. Conclusions: Compared with HER2-zero status, HER2-Low status appears to be associated with an increased OS both in the advanced and early settings, regardless of hormone-receptor expression. [Table: see text]

BACKGROUND:The potential gonadotoxicity of anti-HER2 agents remains largely unknown, and limited, conflicting evidence exists for taxanes. Antimüllerian hormone (AMH) is an established biomarker of ovarian reserve that may aid in quantifying anticancer treatment-induced gonadotoxicity. PATIENTS AND METHODS:The present biomarker analysis of the randomized phase III neoadjuvant NeoALTTO trial included premenopausal women aged ≤45 years at diagnosis of HER2-positive early breast cancer with available frozen serum samples at baseline (ie, before anticancer treatments), at week 2 (ie, the "biological window" of anti-HER2 therapy alone), and/or at the time of surgery (ie, after completing paclitaxel + anti-HER2 therapy, before starting adjuvant chemotherapy). RESULTS:The present analysis included 130 patients with a median age of 38 years (interquartile ratio [IQR], age 33-42 years). AMH values at the 3 time points differed significantly (P<.001). At baseline, median AMH levels were 1.29 ng/mL (IQR, 0.56-2.62 ng/mL). At week 2, a small but significant reduction in AMH levels was observed (median, 1.10 ng/mL; IQR, 0.45-2.09 ng/mL; P<.001). At surgery, a larger significant decline in AMH levels was observed (median, 0.01 ng/mL; IQR, 0.01-0.03 ng/mL; P<.001). Although the type of anti-HER2 treatment (trastuzumab and/or lapatinib) did not seem to impact the results, age and pretreatment ovarian reserve had a major influence on treatment-induced gonadotoxicity risk. CONCLUSIONS:This NeoALTTO biomarker analysis showed that anti-HER2 therapies alone had limited gonadotoxicity but that the addition of weekly paclitaxel resulted in marked AMH decline with possible negative implications for subsequent ovarian function and fertility.

Background: Treatment options for advanced melanoma have increased with the US Food and Drug Administration approval of the anti-LAG3 plus anti-PD-1 relatlimab/ nivolumab combination. To date, ipilimumab/nivolumab is the benchmark of overall survival, despite a high toxicity profile. Furthermore, in BRAF-mutant patients, BRAF/MEK in-hibitors and the atezolizumab/vemurafenib/cobimetinib triplet are also available treatments, making the first-line therapy selection more complex. To address this issue, we conducted a systematic review and network meta-analysis of the available first-line treatment options in advanced melanoma. Methods: Randomised clinical trials of previously untreated, advanced melanoma were in-cluded if at least one intervention arm contained a BRAF/MEK or an immune-checkpoint inhibitor (ICI). The aim was to indirectly compare the ICIs combinations ipilimumab/nivo-lumab and relatlimab/nivolumab, and these combinations with all the other first-line treat-ment options for advanced melanoma (irrespective of BRAF status) in terms of activity and safety. The coprimary end-points were progression-free survival (PFS), overall response rate (ORR) and grade >= 3 treatment-related adverse events (>= G3 TRAEs) rate, defined according to Common Terminology Criteria for Adverse Events. Results: A total of 9070 metastatic melanoma patients treated in 18 randomised clinical trials were included in the network meta-analysis. No difference in PFS and ORR was observed between ipilimumab/nivolumab and relatlimab/nivolumab (HR = 0.99 [95% CI 0.75-1.31] and RR = 0.99 [95% CI 0.78-1.27], respectively). The PD-(L)1/BRAF/MEK inhibitors triplet combinations were superior to ipilimumab/nivolumab in terms of both PFS (HR = 0.56 [95% CI 0.37-0.84]) and ORR (RR = 3.07 [95% CI 1.61-5.85]). Ipilimumab/nivolumab showed the highest risk of developing >= G3 TRAEs. Relatlimab/nivolumab trended to a lower risk of >= G3 TRAEs (RR = 0.71 [95% CI 0.30-1.67]) versus ipilimumab/nivolumab. Conclusion: Relatlimab/nivolumab showed similar PFS and ORR compared to ipilimumab/ nivolumab, with a trend for a better safety profile. (c) 2023 The Author(s). Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

BACKGROUND Asbestos is a known human carcinogen and is causally associated with malignant mesothelioma, lung, larynx and ovarian cancers. METHODS Cancer risk was studied among a pool of formerly asbestos-exposed workers in Italy. Fifty-two Italian asbestos cohorts (asbestos-cement, rolling-stock, shipbuilding, and other) were pooled and their mortality follow-up was updated to 2018. Standardized mortality ratios (SMRs) were computed for major causes of death considering duration of exposure and time since first exposure (TSFE), using reference rates by region, age and calendar period. RESULTS The study included 63,502 subjects (57,156 men and 6346 women): 40% who were alive, 58% who died (cause known for 92%), and 2% lost to follow-up. Mortality was increased for all causes (SMR: men = 1.04, 95% confidence interval [CI] 1.03-1.05; women = 1.15, 95% CI 1.11-1.18), all malignancies (SMR: men = 1.21, 95% CI 1.18-1.23; women = 1.29, 95% CI 1.22-1.37), pleural and peritoneal malignancies (men: SMR = 10.46, 95% CI 9.86-11.09 and 4.29, 95% CI 3.66-5.00; women: SMR = 27.13, 95% CI 23.29-31.42 and 7.51, 95% CI 5.52-9.98), lung (SMR: men = 1.28, 95% CI 1.24-1.32; women = 1.26, 95% CI 1.02-1.53), and ovarian cancer (SMR = 1.42, 95% CI 1.08-1.84). Pleural cancer mortality increased during the first 40 years of TSFE (latency), reaching a plateau thereafter. CONCLUSIONS Analyses by time-dependent variables showed that the risk for pleural neoplasms increased with latency and no longer increases at long TSFE, consistent with with asbestos clearance from the lungs. Peritoneal neoplasm risk increased over all observation time.

As part of a large human biomonitoring study, we conducted occupational monitoring in a glass fibre factory in Slovakia. Shopfloor workers (n = 80), with a matched group of administrators in the same factory (n = 36), were monitored for exposure to glass fibres and to polycyclic aromatic hydrocarbons (PAHs). The impact of occu-pational exposure on chromosomal aberrations, DNA damage and DNA repair, immunomodulatory markers, and the role of nutritional and lifestyle factors, as well as the effect of polymorphisms in metabolic and DNA repair genes on genetic stability, were investigated.The (enzyme-modified) comet assay was employed to measure DNA strand breaks (SBs) and apurinic sites, oxidised and alkylated bases. Antioxidant status was estimated by resistance to H2O2-induced DNA damage. Base excision repair capacity was measured with an in vitro assay (based on the comet assay).Exposure of workers to fibres was low, but still was associated with higher levels of SBs, and SBs plus oxidised bases, and higher sensitivity to H2O2. Multivariate analysis showed that exposure increased the risk of high levels of SBs by 20%. DNA damage was influenced by antioxidant enzymes catalase and glutathione S-transferase (measured in blood). DNA repair capacity was inversely correlated with DNA damage and positively with antioxidant status. An inverse correlation was found between DNA base oxidation and the percentage of eosinophils (involved in the inflammatory response) in peripheral blood of both exposed and reference groups. Genotypes of XRCC1 variants rs3213245 and rs25487 significantly decreased the risk of high levels of base oxidation, to 0.50 (p = 0.001) and 0.59 (p = 0.001), respectively.Increases in DNA damage owing to glass fibre exposure were significant but modest, and no increases were seen in chromosome aberrations or micronuclei. However, it is of concern that even low levels of exposure to these fibres can cause significant genetic damage.

Environmental pollution of megacities can cause early biological damage such as DNA strand breaks and micronuclei formation. Comet assay tail length (TL) reflects exposure in the uterus to high levels of air pollution, primarily ozone and air particles (PM10), including mothers’ smoking habits during pregnancy, conditions which can lead to low birth weight. In this biomonitoring study, we evaluated basal DNA damage in the cord blood cells of newborn children from Mexico City. We found a correlation between DNA damage in mothers and their newborns, including various parameters of environmental exposure and complications during pregnancy, particularly respiratory difficulties, malformations, obstetric trauma, neuropathies, and nutritional deficiencies. Mothers living in the southern part of the city showed double DNA damage compared to those living in the northern part (TL 8.64 μm vs. 4.18 μm, p < 0.05). Additionally, mothers’ DNA damage correlates with exposure to NOx (range 0.77–1.52 ppm) and PM10 (range 58.32–75.89 μg/m3), as well maternal age >29. These results highlight the sensitivity of the comet assay in identifying differential in utero exposure for newborns whose mothers were exposed during pregnancy. They also suggest the importance of antioxidants during pregnancy and the role of the placental barrier in protecting the newborn from the DNA-damaging effects of oxidative pollution.

Among patients (pts) with ALK+ advanced non-small cell lung cancer (NSCLC) naïve to ALK-inhibitors, A significantly prolonged progression-free survival (PFS) over C. We present results of a post-hoc patient-level pooled analysis at interim data cut-off of the randomized phase III trials ALEX (NCT02075840) and J-ALEX (JapicCTI-132316), exploring new prognostic factors. In both studies, the primary endpoint was PFS by RECIST v1.1. Treatment crossover was only allowed in the J-ALEX trial. Multivariate analysis was performed by Cox’s model, the independence of the two trial data sets was managed by random effects models. Survival outcomes were correlated with baseline characteristics including high tumor burden (hTB, i.e. > median sum of diameter of target lesions) and body mass index (BMI). The pooled set included 500 pts (A=249, C=251) with data available for survival and safety analysis. There was no imbalance between A and C groups in age (median 58 vs 56), sex (female 58% vs 59%), brain metastases (29% vs 34%), BMI (<25 70% vs 67%). At a median follow-up of 17.1 months, A provided prolonged PFS over C (median not reached vs. 10.2 months, HR 0.41, 95% CI 0.31-0.55, p<0.001), with median OS not reached in any arm (HR 0.80, 95% 0.50-1.28, p=0.353). In the multivariate analysis with correction for ethnicity, hTB (>55mm) was linked to worse PFS regardless of the treatment received (HR 1.66, 95% CI 1.26-2.20, p<0.001), and BMI ≥25 was correlated with better OS compared to BMI <25 (HR 0.50, 95% 0.29-0.88, p=0.025). Treatment effectiveness in subgroups is shown in table. Significant interaction between treatment and TB (p=0.002) was found in subgroup PFS analysis. Grade ≥3 adverse events occurred in 36% of pts with A vs 51% with C, 15% of pts discontinued A vs 20% C.Table: 186PSubgroup analysisHR for PFS A vs C (95% CI)p value for PFSHR for OS A vs C (95% CI)p value for OSRef. A vs C whole cohort0.41 (0.31-0-55)<0.0010.80 (0.50-1.28)0.353Sum diam <55mm0.25 (0.16-0.41)<0.0010.79 (0.35-1.80)0.572Sum diam >55mm0.52 (0.36-0.76)0.0010.87 (0.49-1.55)0.645BMI <250.44 (0.32-0.62)<0.0010.99 (0.58-1.71)0.976BMI >250.35 (0.19-0.63)0.0010.39 (0.12-1.21)0.103 Open table in a new tab hTB is a prognostic and predictive factor in patients with advanced ALK+ NSCLC under ALK-inhibitors, while a BMI ≥25 is linked to a reduced risk of death. Escalation strategies could be explored for hTB.

Studies have indicated that air pollution, including surface-level ozone (O3), can significantly influence the risk of chronic diseases. To better understand the carcinogenic mechanisms of air pollutants and identify predictive disease biomarkers, we examined the association between traffic-related pollutants with DNA methylation alterations and bulky DNA adducts, two biomarkers of carcinogen exposure and cancer risk, in the peripheral blood of 140 volunteers—95 traffic police officers, and 45 unexposed subjects. The DNA methylation and adduct measurements were performed by bisulfite-PCR and pyrosequencing and 32P-postlabeling assay. Airborne levels of benzo(a)pyrene [B(a)P], carbon monoxide, and tropospheric O3 were determined by personal exposure biomonitoring or by fixed monitoring stations. Overall, air pollution exposure was associated with a significant reduction (1.41 units) in global DNA methylation (95% C.I. −2.65–0.04, p = 0.026). The decrement in ALU repetitive elements was greatest in the policemen working downtown (95% C.I. −3.23–−0.49, p = 0.008). The DNA adducts were found to be significantly increased (0.45 units) in the municipal officers with respect to unexposed subjects (95% C.I. 0.02–0.88, p = 0.039), mainly in those who were controlling traffic in downtown areas (95% C.I. 0.39–1.29, p < 0.001). Regression models indicated an increment of ALU methylation at higher B(a)P concentrations (95% C.I. 0.03–0.60, p = 0.032). Moreover, statistical models showed a decrement in ALU methylation and an increment of DNA damage only above the cut-off value of 30 µg/m3 O3. A significant increment of 0.73 units of IL-6 gene methylation was also found in smokers with respect to non-smokers. Our results highlighted the role of air pollution on epigenetic alterations and genotoxic effects, especially above the target value of 30 µg/m3 surface-level O3, supporting the necessity for developing public health strategies aimed to reduce traffic-related air pollution molecular alterations.

Inferior overall response rate with abemaciclib plus endocrine therapy was observed in patients with hormone receptor-positive/HER2-negative advanced breast cancer (BC) and BMI ≥ 25. We assessed the impact of baseline BMI on KI67% changes, achievement of complete cell cycle arrest (CCCA), clinical, and radiological responses in patients included in the NEOMONARCH trial. Exploratory post hoc analysis of the NEOMONARCH trial was performed. Patients were classified according to baseline BMI into underweight/normal weight (BMI < 25 kg/m2) and overweight/obese (BMI ≥ 25 kg/m2). 222 patients (84.4%) had baseline BMI information available. In the overall cohort, mean Ki67% changes at 2 weeks were similar between the two BMI groups: − 19 (IQR − 27.8 to − 10.4) for patients with BMI < 25 and − 17.2 (IQR − 26.8 to − 11) for patients with BMI ≥ 25 (p = 0.760). There was no statistical difference in patients achieving CCCA after 2 weeks of treatment according to BMI (p = 0.096). Mean Ki67% reduction at 2 weeks was significantly higher for patients receiving abemaciclib plus anastrozole when compared to either anastrozole or abemaciclib alone, regardless of BMI. At the end of treatment, there was no significant difference regarding radiological (p = 0.366) or clinical response (p = 0.261). BMI categorized by the threshold of 25 did not significantly impact KI67% changes or clinical and radiological response. Although limited by the small sample size, these results are reassuring that the combination of abemaciclib plus anastrazole appears to be active in the early setting regardless of baseline BMI. Trial registration: ClinicalTrials.gov identifier: NCT02441946.

12067 Background: Improvements in breast cancer (BC) care have led to increased survival of patients; hence, more attention to long-term treatment-related adverse events and quality of life (QoL) is required. Symptoms of spontaneous and treatment-induced menopause significantly affect the QoL and adherence to endocrine therapy among BC survivors, with potential negative implications on outcome. Use of systemic hormone replacement therapy (HRT) to mitigate menopause-associated symptoms is not recommended to reduce the burden of these side effects being historically associated with an increased risk of disease recurrence. This systematic review and metanalysis aimed to estimate the effect of HRT on risk of disease recurrence in BC survivors. Methods: A systematic search of Pubmed and Embase libraries up to January 15, 2021, was conducted in order to identify randomized controlled trials (RCTs) investigating the risk of disease recurrence with the use of HRT in BC survivors. We used the random-effect model to calculate the overall risk of recurrence, reported as pooled hazard ratio (HR) with 95% confidence intervals (CI). Moreover, we performed a subgroup analysis to estimate the risk of recurrence according to hormone receptor status. The Higgins I 2 index was computed to assess the heterogeneity between studies. The likelihood of publication bias was assessed by Egger’s test. Results: Four RCTs were found and three were included in the metanalysis (n = 3.973 patients); one study (n = 100 patients) was excluded due to the impossibility to extract the HR for disease recurrence. Overall, 1.990 patients were randomized to receive HRT (estrogen-progesteron combination or tibolone), while 1.983 patients were included in control groups (placebo or no HRT). As compared to control group, HRT significantly increased the risk of BC recurrence (HR 1.49, 95% CI 1.15-1.93, p = 0.002). The heterogeneity between the studies was low (39%, p = 0.194), and no publication bias was found ( p = 0.537). Two studies reported the HR according to hormone receptor status. At the subgroups analysis, the risk of BC recurrence with the use of HRT was significantly increased in hormone receptor-positive patients (HR 1.8, 95% CI 1.15-2.82, p = 0.010) but not in those with hormone receptor-negative tumors (HR 1.25, 95% CI 0.83-1.88, p = 0.290). Conclusions: Use of HRT significantly increases the risk of recurrence in BC survivors, particularly in those with hormone receptor-positive disease. Therefore, this approach remains contraindicated in this setting. Alternative interventions to mitigate menopause-related symptoms should be proposed to these patients.

Background: Controlled ovarian stimulation (COS) for oocyte/embryo cryopreservation before starting chemotherapy is standard of care for young women with breast cancer wishing to preserve fertility. However, some oncologists remain concerned on the safety of COS, particularly in patients with hormone-sensitive tumors. Moreover, limited evidence exists on the safety of assisted reproductive technologies (ART) in breast cancer survivors after completion of anticancer treatments. Material and methods: A systematic literature review with no date restriction up to June 30, 2021 was conducted to identify studies reporting results of oncological outcomes in breast cancer patients and survivors who underwent COS or other ART compared to patients and survivors who did not access these techniques. From each included study, recurrence ratio, event-free survival (EFS) and mortality rate were extracted. Pooled relative risks (RRs) and hazard ratios (HRs) with 95% confidence intervals (CI) were calculated using the random effects models. Results: Out of 15 included studies (n=4,643), 11 reported outcomes of patients who underwent COS for fertility preservation before starting chemotherapy, and 4 of survivors who underwent ART following anticancer treatment completion. Compared to women who did not receive fertility preservation at diagnosis (n=2,386), those who underwent COS (n=1,594) had reduced risk of recurrence (RR 0.58, 95% CI 0.46-0.73) or mortality (RR 0.54, 95% CI 0.38-0.76). No detrimental effect of COS on EFS was observed (HR 0.76, 95% CI 0.55-1.06). A similar trend of better outcomes in terms of EFS was observed in women with hormone-receptor positive disease who underwent COS (HR 0.36, 95% CI 0.20-0.65).Compared to women not exposed to ART following completion of anticancer treatments (n=540), those exposed to ART (n=123) showed a tendency for better outcomes in terms of recurrence ratio (RR 0.34, 95% CI 0.17-0.70) and EFS (HR 0.43, 95% CI 0.17-1.11). Conclusions: Despite including mostly retrospective studies, this meta-analysis suggests that accessing COS at diagnosis, also in hormone receptor-positive disease, or ART following treatment completion is not associated with detrimental prognostic effect in young women with breast cancer. These results are important to reassure patients and oncologists on the safety of these procedures to increase the chances of future conception. Citation Format: Luca Arecco, Eva Blondeaux, Marco Bruzzone, Marcello Ceppi, Maria Maddalena Latocca, Andrea Boutros, Camilla Marrocco, Maria Grazia Razeti, Maurizio Cosso, Stefano Spinaci, Margherita Condorelli, Claudia Massarotti, Lucia Del Mastro, Isabelle Demeestere, Matteo Lambertini. Safety of assisted reproductive technologies before and after anticancer treatments in young women with breast cancer: A systematic review and meta-analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr PD5-07.