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Purpose: The SARS-CoV-2 pandemic was declared a global public health emergency. Determinants of mortality in the general population are now clear, but specific data on patients with breast cancer (BC) remain limited, particularly in developing nations. Materials and methods: We conducted a longitudinal, multicenter cohort study in patients with BC and confirmed SARS-CoV-2 infection. The primary end point was the proportion of patients on treatment for severe SARS-CoV-2 infection (defined as need for hospitalization) or early death (within 30 days of diagnosis). Data were evaluated sequentially in the following way: i) univariate Fisher’s exact test; ii) multivariable logistic regression analysis; and iii) multivariable logistic regression. In items i and ii only those with P< 0.1 are considered significant and in stage iii only those with p< 0.05 were the final significant variables. We divided patients’ data into three major variable domains: a) signs and symptoms; b) comorbidities; and c) tumor and treatment characteristics; in item ii each variable domain was tested separately, finally, in item iii the significant variables of all domains were tested together and we called it the integrative step. Results: From April 2020 to June 2021, 413 patients with BC and COVID-19 were retrospectively registered, of which 288 (70%) had an identified molecular subtype and 273 (66%) had stage information. Most patients were on active systemic therapy or radiotherapy (73.2%), most of them in the curative setting (69.5%). The overall rate of severe SARS-CoV-2 was 19.7% (95% CI, 15.3-25.1). In the integrative multivariate analysis, factors associated with severe infection were metastatic setting, chronic pain, acute dyspnea, and cardiovascular comorbidities. Recursive partitioning modeling used acute dyspnea, metastatic setting, and cardiovascular comorbidities to predict non-progression to severe infection, yielding a negative predictive value of 84.9% (95% CI, 78.9%-88.3%). Conclusion: The rate of severe COVID-19 in patients with BC is influenced by prognostic factors that partially overlap with those reported in the general population. High-risk patients should be considered candidates to active preventive measures to reduce the risk of infection, close monitoring in the case of exposure or SARS-CoV-2 -related symptoms and prophylactic treatment once infected. Citation Format: Fanny Cascelli, Matheus Costa e Silva, Rodrigo Dienstmann, Bruno L. Ferrari, Carlos Gil Ferreira, Max S. Mano, Jorge Canedo, Diego Cunha, Daniel Luiz Gimenes, Aline Goncalves. Determinants of severe COVID-19 infection in Patients with Breast Cancer from a Community Oncology Practice in Brazil [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P4-03-36.

Activating mutations of K-ras are the most common oncogenic alterations found in lung cancer. Unfortunately, attempts to target K-ras–mutant lung tumors have thus far failed, clearly indicating the need for new approaches in patients with this molecular profile. We have previously shown NF-κB activation, release of IL6, and activation of its responsive transcription factor STAT3 in K-ras–mutant lung tumors, which was further amplified by the tumor-enhancing effect of chronic obstructive pulmonary disease (COPD)-type airway inflammation. These findings suggest an essential role for this inflammatory pathway in K-ras–mutant lung tumorigenesis and its enhancement by COPD. Therefore, here we blocked IL6 using a monoclonal anti-IL6 antibody in a K-ras–mutant mouse model of lung cancer in the absence or presence of COPD-type airway inflammation. IL6 blockade significantly inhibited lung cancer promotion, tumor cell–intrinsic STAT3 activation, tumor cell proliferation, and angiogenesis markers. Moreover, IL6 inhibition reduced expression of protumor type 2 molecules (arginase 1, Fizz 1, Mgl, and IDO), number of M2-type macrophages and granulocytic myeloid-derived suppressor cells, and protumor T-regulatory/Th17 cell responses. This was accompanied by increased expression of antitumor type 1 molecule (Nos2), and antitumor Th1/CD8 T-cell responses. Our study demonstrates that IL6 blockade not only has direct intrinsic inhibitory effect on tumor cells, but also reeducates the lung microenvironment toward an antitumor phenotype by altering the relative proportion between protumor and antitumor immune cells. This information introduces IL6 as a potential druggable target for prevention and treatment of K-ras–mutant lung tumors. Cancer Res; 76(11); 3189–99. ©2016 AACR.

Worldwide, lung cancer (LC) leads in cancer mortality and cigarette smoking (CS) is its principal cause. Activating mutations of K-ras are one of the most common alterations in LC and are associated with CS exposure. However, several studies have shown that smokers with chronic obstructive pulmonary disease (COPD), an inflammatory disease of the lung, have a higher risk of developing LC when compared to smokers without COPD. These facts suggest a strong link between COPD-type inflammatory lung microenvironment and K-ras mutant lung cancer. Unfortunately, attempts to directly target K-ras have thus far failed, clearly stating the need for new approaches to bring clinical benefits to patients with this undrugabble profile. Using a conditional K-ras induced lung cancer mouse model (CC-LR) we showed that K-ras mutant lung tumors have intrinsic inflammatory characteristics, and a bacterial lysate-induced COPD-like airway inflammation promotes lung cancer in this model. This was associated with release of the cytokine IL-6 and activation of the IL-6-responsive transcription factor STAT3. We showed that genetic ablation of IL-6 in this model results in a significant tumor reduction indicating an essential role for IL-6/STAT3 pathway in lung cancer promotion and introducing IL-6 as a druggable target for K-ras mutant lung tumor. Therefore, we blocked IL-6 using a monoclonal anti-IL-6 immunotherapy in our K-ras mutant model. Six week old CC-LR mice were injected intraperitoneally with 20 mg/kg dose of an anti-IL-6 monoclonal IgG1 antibody twice a week for eight weeks, while been exposed to the aerosolized bacterial lysate once weekly for 8 weeks. Anti-IL-6 therapy not only inhibited intrinsic lung cancer development by ∼78%, but also inhibited the tumor promoting effect of the COPD-like airway inflammation. It also decreased the expression of P-STAT3, proliferation marker, Ki67, and pro-angiogenic factors: VEGF, MMP-9 and CD31 in lung tissue. qPCR analysis of lung tissues from anti-IL-6 treated mice showed a decrease in Arginase1, FIZZ1, FOXP3, and IL-17 expression, with increased expression of Th1 markers, IFNγ and TBx21. Flow cytometry analysis of total lung inflammatory cells in CC-LR mouse showed a significant increase in the population of tumor associated macrophages (TAMs) during tumor progression from age 6 to 14 weeks, and COPD-like inflammation induced an increase in myeloid derived suppressor cell (MDSCs) population. Interestingly, we found a significant decrease in TAMs and MDSCs population after anti-IL-6 treatment. Taken together, we conclude that IL-6 blockade not only has cell intrinsic effect in K-ras mutant tumors but also edit the lung microenvironment toward an anti-tumor phenotype. Therefore, we propose pharmacological targeting of IL-6 alone or in combination with conventional cytotoxic therapy, or other targeted therapies for prevention and treatment of lung cancer patients with K-ras mutation. Citation Format: Mauricio S. Caetano, Amber M. Cumpian, Lei Gong, Seon H. Chang, Huiyuan Zhang, Humam N. Kadara, Cinthya Sternberg, Carlos G. Ferreira, Stephanie S. Watowich, Seyed J. Moghaddam. Targeting IL-6 as a preventive and therapeutic strategy for K-ras mutant lung cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 413. doi:10.1158/1538-7445.AM2015-413

Background: Cervical cancer (CC) represents the second most commonly diagnosed cancer in women. The combined treatment involving C and R has been the standard treatment for stages IIB-IIIB. However the results are still disappointing with 5-year survival rates lower than 50%. There is a great need to explore new strategies in order to improve the prognosis of these patients. E inhibits the mammalian target of rapamycin (mTOR). The high aberrant activity of mTOR complexes is part of the underlying cause of carcinogenesis in CC. Further E inactivates the oncoprotein E7 (essential in the carcinogenesis of HPV) and inhibits its proliferation. Preclinical models have suggested that mTOR inhibitors sensitize tumoral cells and vasculature to C and R effects. Therefore mTOR inhibition may represent a promising treatment approach in CC. Methods: The primary objective of this trial is to evaluate the safety, toxicity (according to NCI CTCAE 3.0) and the maximum tolerated dose (MTD) of E in association to C and R in the treatment of locally advanced CC. The secondary objectives are to quantify PK and PD parameters, and to evaluate the response rate (using RECIST 1.1). In a modified Fibonacci design the trial aims to evaluate three cohorts of at least three patients treated with daily escalating doses of E (2.5/5/10 mg) in association with C (40 mg/m2 of body surface per week, for 5 weeks during teletherapy) and R (teletherapy - 4.500 cGy in 25 fractions, followed by 4 fractions of 600 cGy weekly of brachytherapy - B) in squamous cell cervical carcinoma patients stage IIB to IIIB. Patients are treated with E from day -7 to day 0 (one week before the C+R starting) up to the last day of B. Results: As of December 01, 2013, 13 patients were enrolled, 6 in the cohort #1, 3 in the cohort #2 and 4 in the cohort #3. Two patients did not completed the planned schedule, one at dose level of 2,5 mg presented grade 4 acute renal failure interpreted as dose limiting toxicity (DLT) and one at dose level of 10 mg with disease progression. Grade 3 toxicity occurred in cohorts #1 and #2 as follows: lymphopenia in 6 patients, neutropenia in 3 patients and leukopenia in 1 patient. Three patients in the cohort #3 are still on treatment. PK and PD studies will be performed together, after collection of the entire set of samples. Conclusions: The end of treatment of the last cohort is due to February 2014, when the MTD will be established. To the best of our knowledge this is the first study of everolimus, cisplatin and pelvic radiotherapy combination. Citation Format: Carlos Gil Ferreira, Flávia V. Guerra Alves, Rachele Grazziotin, Felipe Erlich, Giulliana Moralez, Michel P. Carneiro, Mariane Fontes Dias, Andréia C. de Melo. A Phase I study of oral administration of mTOR inhibitor everolimus (E) in association with cisplatin (C) and radiotherapy (R) for the treatment of locally advanced cervix cancer (LACC) - PHOENIX I. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr CT403. doi:10.1158/1538-7445.AM2014-CT403

Platinum compounds remain the cornerstone for both early and advanced stages NSCLC management. However, mechanisms underlying platinum resistance and sensitivity are poorly understood, and no major impact in patient selection or treatment modulation has been achieved to date. Apoptosis inhibition and platinum-efflux are potential mechanisms, therefore we evaluated the role of XIAP, pAkt, and ATP7A in this setting. We have analyzed the tumor cell lines, LC94, LC319, and A549, all of adenocarcinoma histology and harboring KRAS mutations. The cisplatin (CPT) IC50 was assessed using MTT assay, after 48 h incubation. mRNA expression was evaluated by Real-time PCR, while Western blotting was performed to analyze protein expression. Also, two distinct cohorts of NSCLC patients were evaluated. The first was comprised of 39 patients diagnosed as early-stage NSCLC (IA-IIIB), whereas the second included patients with metastatic disease (IV). In the latter, patients were clinically classified as platinum-sensitive (N=4) and platinum-non-sensitive group (N=47). We have analyzed either mRNA expression or protein expression. NSCLC cell lines exhibited distinct profiles of CPT sensitivity. LC94 was especially sensitive to CPT, in contrast to LC319 and A549. Resistant cell lines (LC319 and A549) showed a positive correlation between high XIAP and ATP7A mRNA expression when compared to LC94. These data was corroborated by XIAP and ATP7A mRNA expression, which also showed a significant positive correlation (R2=0,88) in early-diagnosed patients (IA-IIIB). we did not correlate these data to response to CPT, since only few patients of this cohort received adjuvant therapy. XIAP protein expression was evaluated in cell lines and in the second clinical cohort. In fact, XIAP showed a considerably higher expression in LC 319 and A549 than in LC 94. Interestingly, XIAP shRNA lead not only to XIAP downregulation (85% reduction in mRNA compared to empty-vector control), but also to ATP7A (60% of reduction in mRNA). These changes were accompanied by reduction in the respective protein levels. Among patients with metastatic NSCLC, XIAP was expressed in 45% (21/47) in the platinum-non-sensitive group, while no expression was observed in the sensitive (0/4). Knowing that XIAP is regulated by PI3K/Akt pathway through phosphorylation at the serine 87 residue, which increases XIAP stability and accumulation, we further analyzed the Akt phosphorylation. LC319 displayed superior Akt phosporylation, in comparison to the lower level in LC 94. XIAP, pAkt, and ATP7A mRNA expression were positively correlated to CPT resistance/sensitivity in NSCLC. Furthermore, XIAP seems to indirectly regulate ATP7A transcritption and the correlation of expression of both proteins might cooperate for NSCLC chemoresistance. Further analyses are warranted to validate these findings and explore their potential as biomarkers in this setting. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1731. doi:1538-7445.AM2012-1731

Apoptosis is a phenomenon of cellular degeneration highly conserved evolutionarily, being observed not only during development, but also associated with a number of diseases. Apoptosis is regulated by a complex set of proteins and accomplished by biochemical mechanisms that act to initiate and complete the destruction of the cell. Recently, typical biochemical and morphological changes associated to cell death were correlated with other vital cellular events, such as proliferation and differentiation. Despite the general tendency to treat apoptosis and cell differentiation as the result of different signaling pathways, several studies have shown that there is a high degree of morphological similarity between these events. The molecules involved in the regulation of apoptosis-like processes of differentiation have not been fully described. Since the main endogenous inhibitor of caspase-3 is the protein XIAP, which in turn is regulated by XAF1, we analyzed the expression of these proteins in the context of differentiation of different cell lines. The objective of this study was to evaluate the activation pathways of cell death in the process of monocytic/macrophage differentiation. We have observed that the expression of XAF1 protein decreases during monocytic/macrophage differentiation of HL60 cell line induced by PMA, but levels of its mRNA do not change. Interestingly, we have found that HL60 cell lines overexpressing either Bcl-XL or Bcl-2 cell lines have decreased expression of XAF1 due to methylation of its promoter. Also, besides rendering cells resistant to apoptosis as expected, HL60 cells overexpressing either Bcl-XL or Bcl-2 were more prone to differentiate by PMA treatment than parental cells. The correlation between high levels of mRNA expression of Bcl-2 with low expression of XAF1 mRNA was also observed in the analysis of samples from patients with follicular lymphoma retrieved from Oncomine database (www.oncomine.com). These results demonstrate the differential activation of pathways of cell death in monocytic / macrophagic differentiation, suggesting that a descrease in XAF1 expression is a necessary event during this process. Furthemore, our results reveal a transcriptional regulatory loop exerted by Bcl-2 family of proteins that had not yet been described. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 195. doi:10.1158/1538-7445.AM2011-195

The mechanisms involved in in the initiation of lung carcinogenesis are not yet well understood. Literature suggests that the initial events related with inflammation could drive induce an oxidative-prone microenvironment formation and determine the final fate of the organ. Oxidative stress is suggested to play a significant role in the initial phases of the inflammatory process. In the present study our purpose was to investigate the role of redox imbalance induced by urethane exposure, a known lung adenocarcinoma inducer, using resistant and susceptible mice models of lung cancer. C57/B6 and A/J 8-12 weeks-old mice were treated with weekly intra-peritoneal injections of 1mg of Urethane in saline per gram of animal weight for 4 weeks. The control mice were saline-injected under the same weekly regimen. The mice were weekly weighed during the experiment. Total lung tissue was collected at different time periods of both control and urethane-injected mice. Lung tissue was either processed histologically or stored as a homogenate for further biochemical measurements. The susceptible urethane-injected A/J mice presented a delay in weight gain when compared to saline control, whereas C57/B6 mice do not show differences in weight gain in both urethane-injected and saline groups. Measurements performed in resistant C57/B6 mice treated with urethane showed a decrease in catalase activity that correlated to accumulation of carbonylated proteins 2 weeks after the end of the urethane treatment. Such levels are indicative of oxidative stress. However, from the third week on, these levels were back to control levels. The modulation of oxidative state of the C57/B6 lung was not accompanied by histological modifications. Surprisingly, we did not observe the same results in the susceptible A/J mice. In the present study, we have shown that urethane modulates redox components in the lung and this effect seems to be strain dependent. It is known that urethane-treated A/J mice will develop lung adenocarcinoma within 16-20 weeks after the first injection and that only a very small percentage of C57/B6 will develop lung cancer under the same conditions. Our results suggest that the differences in the initial responses observed in the two mice strains collaborate to the formation of a different lung microenvironment. Therefore, we put forward the idea that the ability of resistant mice to upregulate a proper stress response at the initial stage constitutes a protective mechanism against carcinogenesis. On the other hand, the apparent lack of response observed in susceptible mice might mitigate the establishment of a chronic nocive environment that would contribute to the development of lung adenocarcinoma. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4208. doi:10.1158/1538-7445.AM2011-4208