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BACKGROUND: Breast cancer (BC) is the most common cancer and the second leading cause of cancer-related deaths worldwide. Mutations in tumor suppressor genes BRCA1 and BRCA2 are the most common cause of hereditary breast and ovarian cancer. Additionally, carriers of germline BRCA1/2 mutations also have an elevated risk of other malignancies. Identification of mutations within these genes is essential for determining early cancer detection and risk-reducing strategies in carriers and establishing a therapeutic approach in breast cancer patients. The aims of this study were to evaluate the prevalence and spectrumof germline BRCA1 and BRCA2 variants in peruvian breast cancer patients. METHODS: Patients with HER2Neu negative BC referred to ONCOGENOMICS laboratory from 2019 to2021 to assessed poly (adenosine diphosphate-ribose) polymerase (PARP) inhibitor treatment were included in the study. Blood samples were collected to assess the status of germline BRCA1 and BRCA2. Next Generation Sequencing (NGS) was performed using the Ampliseq for Illumina BRCA panel and run on the Illumina MiSeq. The Human Genome Variation Society (HGVS) nomenclature guidelines (http://varnomen.hgvs.org/) were used to annotate identified variants and the ClinVar database (www.ncbi.nlm.nih.gov/clinvar/) was used to determine the clinical significance of all reported variants. Current American College of Medical Genetics (ACMG) guidelines were also used for further classification. RESULTS: A total of 155 HER2Neu negative BC cases were evaluated. Median age at BRCA1/2 evaluation was 51 (23-82) years, 78.1% (121) were negative HR status (triple-negative BC, TNBC); 21.9% (34) were positive HR status; 33.5% (52) were clinical stage III and 66.5% (103) were clinical stage IV. Most patients were from Lima-Callao (65.8%) followed by patients from the coast (23.9%), highlands (9%) and rainforest(1.3%). Only 18.7% of patients were from public health centers. The prevalence of pathogenic (P) and likely pathogenic (LP) variants in BRCA1/2 was 13.5% (21) (13 in BRCA1 and 8 in BRCA2). The pathogenic variant in BRCA1 c.2105dupT (p.Leu702Phefs*10) was found in 3 cases (2 Lima-Callao and 1 coast). All variants identified in BRCA1 were in TNBC. In BRCA2, half of pathogenic variants were found in TNBC. The prevalence of variants of uncertain significance (VUS) was 6.4% (10). In BRCA2, we identified 7 VUS and the variant c.5465A>T (p.Asn1822Ile) was found in 3 cases with positive HR status. Only one VUS was found in BRCA1. CONCLUSION: BRCA1 and BRCA2 germline mutations were identified in 13.5% of peruvian HER2Neu negative BC patients. A higher rate of P/LP variants was found in BRCA1. TNBC patients demostrated a higher prevalence in BRCA1 variants. Citation Format: Joseph A Pinto, Yomali Ferreyra, Alicia M Cock-Rada, Franco Doimi, Jhoysi Casas, Jhajaira Araujo, Gina Rosas, Leny Bravo, Carolina Belmar-López. Landscape of germline BRCA1 and BRCA2 mutations in breast cancer in Peru [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 P3-12-24.

Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer with limited options of targeted therapy. Recent findings suggest that the clinical course of TNBC may be modified by the presence of tumor-infiltrating lymphocytes (TILs) and chemokine’s expression, such as CCL5. Diverse studies have shown that CCL5 suppresses anti-tumor immunity and it has been related to poor outcome in different types of cancer while in other studies, this gene has been related with a better outcome. We sought to determine the association of CCL5 with the recruitment of TILs and other immune cells. With this aim we evaluated a retrospective cohort of 72 TNBC patients as well as publicly available datasets. TILs were correlated with residual tumor size after neoadjuvant chemotherapy (NAC) and CCL5 expression. In univariate analysis, TILs and CCL5 were both associated to the distant recurrence free survival; however, in a multivariate analysis, TILs was the only significant marker (HR = 0.336; 95%IC: 0.150–0.753; P = 0.008). CIBERSORT analysis suggested that a high CCL5 expression was associated with recruitment of CD8 T cells, CD4 activated T cells, NK activated cells and macrophages M1. The CD8A gene (encoding for CD8) was associated with an improved outcome in several public breast cancer datasets.

Triple-negative breast cancer (TNBC) is a heterogeneous and complex disease characterized by the absence of immunohistochemical expression of estrogen receptor, progesterone receptor and HER2. These breast tumors present an aggressive biology and offer few opportunities to be treated with targeted therapy resulting in bad disease outcomes. The epidemiology of TNBC is intriguing where the understanding of its biology has progressed quickly. One of the peculiarities of this type of cancer is a high prevalence in Afrodescendants and Hispanic patients compared to Caucasian women. In this review we describe some features of TNBC, focusing in the Hispanic population, such as epidemiological, clinicopathological features and molecular features and the correlation between TNBC prevalence and the human development index.

Background: Triple-negative breast cancer (TNBC) is a heterogeneous disease with aggressive biology and complex tumor evolution. Our purpose was to identify enrichment patterns of genomic alterations in metastatic triple-negative breast cancer (mTNBC). Methods: Genomic data were retrieved (mutations and copy number variations) from 550 primary TNBC tumors from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) and The Cancer Genome Atlas (TCGA) data sets and 58 mTNBC tumors from “Mutational Profile of Metastatic Breast Cancers” and “The Metastatic Breast Cancer Project.” Statistical analysis of microarray data between primary and metastatic tumors was performed using a chi-square test, and the percentage of mutation enrichment in mTNBC cases was estimated. P-values were adjusted for multiple testing with Benjamini-Hochberg method with a false-discovery rate (FDR) Results: Seven genes with mutations were enriched in mTNBC after correcting for multiple testing. These included TTN, HMCN1, RELN, PKHD1L1, DMD, FRAS1, and RYR3. Only RPS6KB2 amplification was statistically significant in mTNBC; on the contrary, deletion of the genes TET1, RHOA, EPHA5, SET, KCNJ5, ABCG4, NKX3-1, SDHB, IGF2, and BRCA1 were the most frequent. The molecular alterations related to the hallmark of “genetic instability and mutation” were predominant in mTNBC. Interestingly, the hallmark of “activating immune destruction” was the least represented in mTNBC. Conclusion: Despite the study limitations, we identified recurrent patterns of genomic alterations with potential contribution to tumor evolution. Deletions were the aberrations more commonly found in mTNBC. Several molecular alterations are potentially targetable.

Advances in high-throughput technologies and their involvement in the ‘omics’ of cancer have made possible the identification of hundreds of biomarkers and the development of predictive and prognostic platforms that model the management of cancer from evidence-based medicine to precision medicine. Latin America (LATAM) is a region characterised by fragmented healthcare, high rates of poverty and disparities to access to a basic standard of care not only for cancer but also for other complex diseases. Patients from the public setting cannot afford targeted therapy, the facilities offering genomic platforms are scarce and the use of high-precision radiotherapy is limited to few facilities. Despite the fact that LATAM oncologists are well-trained in the use of genomic platforms and constantly participate in genomic projects, a medical practice based in precision oncology is a great challenge and frequently limited to private practice. In breast cancer, we are waiting for the results of large basket trials to incorporate the detection of actionable mutations to select targeted treatments, in a similar way to the management of lung cancer. On the other hand and paradoxically, in the ‘one fit is not for all’ era, clinical and genomic studies continue grouping our patients under the single label ‘Latin American’ or ‘Hispanic’ despite the different ancestries and genomic backgrounds seen in the region. More regional cancer genomic initiatives and public availability of this data are needed in order to develop more precise oncology in locally advanced breast cancer.

e19258 Background: Immunotherapy has changed the landscape of cancer treatment. The aim of this work was to describe the adverse events related to immunotherapy treatment in diverse type of malignant tumors using real-world data. Methods: This is a retrospective review of patients with diverse type of advanced malignancies treated with immunotherapy at Oncosalud-AUNA (Lima-Peru) during the period 2016-2018. We present a descriptive analysis of the clinicopathological and treatment features of the patients, as well as data of safety of immunotherapeutic agents. Results: In total, 37 patients were included in the study. The median age was 67 years (38 to 84 years); 64.9% of patients were male; 54.1% were smoker/former smoker and 45.9% non-smokers. Regarding to the primary tumor, 75.7% were lung cancers (82.1%, adenocarcinomas and 17.9%, squamous cell carcinomas), 16.2% were melanomas, 5.4, head and neck cancers and 2.7%, were bladder cancers. Central nervous system metastases were present in 29.7% of patients. Immunotherapy was given after a first line in 43.2% of cases, 40.5% after the second line and 16.2%, after the third line of treatment. The types of immunotherapy were prembrolizumab in 54.1%, nivolumab in 40.5%, atezolizumab in 2.7% and avelumab in 2.7%. 27% of cases had combination of immuno with chemotherapy. Finally, regarding to adverse events, 94.6% had any adverse event; 48.6% fatigue and asthenia; 35.1%, nausea; 32.4, pruritus/rash; 27.7%, decreased appetite; 18.9%, hypo/hyperthyroidism; 13.5%, diarrhea/colitis; 10.8%, pneumonitis and 5.4%, infusion-related reactions. Conclusions: During the study period we had a slightly higher incidence of adverse events than reported by other works. It could be probably due to the age of patients and several prior lines of treatment.

DDIT4 gene encodes a protein whose main action is to inhibit mTOR under stress conditions whilst several in vitro studies indicate that its expression favors cancer progression. We have previously described that DDIT4 expression is an independent prognostic factor for tripe negative breast cancer resistant to neoadjuvant chemotherapy. We herein report that high DDIT4 expression is related to the outcome (recurrence-free survival, time to progression and overall survival) in several cancer types. We performed in silico analysis in online platforms, in pooled datasets from KM Plotter and meta-analysis of individual datasets from SurvExpress. High levels of DDIT4 were significantly associated with a worse prognosis in acute myeloid leukemia, breast cancer, glioblastoma multiforme, colon, skin and lung cancer. Conversely, a high DDIT4 expression was associated with an improved prognostic in gastric cancer. DDIT4 was not associated with the outcome of ovarian cancers. Analysis with data from the Cell Miner Tool in 60 cancer cell lines indicated that although rapamycin activity was correlated with levels of MTOR, it is not influenced by DDIT4 expression. In summary, DDIT4 might serve as a novel prognostic biomarker in several malignancies. DDIT4 activity could be responsible for resistance to mTOR inhibitors and is a potential candidate for the development of targeted therapy.

Cervical cancer is the leading malignant neoplasm in Peruvian women. This malignancy is a public health problem and several efforts were previously performed to develop cancer control plans. Geographical, cultural, structural, infrastructural and procedural barriers can limit the implementation of such strategies. Several previous studies have characterized human papilloma virus (HPV) epidemiology, where prevalence of high-risk HPV in adult females is ~12% and the prevalence in cervical cancer is 90-95%. The predominant barriers for the control of cervical cancer are lack of specialists in remote villages, education/cultural issues, loss of patients in follow-up, lack of access to HPV testing and lack of compliance for HPV vaccination. A good strategy for the prevention and early detection of high-risk HPV, pre-malignant neoplasms and cervical cancer, identified by interventional studies, is the self-sampling test, which assists with overcoming the cultural and geographic barriers. The current cancer control plan, termed 'Plan Esperanza', is performed with massive training of health professionals and social sensitization campaigns leading to filling the gaps regarding education and, in addition, it provides cancer care coverage for poorer individuals. In our experience at Oncosalud-AUNA, with a cohort of ~750,000 affiliates using a pre-paid system with annual screenings for cervical cancer for women, offered free-of-charge, a lower incidence of this malignancy (5.8/100,000) is now observed compared with the national incidence (32.7/100,000). As in other countries, the HPV vaccination can be a cost-utility strategy to reduce the high burdens of cervical cancer in Peru, a rapid and cheap HPV molecular sub-typification is rapidly required.

e24325Background: POLR1C is a gene encoding a subunit common to RNA polymerases I and III. Currently, mutations in this gene are known have been associated with Treacher Collins Syndrome and hypomy...

Introduction: In a previous work we found differences in immune gene sets enrichment in NSCLC between genders, regardless their smoking status, where women had higher expression of gene sets associated with immune processes. Based in this fact, we hypothesize fewer benefits from immune checkpoint inhibitors in women patients compared than men patients. Objectives: Evaluate the benefit (in terms of progression-free survival) of women patients from immune checkpoint inhibitors nivolumab and pembrolizumab in published randomized phase III trials. Methods: We evaluated by meta-analysis four randomized phase III studies, two of prembrolizumab (Herbst et al., 2015 and Reck et al., 2016) and two of nivolumab (Borghaei et al., 2015 and Brahmer et al., 2015). We analyzed TCGA data for lung adenocarcinoma to evaluate differences in the expression of PDCD1, CD274 genes (encoding for PD-1 and PD-L1, respectively). Results: For all studies, it was observed an overall HR=0.79 (CI95%:0.71-0.87;P Conclusion: Although there are not differences between genders in the expression of PDCD1 and CD274 genes , such as is previously described for expression for PD-1 and PDL-1 proteins, in our meta-analysis we shown that women have modest benefit from anti immune checkpoint inhibitors. Blockade of PD1 and PD-L1 is a promising therapy in lung cancer; however, a better stratification of patients should be done. Meta-analysis of four phase III randomized studiesStudyAll patientsMenWomenWeightHazard Ratio IV, Fixed, 95% CIWeightHazard Ratio IV, Fixed, 95% CIWeightIV, Fixed, 95% CIReck et al., 201610.6%0.50 [0.37, 0.68]10.4%0.39 [0.26, 0.581]8.0%0.71[0.40, 1.26Brahmer et al., 201513.7%0.63 [0.48, 0.8217.8%0.63 [0.46, 0.86]11.2%0.75[0.46, 1.22]Borghaei et al., 201530.3%0.91 [0.76, 1.0926.6%0.81 [0.63, 1.04]37.8%1.02[0.78, 1.33]Herbst et al., 201545.40.85 [0.73, 0.98]45.2%0.78 [0.64, 0.95]43.0%1.04[0.81, 1.33]Total (95% Cl)100.0%0.79 [0.71, 0.87]100.0%0.71 [0.62, 0.80100.0%0.97[0.82, 1.14]Heterogeneity: Chi2=14.73,df=3 (P=0.002); I2= 80% Test for overall effect: Z= 4.73 (P Citation Format: Joseph A. Pinto, Luis A. Mas, Carlos S. Vallejos, Jhajaira Araujo, Leny Bravo, Alfredo Aguilar, Zaida Morante, Denisse Bretel, Henry L. Gomez, Christian Rolfo. Decrease of benefit from immune checkpoint inhibitors in women with non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2614. doi:10.1158/1538-7445.AM2017-2614

In a meta-analysis, our team identified previously that DDIT4 expression is related with a worse outcome of several cancer types, including acute myeloid leukemia (AML). DDIT4 gene product is a repressor of mTOR activity and recent findings in the triple negative breast cancer model suggest that mTOR pathway inhibition lead to the enrichment of cancer stem cells, explaining indirectly the relationship between DDIT4 and the outcome and suggesting that a high DDIT4 expression could be related with expression of stem-cells markers, such as NOTCH1. We evaluated 200 AML patients from the TCGA dataset. Clinical features and level 2 data of gene expression were retrieved from the website cbioportal.org for mTOR pathway and stem cell markers including ALDH genes. Gene Set Enrichment Analysis (GSEA) for biological processes was done comparing patients with high risk vs low risk determined by molecular abnormalities. GSEA analysis found not differences in the mTOR pathway. DDIT4 is not included in none gene ontology datasets. NOTCH1 and DDIT4 expression was enriched in patients with high molecular risk and statistical differences were found mainly between good and poor prognostic groups (score -0.45 and -0.46, respectively). We next compared the correlation between DDIT4 and NOTCH1 in the entire cohort. The correlation was significant (R2=0.121; P This work shows the relevance of DDIT4 and NOTCH1 in the biology of AML and his association with most undifferentiated subtypes. Association between DDIT4 with NOTCH1 should be evaluated with the intention of explore therapeutic opportunities. Disclosures No relevant conflicts of interest to declare.