Breast Cancer Cases Research Articles

Germline pathogenic variants associated with triple-negative breast cancer in US Hispanic and Guatemalan women using hospital and community-based recruitment strategies

PurposeRecruit and sequence breast cancer subjects in Guatemalan and US Hispanic populations. Identify optimum strategies to recruit Latin American and Hispanic women into genetic studies of breast cancer.MethodsWe used targeted gene sequencing to identify pathogenic variants in 19 familial breast cancer susceptibility genes in DNA from unselected Hispanic breast cancer cases in the US and Guatemala.Recruitment across the US was achieved through community-based strategies. In addition, we obtained patients receiving cancer treatment at major hospitals in Texas and Guatemala.ResultsWe recruited 287 Hispanic US women, 38 (13%) from community-based and 249 (87%) from hospital-based strategies. In addition, we ascertained 801 Guatemalan women using hospital-based recruitment. In our experience, a hospital-based approach was more efficient than community-based recruitment. In this study, we sequenced 103 US and 137 Guatemalan women and found 11 and 10 pathogenic variants, respectively. The most frequently mutated genes were BRCA1, BRCA2, CHEK2, and ATM. In addition, an analysis of 287 US Hispanic patients with pathology reports showed a significantly higher percentage of triple-negative disease in patients with pathogenic variants (41% vs. 15%). Finally, an analysis of mammography usage in 801 Guatemalan patients found reduced screening in women with a lower socioeconomic status (p < 0.001).ConclusionGuatemalan and US Hispanic women have rates of hereditary breast cancer pathogenic variants similar to other populations and are more likely to have early age at diagnosis, a family history, and a more aggressive disease. Patient recruitment was higher using hospital-based versus community enrollment. This data supports genetic testing in breast cancer patients to reduce breast cancer mortality in Hispanic women.

Abstract 1643: Relative telomere length analysis in breast cancer patients with TP53 p.R337H and XAF1 p.E134* germline variants

Abstract Background: Telomere deregulation is one of the forms of genomic instability, an enabling characteristic of the cancer hallmarks. The TP53 gene plays a fundamental role in genome integrity maintenance by controlling cell cycle, apoptosis, senescence, and DNA repair. The germline variant TP53 p.R337H, a low penetrance variant, has been described in several types of cancer, including sporadic and familial breast cancer. The XAF1 p.E134*, a germline variant of the tumor-suppressor gene X-linked inhibitor of apoptosis (XIAP)-associated factor 1 (XAF1), is a genetic modifier of p53 function and was found to co-segregate with TP53 p.R337H variant on the 17p13 region. The main objective of this study was to determine the impact of the TP53 p.R337H and XAF1 p.E134* germline variants on the relative telomere length (RTL) in breast cancer patients. Materials and methods: Peripheral blood samples from three distinct groups of patients were collected: patients with breast cancer (BC; n=56) (test group), patients with other types of cancer (non-BC; n=59), and individuals without cancer and cancer family history (non-CA; n=100) (control groups). The samples were genotyped for the TP53 p.R337H and XAF1 p.E134* variants. The RTL analysis was performed by RT-qPCR, using primers for the TEL gene (T) and 36B4 gene (S) (reference) and calculated based on the T/S ratio. Results: BC cases with TP53 p.R337H variant exhibited higher RTL compared to cases without the variant. No RTL differences were observed for the XAF1p.E134* variant or for the concomitant presence of these variants. However, in the non-BC cases higher RTL were observed in all the cases positive for the variants compared to the negative cases. The same was observed for the BC and non-BC cancer cases combined (CA cases). In the non-CA cases no difference in the RTL was observed in relation to the variants. The stratification of the cases by age (≤ or &amp;gt;45 years old), showed that the TP53 p.R337H variant was significantly associated to longer telomeres in the BC and CA patients across all ages. XAF1 p.E134* showed age-dependent effects, with longer telomeres in BC and CA patients ≤ 45 years. Non-BC cases had similar results. Conclusion: This study indicates that TP53 p.R337H significantly impacts telomere length in BC cases, while XAF1 p.E134* shows age-dependent effects. Despite the observed variability, these findings highlight an association between these germline variants and telomere length regulation. Further research is needed to elucidate the functional impact and underlying mechanisms of these variants, particularly in the context of breast cancer. Citation Format: Larissa M. Okano, Stéfanne M. Bortoletto, Mariana Paraizo, Aline S. Fonseca, Bonald C. Figueiredo, Enilze M F. Ribeiro, Ariana Centa, Luciane R. Cavalli. Relative telomere length analysis in breast cancer patients with TP53 p.R337H and XAF1 p.E134* germline variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1643.

Abstract 6256: Prevalence of BRCA1 and BRCA2 proteins in breast cancer in a nigerian population and their relationship with different breast cancer morphological variants

Abstract Background: Breast cancer is the commonest site specific cancer in women and a leading cause of cancer death among women in Nigeria and globally. The trend in Nigeria and Africa is that breast cancers are seen in younger age groups, are of higher grades and follow an aggressive course. It has been suggested that this may largely be due to mutation in BRCA genes with the attendant alteration in function of its proteins. This study aimed at determining the prevalence of BRCA1 and BRCA2 proteins in breast cancers seen in our environment as well as to see any association between these proteins and different morphological variants. Materials and Methods: A descriptive study using tissue blocks of all histologically diagnosed breast cancer in our department between 2013 and 2017. Fresh sections were recut for histological grading and immunohistochemistry. Proteintech BRCA1 and BRCA2 polyclonal antibodies and detection kit were used. Results: One hundred and thirty (130) cases met the inclusion criteria for this study. The mean (SD) age of the patients was 44.8 (10.3) years with ages ranging from 26 to 79 years. There were more cases of breast cancer (73.1%) seen before 50 years. Two (2) Male Breast Cancer (MBC) cases were seen, giving the female to male ratio of 64:1. The commonest morphological variant encountered was Invasive Carcinoma, No Special Type at 84.6% of cases. This was followed by invasive medullary (7.8%). The least common variant was papillary cancer at 0.8%. The tumors seen were mostly grade 3 (71.2%), followed by grade 2 at 22.7% and the least was grade 1 at 6.1%. Positivity for BRCA1 and BRCA2 proteins was seen in 27.7% and 30.0% of cases respectively. One of the MBC showed reactivity for BRCA1 protein. No significant relationship was seen between BRCA 1/2 proteins expression and age or breast cancer histotypes. Conclusion: BRCA 1 and 2 proteins are an important risk factor for breast cancers seen in this environment. However, there is no association with age distribution and morphological variants of the breast cancer in our population. Citation Format: Solomon Raphael, Abdul Oluwasesan. Prevalence of BRCA1 and BRCA2 proteins in breast cancer in a nigerian population and their relationship with different breast cancer morphological variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6256.

Abstract 5722: Preclinical activity of CDK4/6 inhibitor alone or in sequential combination with chemotherapy using breast cancer cell line-derived organoid culture

Abstract Breast cancer ranks as the most prevalent cancer globally, with lung and colorectal cancers following closely. Dysregulation of the cyclinD:CDK4/6:Rb axis has been shown to be a common feature in a number of human malignancies, including breast cancer. Targeting this pathway has emerged as a promising strategy for breast cancer treatment. Currently, the U.S. Food and Drug Administration has approved three CDK4/6 inhibitors for advanced hormone receptor-positive, HER2-negative breast cancer, when used in combination with endocrine therapy. However, there are still many breast cancer cases that do not qualify for these criteria and, therefore, do not benefit from CDK4/6 inhibitors prompting investigations into their potential synergy between CDK4/6 inhibitors with chemotherapy. Efforts are currently being made to test the application of these drugs in combination with chemotherapy. Previous studies have demonstrated a synergetic effect of combining CDK4/6 inhibitors and other therapies to treat breast and prostate cancers. While many studies administer these drugs concurrently, our hypothesis proposes a sequential combination approach. This method involves arresting cell cycle at the G0G1 phase using CDK 4/6 inhibitors and then releasing the drug when the cells are more vulnerable to chemotherapy treatment. Such an approach has the potential to expand the application of CDK4/6 inhibitors beyond ER+/HER2- breast cancer. The primary objective of this study is to evaluate the effectiveness of CDK4/6 inhibitors, both alone and in sequential combination with chemotherapy, across a range of breast cancer subtypes. Breast cancer cell lines (MDA-MB-231, HCC70 and T47D) were used in the study. For each cell line, a total of 3x105 cells were seeded in a 6-well plate, and after an overnight incubation, the media was changed with or without a CDK4/6 inhibitor (abemaciclib) and cultured for up to 72 hours. We monitored the drug's efficacy through flow cytometry and cell counting. Abemaciclib suppressed cell proliferation and cell cycle in G0G1 phase in the treated cells compared with the control. The results were similar in both receptor-positive and triple-negative breast cancer cell lines. The effect of abemaciclib was dose-dependent, and reversible at least 48 hours after drug withdrawal, suggesting an opportune time for administering chemotherapy. Future research will delve into investigating the efficacy of sequential treatment with chemotherapy after CDK 4/6 inhibitor withdrawal, utilizing 2D and 3D culture systems. Citation Format: Moses Kamita, Haythem Ali, Evelyn Jiagge, Jessica Bensenhaver, Eleanor Walker. Preclinical activity of CDK4/6 inhibitor alone or in sequential combination with chemotherapy using breast cancer cell line-derived organoid culture [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5722.

Abstract 325: Validation of Aventa FusionPlus: An LDT NGS assay for comprehensive cancer genomic profiling

Abstract Next-generation sequencing (NGS) assays play a pivotal role in illuminating the genomic landscape of cancer by providing insights into gene regulation and biomarker detection for the purpose of guiding therapeutic decisions to advance personalized medicine. We validated the Aventa FusionPlus Test, a Laboratory-Developed Test (LDT) that integrates HiC technology to enhance detection of actionable gene fusions and rearrangements in solid tumors, including those that are missed by current standard of care tests. This is a DNA-based test that is robust to DNA degradation in FFPE specimens, in contrast with RNA-seq and long-read technologies. The test utilizes the Element Biosciences AVITI sequencing platform to achieve high quality sequencing data at low cost per sample. The Aventa FusionPlus test enables gene-level detection of structural variants near or within 361 medically actionable or diagnostically relevant cancer genes. The 3D structure and long-range linkages captured by the test amplify the signal counts for each rearrangement. The test integrates the Arima-HiC+ FFPE sample prep and the Arima Library Prep Kit workflow. After dewaxing and rehydrating the FFPE tissue, the chromatinized DNA is fragmented and the fragmented ends are filled in with a biotinylated nucleotide. Next, spatially proximal fragmented ends of DNA are ligated, capturing the 3D structure of the genome. The proximally-ligated DNA is then purified and further fragmented, and the biotinylated ligation fragments are enriched. DNA libraries are prepared from these enriched fragments and sequenced in “paired-end” mode. Genes involved in genomic rearrangements were detected using the Arima-SV pipeline along with manual curation. The test achieved robust detection of structural variants, with accuracy of 98.8% relative to reference methods. FFPE tumor specimens from 10 different tissue types and a wide range of tumor content (20%-100%) were included. No correlation between tumor cellularity and sensitivity was observed, suggesting that samples with as low as 20% tumor cellularity can be tested. When comparing to RNA-based and other targeted reference methods, we found additional fusions nearby oncogenes missed by these reference methods. As an example, in a breast cancer case, a fusion of genomic regions neighboring BRAF and MYC oncogenes on chromosomes 7 and 8 respectively, was missed by the reference method but was successfully detected by the Aventa FusionPlus test. The Aventa FusionPlus test is a highly sensitive, specific, and accurate method for comprehensive cancer genomic profiling. The enhanced understanding of gene fusions and rearrangements positions the test as a valuable tool for clinical decision-making in oncology. Citation Format: Shadi Melnyk, Jon Belton, Sofia Nomikou, Katelyn Powell, Daniel Heiney, Roy Khalife, Damien Jones, Anthony Schmitt, Catherine Wilson, Melissa Won, Anthony Magliocco, Chris Roberts. Validation of Aventa FusionPlus: An LDT NGS assay for comprehensive cancer genomic profiling [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 325.

Abstract 4855: Identifying hot spots of breast cancer and industrialized areas in Hermosillo, Sonora, Mexico

Abstract Background: Sonora, a state in Mexico, has the highest rates of breast cancer in the country and has a history of industrial pollution. These factors may contribute to an increased risk of breast cancer. Hermosillo, the state capital, exhibits both of these characteristics. Given these conditions, it is important to further evaluate the prevalence of breast cancer hotspots and the potential links between breast cancer and industrialized areas. Objective: Identify breast cancer hot spots and their association to industrialized areas in Hermosillo, Sonora, Mexico. Methods: This study collected clinical data on breast cancer cases (current, survivors, deceased) from hospital files in Hermosillo that were 10 years old. The primary unit of analysis was neighborhoods. The study estimated breast cancer prevalence by analyzing the number of females per neighborhood, based on data reported by INEGI Census 2020. The data was categorized by age groups (age group no. 1 of 18 to 59 years old, no. 2 of 60 to 64 years old, and no. 3 of 65 years old or older). The estimated prevalence was depicted on a map using ArcGIS software, version 10.8.2. Hot spot analysis was used to identify neighborhoods with high breast cancer prevalence. The study also categorized neighborhoods as industrialized areas if they contained at least six hazard-generator industries. Results: A total of 1394 cases of breast cancer were gathered from hospitals. Location information for 3697 industries was provided by INEGI. Out of the 756 neighborhoods studied, 95 (12.6 %) were found to be industrialized areas, while 661 (87.4 %) were non-industrialized. Four neighborhoods in Hermosillo's southeast were observed to have breast cancer hot spots (unadjusted). After adjusting for age, one hot spot was found in the southeast for age group no. 1 (one neighborhood), while hot spots for group no. 2 (three neighborhoods) and no. 3 (33 neighborhoods) were in Hermosillo's northwest. The hot spots were related to industrialized areas (unadjusted OR = 6.94, 95% CI (0.94, 50.8), p-value = 0.05). After age adjustment, this association was statistically significant for group no. 3 (OR = 2.70, 95% CI (1.27, 5.72), p-value = 0.009), but not for group no. 1 (OR = 1.69, 95% CI (0.06, 41.74), p-value = 0.748) or group no. 2 (OR = 2.56, 95% CI (0.23, 28.46), p-value = 0.44). Conclusions: Our research found a link between industrialized areas and high breast cancer rates. We also found hotspots for women aged 65+ in Hermosillo, with 33 affected neighborhoods in the city's northwest. This is the first comprehensive study examining breast cancer prevalence in Hermosillo over a ten-year period. More extensive studies are needed in other cities in Sonora, Mexico, to confirm our findings. Citation Format: Diana Evelyn Villa-Guillen, Aurelio A. Mata-Valenzuela, Hector Tecuanhuey-Tlahuel, Andres M. Galvez-Arevalo, Kenneth L. Garcia-Castellon, Yoahana E. Guzman-Hernandez, Karla S. Ortega-Landa, Fatima Y. Pelayo-Rodriguez, Jose R. Silva-Rivera, Rogelio A. Ureña-Acosta, David O. Garcia, Jorge A. Villa-Carrillo. Identifying hot spots of breast cancer and industrialized areas in Hermosillo, Sonora, Mexico [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4855.

Abstract 5686: Identifying rare microRNA risk variants for hereditary breast cancer in African American individuals

Abstract Background: In the United States, breast cancer is the most frequently diagnosed cancer in women. However, African American women tend to have a higher incidence of triple negative breast cancer cases, and an earlier age of disease onset, which are hallmark characteristics of heredity disease. Even with current breakthroughs in breast cancer research, limited research participation from women of African descent has led to a gap in our knowledge of heredity factors that are involved in disease in this population. Furthermore, most breast cancer research has focused on protein coding genes being the culprit of tumorigenesis; however, within the last three decades, research efforts have begun to focus on noncoding RNAs, like microRNAs (miRNAs), as potential factors to promote carcinogenesis. miRNAs are short, noncoding RNA molecules that control gene expression at the post-translational level. miRNAs have several mechanisms to affect gene expression of cellular processes like cell proliferation, apoptosis, invasion, and metastasis. However, the identification and functional role miRNA risk variants play in African American breast cancer is still not fully understood. Methods: 30X whole genome sequencing (WGS) was carried out on an Illumina platform on blood- or saliva-derived DNA from 120 African American breast cancer cases from the Alabama Hereditary Cancer Cohort. The WGS data was analyzed using our established bioinformatics pipeline, which has been adapted from the Genome Analysis Toolkit (GATK) Best Practice Pipeline. Focusing on miRNA variants as risk factors, a miRNA BED file was used to extract regions harboring miRNA genes. The resulting file was then filtered for rare miRNA variants (minor allele frequency &amp;lt;1%) in the African American population based on the Genome Aggregation Database (gnomAD) allele frequency. P-values for variants of interest were calculated using Fisher’s Exact tests. Results: Sequencing data have revealed three rare miRNA variants from our African American cohort that can be potentially associated with breast cancer risk. Upon statistical analysis comparing allele frequencies between the African American general population and the Alabama Hereditary Cancer Cohort, miR7850, miR3145, and miR8074 had p-values 5.21E-05, 3.58E-05, and 2.19E-04, respectively. Conclusions: We have identified three rare miRNA variants that were not previously known to be associated with breast cancer risk. Interestingly, both miR7850 and miR8074 target TP53 and miR3145 targets GREM1 and PALB2, which these targets are known breast cancer susceptibility genes. Understanding the consequence of these variants is important to add to our knowledge of miRNAs that play critical roles in carcinogenesis leading to better treatment strategies. Citation Format: Sheniqua R. Glover, Troy LoBue, Nancy D. Merner. Identifying rare microRNA risk variants for hereditary breast cancer in African American individuals [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5686.

Abstract 1716: A proteome-wide association study identifies putative causal proteins for breast cancer

Abstract Background: Genome-wide association studies (GWAS) have identified over 200 breast cancer risk associated genetic loci, yet the causal genes and biological mechanisms for most loci remain elusive. Proteins, as final gene products, are pivotal in cellular function. In this study, we conducted a proteome-wide association study (PWAS) to identify proteins in breast tissue in relation to breast cancer risk. Methods: We profiled the proteome in breast tissue samples from 120 cancer-free European-ancestry women from the Susan G. Komen Tissue Bank. Protein expression levels were log2 transferred and then normalized via quantile and inverse-rank transformations. The elastic net method was used to build statistical models to predict protein expression levels via genetic variants. The prediction models were then applied to the GWAS summary statistics data of 133,384 breast cancer cases and 113,789 controls to assess the associations of genetically predicted protein expression levels with breast cancer risk overall and its sub-types using the S-PrediXcan method. Results: A total of 6,388 proteins were detected in the normal breast tissue samples from 120 women with a high detection false discovery rate (FDR). Among the 5,823 proteins detected in more than 80% of participants, prediction models were successfully built for 2,041 proteins with R&amp;gt;0.1 and P&amp;lt;0.05. Among these 2,041 proteins, six proteins were significantly associated with overall breast cancer risk at an FDR P&amp;lt; 0.05. Among these six proteins, the corresponding genes for proteins DCTN3 and DDX6 were located at least 500kb away from the GWAS-identified breast cancer risk variants. Both DCTN3 and DDX6 were associated with a decreased risk of breast cancer with P values of 8.46 × 10−4 and 2.27 × 10−4, respectively. The corresponding genes for the remaining four proteins, LMNA, LSP1, RPS6KA5, and DNAJA3, were located in previously GWAS-identified breast cancer risk loci. After adjusting for GWAS-identified risk variants, the associations for LMNA and RPS6KA5 were still significant (P=2.54 × 10−7 and 2.79 × 10−5, respectively), however, the associations for LSP1 and DNAJA3 became weaker with P values of 0.65 and 2.10 × 10−4 respectively.Stratification analyses by breast cancer subtypes identified three proteins, LMNA, LSP1, and NCKAP1L, associated with luminal A, luminal B, and ER-positive subtypes. NCKAP1L was located at least 500kb away from risk loci. After adjusting for GWAS-risk variants, the associations for LMNA were still significant (P=2.58 × 10−5 and 4.08 × 10−6 for luminal A and ER-positive respectively). Conclusion: We conducted the first breast-tissue-based PWAS and identified seven proteins associated with breast cancer, including six proteins that were not previously implicated. These findings help improve our understanding of the underlying genetic mechanism of breast cancer development. Citation Format: Tianying Zhao, Shuai Xu, Jie Ping, Guochong Jia, Yongchao Dou, Bing Zhang, Xingyi Guo, Qiuyin Cai, Xiao-Ou Shu, Wei Zheng, Jirong Long. A proteome-wide association study identifies putative causal proteins for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1716.

Metformin and other anti-diabetic medication use and breast cancer incidence in the Nurses' Health Studies.

We aimed to examine the association between the use of metformin and other anti-diabetic medications and breast cancer incidence within two large prospective cohort studies. We followed 185,181 women who participated in the Nurses' Health Study (NHS; 1994-2016) and the NHSII (1995-2017), with baseline corresponding to the date metformin was approved for type 2 diabetes (T2D) treatment in the US Information on T2D diagnosis, anti-diabetes medications, and other covariates was self-reported at baseline and repeatedly assessed by follow-up questionnaires every 2 years. Breast cancer cases were self-reported and confirmed by medical record review. Hazard ratios (HRs) and 95% confidence intervals (CIs) for the association between medication use and breast cancer were estimated using Cox proportional hazards regression models, adjusting for breast cancer risk factors. During 3,324,881 person-years of follow-up, we ascertained 9,192 incident invasive breast cancer cases, of which 451 were among women with T2D. Compared with women without T2D (n = 169,263), neither metformin use (HR = 0.97; 95% CI = 0.81-1.15) nor other anti-diabetic medications use (HR = 1.11; 95% CI = 0.90-1.36) associated with significantly lower breast cancer incidence. Among women with T2D (n = 15,918), compared with metformin never users, metformin ever use was not significantly inversely associated with breast cancer (HR = 0.92; 95% CI = 0.74-1.15). Although we observed that past use of metformin was inversely associated with breast cancer in the T2D population (HR = 0.67; 95% CI = 0.48-0.94), current use (HR = 1.01; 95% CI = 0.80-1.27) and longer duration of metformin use were not associated with breast cancer (each 2-year interval: HR = 1.01; 95% CI = 0.95-1.07). Overall, metformin use was not associated with the risk of developing breast cancer among the overall cohort population or among women with T2D.

Abstract 6440: Novel N-myristoyltransferase immunohistochemistry-based predictive and prognostic tests for breast cancer

Abstract Breast cancer (BC) is the most common cancer worldwide, surpassing lung cancer incidence for the first time in 2020, and is the most common cancer diagnosed in American women. Despite the relative success of endocrine therapies in treating hormone receptor-positive (HR+) BC, de novo and developed resistances to these therapies (endocrine resistance) are still significant concerns. Furthermore, triple-negative breast cancer has a poor prognosis and remains one of the most challenging cancers to treat. We have discovered that the expression and localization of N-myristoyltransferase 2 (NMT2) could be prognostic and predictive markers for metastatic BC. We determined the expression patterns of NMT2 by immunohistochemical (IHC) analyses on primary tumor samples from treatment naïve BC patients. This retrospective study was blinded, and the tumor tissues in duplicate were stained with NMT2 monoclonal/polyclonal antibodies on an autostainer (Leica Bond). Stained slides were scored, and an "H" score representing the intensity and percent positive cells was given to each sample. In a combined cohort of BC represented by ER+, Triple Positive, and Triple Negative (n= 598) cases, we determined the expression and localization of NMT2. The localization pattern of NMT2 turned out to be a significant prognostic and predictive molecular signature. The nuclear localization serves as both prognostic and predictive markers. In a cohort of 447 ER+ BC cases that included 18 triple positive cases, the majority of the cases showed negative staining for nuclear NMT2 (n=394) and positive nuclear staining with differential expression in 53 cases. Whereas, in a cohort of 151 TNBC cases, nuclear NMT2 staining was positive in most cases (n= 116) and negative in 20 cases (undetermined; n= 15). The most important finding was the dichotomy of the nuclear NMT2 staining in predicting treatment response and prognosis. Both high cytoplasmic H score (&amp;gt;180) and positive nuclear staining (&amp;gt;0) predicted significant association with worse clinical outcomes for OS (HR = 1.72, P = .0284, 95% CI 1.06 to 2.81 for cytoplasmic NMT2 and HR = 1.74, P = 0.0006, CI 1.27 to 2.39 for the nuclear NMT2). Nuclear NMT2 status alone predicted a significant association with worse clinical outcomes to RFS (HR = 1.56, P = 0.0027, CI 1.17 to 2.09). The data from our study indicate that NMT2 could be a potential marker for predicting the likelihood of recurrence of BC and become part of routine first-line prognostic and predictive tests. Citation Format: Anuraag Shrivastav, Dean Reddick, Abinash Meher, Shailly Varma Shrivastav, Sahil Mittal, Vijayakrishna K. Gadi, Leigh Murphy. Novel N-myristoyltransferase immunohistochemistry-based predictive and prognostic tests for breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6440.

Abstract 4854: Breast cancer incidence trends in Ukraine 2010-2019: Rising incidence at young ages

Abstract Background. BC commonly affects women of older age, however, in developing countries around 20-25% cases of BC presented in young woman. Age-specific clinical characteristics or outcomes data for young women are lacking. Most of the standard treatments used in this subpopulation currently are derived from older patients. Early onset BC is often defined aggressive in nature. Several research have attributed this to a hidden unique biology. However, findings remain controversial. Purpose: The aim of this study is to describe recent trends for BC incidence in Ukraine since 2010 by age groups and interpret them to seek clue for improvement. Methods: We analyzed records from the NCR on 143420 BC cases (C50, International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10)) diagnosed in 2010-2019 in female Ukrainian population. The data were submitted on the beginning of 2022. We calculated annual age-standardized incidence rates (ASRWs) for three age groups. The estimated annual percent change (EAPC) of the rates was calculated using the generalized linear regression. The difference of the rates with its statistical significance was determined with the standardized rate ratio. Results: During 2010-2019, the proportion of BC in all cancers detected at the age of 20-44 increased from 21.7% to 25.9%, while the frequency of BC detection at the age of 45+ did not change and ranged 19.3-20.2%. During the study period, the BC incidence rate has increased significantly (≤0.01): the ASRW of females aged 0-85+ grew with EAPC=0.6% amounting to 42.4-45.7 per 100,000 population, the incidence rate of women aged 45+ grew with EAPC=0.3% ranging from 130.0 to 139.6 per 100,000 population, while the incidence rate of women aged 20-44 grew with EAPC=1.8% amounting to 22.8-27.8 per 100,000 population. In age group 20-44 years, EAPC of BC incidence (1.8%) significantly exceeds the EAPC of the incidence for all cancers combined (0.2%). The dynamics of stage distribution showed increasing proportion of BC cases detected in women aged 20-44 in stage 1 (by 4.1% from 2010 to 2019) and its decreasing for BC cases detected in stage 2 by 4.5%; the proportion of cases diagnosed in stage 4 decreased by 0.5% along with increase in number of cases with undefined stage by 0.6%. Conclusions: The obtained results indicate trends for increasing the incidence of Early Onset BC in Ukraine and justify need for the further research elucidating prognosis and validating novel biomarkers for customizing therapy for this patient group . Citation Format: Nataliia Verovkina, Olena Sumkina, Liubov Syvak, Wafik El-Diery. Breast cancer incidence trends in Ukraine 2010-2019: Rising incidence at young ages [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4854.

Abstract 6141: Genetic risk, health-associated lifestyle, and risk of early-onset total cancer and breast cancer: A prospective cohort study

Abstract Background Early-onset cancer (diagnosed under 50 years of age) is generally more aggressive. Its rising incidence is a global concern. The associations between genetic risk, lifestyle, and the risk of early-onset cancer may inform preventive strategies. Methods We studied the association between genetic risk, lifestyle and early-onset cancers among 66308 white British participants enrolled in the UK Biobank before age 50. Genetic risk was assessed using sex-specific composite total cancer polygenic risk scores (PRSs). We calculated composite PRSs as weighted sums of previously-developed cancer site-specific PRSs using weights obtained from lasso regression. We considered a breast cancer-specific PRS for analyses on breast cancer among women. A health-associated lifestyle score (HLS) was calculated based on baseline smoking, BMI (men only), physical activity, alcohol intake, and diet. Cox models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of early-onset total cancer and breast cancer across genetic risk and HLS groups in women and men. Results A total of 1247 incident invasive early-onset cancer cases (820 in women, 427 in men) were documented, including 386 cases of early-onset breast cancer. In multivariable-adjusted analyses with 2-year latency, higher genetic risk (highest vs. lowest tertile of PRS) was associated with significantly increased risks of early-onset total cancer in women (composite PRS HR=1.85; 95% CI, 1.50-2.29), early onset total cancer in men (composite PRS HR=1.94; 95% CI, 1.45-2.59), and early-onset breast cancer in women (breast-cancer PRS HR=3.06; 95% CI, 2.20-4.25). The HRs (95% CI) of early-onset total cancer in women and men, and early-onset breast cancer in women associated with adopting an unfavorable lifestyle (highest vs. lowest tertile of HLS) were 1.49 (0.99, 2.25), 1.14 (0.67, 1.95), and 1.78 (0.97, 3.24), respectively, in the total study population; 1.85 (1.02, 3.36), 3.27 (0.78, 13.72), and 1.67 (0.71, 3.90), respectively, in those with high genetic risk; 1.25 (0.60, 2.57), 1.11 (0.42, 2.89), and 1.66 (0.54, 5.11), respectively, in those with intermediate genetic risk; and 1.15 (0.44, 2.98), 1.16 (0.39, 3.40), and 2.10 (0.57, 7.75), respectively, in those with low genetic risk. Compared to individuals with both low genetic risk and a favorable lifestyle, those with high genetic risk and an unfavorable lifestyle had substantially increased risks of early-onset total cancer in women (3.07; 1.64-5.78) and men (2.18; 0.78-6.11), and significantly higher early-onset breast cancer risk in women (4.11; 1.56-10.85). Conclusion Genetic and lifestyle factors were independently associated with risks of early-onset total cancer and breast cancer. Compared to those with low genetic risk, individuals with a high genetic risk may benefit more from adopting a healthy lifestyle in preventing early-onset cancer. Citation Format: Yin Zhang, Yuxi Liu, Kathryn L. Penney, Sara Lindström, Peter Kraft. Genetic risk, health-associated lifestyle, and risk of early-onset total cancer and breast cancer: A prospective cohort study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6141.

Abstract 573: SLC22A17 as a promising target for triple-negative breast cancer

Abstract Introduction: Triple-negative breast cancer (TNBC) represents a highly aggressive subtype of breast cancer, accounting for approximately 15% of all cases of invasive breast cancer globally. The absence of a well-defined cell membrane receptor has significantly limited the therapeutic options available for treating this malignancy. Consequently, there is a compelling need to explore novel receptors that could potentially revolutionize the treatment strategies employed for TNBC. Recent scientific research has unveiled SLC22A17, a cell surface receptor known for its involvement in iron transport, as a substantial contributor to the development of various cancer types. Thus, the primary objective of this study is to comprehensively evaluate the significance of SLC22A17 and its potential as a therapeutic target in TNBC. Experimental Procedures: In this study, we meticulously examined the expression patterns of SLC22A17 across distinct subtypes of breast cancer utilizing immunohistochemistry. Computational tools were employed to delve into the role of SLC22A17 within TNBC datasets. To assess the impact of SLC22A17 on TNBC, we employed various methods, including siRNA-mediated silencing, to investigate its role in cell proliferation, apoptosis, epithelial-mesenchymal transition (EMT), and migration. Additionally, we conducted western blot analyses to assess the expression levels of SLC22A17 and cellular signaling molecules, such as Akt/mTOR and JAK/STAT, within the context of TNBC cells. Results: Our analysis revealed a significant upregulation of SLC22A17 in both TNBC tissues and cell lines, establishing a direct correlation with patient survival outcomes. Silencing the expression of SLC22A17 resulted in reduced cell proliferation, migration, EMT, increased apoptosis, and enhanced autophagy. These effects were accompanied by the inhibition of Akt/mTOR and STAT3 signaling pathways. Moreover, we observed the involvement of the inflammatory cytokine TNF-α, which induced the expression of SLC22A17 in TNBC cell lines and governed various hallmark features of TNBC. Notably, the suppression of SLC22A17 mitigated these processes. Conclusion: In conclusion, this investigation suggests the pivotal role played by SLC22A17 in TNBC and posits its potential as a novel and promising therapeutic target for the management of this formidable disease. Citation Format: Ajaikumar B. Kunnumakkara, Krishan Kumar Thakur. SLC22A17 as a promising target for triple-negative breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 573.

Abstract 5728: YB1 is a novel therapeutic for the treatment of triple negative breast cancer tumors

Abstract Metastatic breast cancer (BC) is the 2nd leading cause of death in women in the US, annually accounting for more than 43,000 deaths and 281,000 new cases of invasive BC. Amongst genetically distinct BC subtypes, those classified as being “triple-negative” (TNBC) are especially devastating due to their highly metastatic behavior, their propensity to recur rapidly, and their low response to standard-of-care therapies. In fact, the acquisition of chemoresistant phenotypes represents the main cause of disease recurrence, metastasis, and death in TNBC patients. Currently, the molecular mechanisms that regulate TNBC progression and metastasis remain unknown, as does the way these metastatic tumors acquire resistance to standard-of-care therapies. We recently established YB1 as a novel driver of these deadly TNBC activities, doing so by stimulating the cancer stem cell phenotype, and by disrupting normal cell cycle progression, therefore promoting therapy resistance and metastasis of TNBC tumors. YB1 is a multifunctional protein that acts as a transcription factor of cancer stem cell genes Nanog, Oct and Sox. Moreover, aberrant activation of YB1 contributes to the metastatic progression of several cancers, including TNBC. Our investigations revealed a major role of YB1 in the regulation of several hallmarks of cancer that drive TNBC tumors progression and metastasis, both in vitro and in preclinical mouse models of TNBC tumors. In extending these discoveries, we now show that aberrant YB1 expression activates oncogenic signaling leading to the dysregulation of cell cycle progression through the regulation of the Cyclin D/CDK4/6 complex signaling and the RB pathway. We also report the identification of a novel small molecule inhibitor, SU056, that specifically targets YB1 and inhibits its oncogenic activity in TNBC cell lines. We further show that the SU056-mediated inhibition of YB1, either as monotherapy or in combination with the CDK4/6 inhibitors, has a significant impact on inhibiting TNBC tumor progression and metastasis. In fact, the SU056-CDK4/6 inhibitors combination showed a synergistic effect when compared to monotherapy, at the same time reducing the toxicity associated with CDK4/6 inhibitors. Mechanistically, our studies revealed that genetic or pharmacologic targeting of YB1 inhibits TNBC tumor progression and metastasis through the regulation cyclin D-CDK4/6-RB pathway and blockade of cell cycle progression. Together, our data support the notion that targeting YB1 represents a potential therapeutic option for the treatment of TNBC, which could be enhanced when combined with standard of care treatment modalities. Citation Format: Wei Wang, Lamyae El Khalki, Neelum Yousaf Zai, Justin Szpendyk, Akram Alkrekshi, Bin Su, Khalid Sossey-Alaoui. YB1 is a novel therapeutic for the treatment of triple negative breast cancer tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5728.

Abstract 275: Deciphering biphasic responses to Sonic Hedgehog pathway inhibition in breast cancer: Insights from a tumor-fibroblast spheroid model and PDXs

Abstract A significant subset (30-40%) of triple-negative breast cancer (TNBC) cases exhibit hyperactivation of the sonic hedgehog (SHH) pathway, correlating with poor clinical outcomes. However, the therapeutic efficacy of SHH inhibitors in TNBC has yielded inconsistent results, showcasing biphasic tumor responses going from complete remission in some patients to faster disease progression in others. Such tumor response discrepancies underscore the need for more relevant culture models to elucidate how stromal cells respond to SHH signals and impact tumor cell reprogramming.We have developed a tumor-fibroblast spheroid model of robust paracrine SHH signaling to examine alterations in aggressive tumor cell phenotypes resulting from altered SHH pathway activity levels to understand better how SHH therapy leads to biphasic effects in tumor tissues. Specifically, tumor stemness alterations were examined as a function of SHH signal strength altered by tumor-fibroblast proximity, and findings were confirmed in two PDX models of TNBC of divergent sensitivity to pharmacological SHH pathway inhibition. In vitro, results show that tumor stemness potency is enriched by tumor-fibroblast proximity and inversely correlates with SHH pathway activity levels. Tumor stemness potency was determined via a mammosphere forming assay and resistance to chemotherapy using docetaxel as treatment. CD44+ sorted tumor cells derived from adjacent fibroblast cultures showed higher mammosphere forming efficiency and docetaxel sensitivity than those from mixed cultures. These effects correlated with differences in SHH pathway activity strengths and were reverted by pharmacological inhibition of SHH confirming pathway activity involvement. In two PDX models, both exhibiting high SHH pathway activity and similar tumor vascularization, we observed variable response to pharmacological SHH inhibition. PDX2 displayed favorable responses with minimal alpha-smooth muscle actin-positive (SMA+) fibroblast infiltration, while PDX1 exhibited no benefit from SHH therapy, accompanied by a high level of SMA+ fibroblasts. Spatial transcriptomic analysis confirmed stemness enrichments in the PDX1 model treated with SHH inhibitor- a scenario our mixed co-culture model resembled. Stemness-enriched tumor regions were positive for the Ki67 proliferation marker and confined to areas of high SMA+ cell abundance. Plotting Ki67 vs SMA+ cell levels revealed a positive correlation, suggesting that SMA levels may predict tumor response to SHH pathway inhibition.In summary, our studies demonstrate that pharmacological SHH inhibition can induce altered tumor plasticity by favoring stemness phenotypes. Strategies targeting tumor stemness may mitigate biphasic effects in response to SHH inhibitors, offering insights for optimizing TNBC therapeutic approaches. Citation Format: Heizel M. Rosado-Galindo, Miosotis Acevedo-Esquillin, Wandaliz Torres-García, Ana M. Reyes-Ramos, Gabriela Ortiz-Soto, Michelle M. Martínez-Montemayor, Maribella Domenech. Deciphering biphasic responses to Sonic Hedgehog pathway inhibition in breast cancer: Insights from a tumor-fibroblast spheroid model and PDXs [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 275.

Abstract 283: Fibroblast diversity and immune microenvironment in pseudoangiomatous stromal hyperplasia (PASH): Associations with breast cancer risk

Abstract Benign breast disease (BBD) affects over one million women annually in the United States and is diagnosed in nearly half of all women during their lifetime. Pseudoangiomatous stromal hyperplasia (PASH), a common BBD subtype, is characterized by an overaccumulation of tissue fibroblasts. Current research suggests a pivotal role of the immune microenvironment in progression of BBD to breast cancer, suggesting its composition as a determinant of breast cancer risk. Our study evaluates whether fibroblast variations and immune microenvironment differences in BBD biopsies containing PASH lesions are associated with subsequent breast cancer development. We evaluated BBD biopsies from women who subsequently developed breast cancer (cases, N=5) or remained cancer-free (controls, N=5). Using Opal-based multiplex immunofluorescence (mIF) assays, we mapped expression of fibroblast markers linked to breast cancer associated fibroblasts (CAFs), including vimentin (VIM), smooth muscle actin (ACTA2), fibroblast specific protein-1 (S100A4/FSP1), fibroblast associated protein (FAP), integrin beta-1 (CD29/ITGB1), and platelet derived growth factor receptor beta (PDGFRβ) and markers of key immune cells (T cells: CD4, CD8; dendritic cells: CD11c; B cells: CD20; and macrophages: CD68) along with MKI67 as a proliferation marker. Our results revealed marked differences in fibroblast marker expression and immune cell populations between these groups in the normal lobules in the BBD biopsies. PASH cases showed elevated PDGFRβ and CD29/ITGB1 expression in VIM-positive fibroblasts, markers characteristic of CAF subtypes known to accumulate in more aggressive tumor microenvironments. Conversely, a higher percentage of FSP1+/VIM+ cells, similar to that of a different CAF subtype, was noted in the lobules of PASH controls. This difference in biomarker expression, along with corresponding variations in immune cell counts, suggests a complex interplay between fibroblast composition and immune response that ultimately modulate cancer risk in PASH-containing BBD tissues. Additionally, increased MKI67 expression in PASH cases potentially signals the higher likelihood of cancer development. This work advances our understanding of fibroblast heterogeneity in BBD and its implications for breast cancer risk and progression, and paves the way for innovative strategies to improve clinical outcomes for BBD patients to reduce their incidence of breast cancer. Citation Format: Nicole Cruz-Reyes, Matilde Rossi, Melody Stallings Mann, Bryan McCauley, Tanya Hoskin, Robert Vierkant, Stacey Winham, Amy Degnim, Mark E. Sherman, Derek C. Radisky. Fibroblast diversity and immune microenvironment in pseudoangiomatous stromal hyperplasia (PASH): Associations with breast cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 283.

Abstract 3666: Multi-cancer early detection using metrics of DNA methylation based epigenetic instability

Abstract Cancers present significant changes in DNA methylation, which has proven to be highly useful in cell-free DNA (cfDNA) based cancer detection. Cancer epigenomes are marked by a high degree of intra- and inter-tumor epigenetic variation, indicative of the high level of epigenetic instability. However, the nature of the regions with high epigenetic instability and its utility as biomarker has not been explored. Here we developed a novel methodology and metric to measure the degree of epigenetic perturbation, termed the Epigenetic Instability Index (EII), for multiple cancer screening through cfDNA. Our novel methodology provides a sample specific score of epigenetic perturbation in relation to the expected normal state as opposed to only looking at CpG sites that change between samples. Through machine learning, we have elucidated 269 CpG-island regions which sufficiently capture the epigenetic instability in cancers. We have built classifier models using the EII metrics of these 269 regions and demonstrate that they can efficiently identify breast and lung cancer cases from cfDNA methylation data. Particularly, the models can differentiate even Stage IA of NSCLC with ~75% sensitivity at 95% specificity and early-stage breast cancer at ~68% sensitivity and 95% specificity. The EII metrics perform significantly better than metrics that measure absolute DNA methylation levels. Our studies highlight the potential of measuring epigenetic instability from cfDNA in any given sample in addition to traditional methods of methylation measurement for non-invasive screenings via liquid biopsies. Citation Format: Sara-Jayne Thursby, Zhicheng Jin, Steve B. Baylin, Malcolm Brock, Thomas Pisanic, Hariharan Easwaran. Multi-cancer early detection using metrics of DNA methylation based epigenetic instability [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3666.

Abstract 3625: Metabolic phenotypes of doxorubicin-induced cardiotoxicity in breast cancer patients

Abstract Background. Doxorubicin (DOX) is a highly effective chemotherapy agent that is commonly used in combination with other chemotherapy regimens to treat a wide range of cancers, including 32% of breast cancer (BC) cases. Although DOX has greatly increased the number of long-term cancer survivors, some DOX recipients have experienced DOX-induced cardiotoxicity (DIC). Currently, there are no validated markers that can predict the early development of DIC. Cardiac troponin released by cardiomyocytes has been used in non-clinical studies as a marker of myocardial injury; however, the false positive rates are high, and the predictive value on cardiotoxicity is limited. Therefore, novel biomarkers of DIC are urgently needed to identify patients who are at an increased risk, allowing early detection of the cardiotoxicity before it causes permanent cardiac damage. Methods. Untargeted metabolomics profiling was performed for plasma samples from a cohort of 28 breast cancer patients who developed abnormal cardiac function (ABN) and those who maintained normal cardiac function (NML). Blood samples were collected before, during, and after DOX-containing chemotherapy. Using both baseline observations and pre-post changes, machine-learning techniques were used to identify metabolite markers that can be used as early indicators of DIC in BC patients. Area under the receiver operating characteristic curve was reported to evaluate the performance of significant metabolites, and metabolite set enrichment analysis (MSEA) and network analysis were used to extrapolate known associations between metabolites and diseases. Results. Significant separation of plasma metabolomics profiles between ABN and NML patients at baseline was observed. From 1,124 metabolites, abundance of 59 metabolites were found to differ between ABN and NML patients at baseline. Across all patients, levels of 78 metabolites changed between baseline and after the 1st chemotherapy cycle. Of the 6 metabolites identified in both baseline and pre-post data, ABN patients had higher levels of dicarboxylic acids suberate and sebacate derived from ω-oxidation of fatty acids at baseline than NML patients. Enrichment analysis on the metabolites from the pre-post analysis suggested myocardio injury and carnitine palmitoyltransferase deficiency. Network analysis of metabolite-disease interactions further suggests potential impact on neurological health after chemotherapy. Conclusion. The metabolomics phenotype identified is indicative of impaired beta-oxidation at baseline for ABN patients. In addition, our findings suggest neurotoxic effect from DOX, implicating the potential brain-heart axis involved behind the cardiotoxicity phenotype. Citation Format: Se-Ran Jun, Katherine Wallis, Reid D. Landes, Valentina K. Todorova, L. Joseph Su, Sam Makhoul, Ping-Ching Hsu. Metabolic phenotypes of doxorubicin-induced cardiotoxicity in breast cancer patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3625.

Abstract 3947: Non-BRCA variants in hereditary breast and ovarian cancer patients in the Northern Mexico population

Abstract Background: Hereditary cancer syndromes explain 5-10% of all cancer cases. Germline pathogenic variants in BRCA1 and BRCA2 genes (BRCA) are present in 2-3% of all breast cancer (BC), and 15% of all ovarian cancer (OC) cases. BRCA1 and BRCA2 pathogenic variants (PV) represent 25-28% of BC and 40% of OC patients with a positive familial history. BRCAs are the most studied genes for the prevalence, family history, preventive surgeries, and target treatment options in both BC and OC. There are other genes, important in the diagnosis, pathogenesis, and treatment options of the patients: TP53, PALB2, CHEK2, among others. This study aims to identify the prevalence of non- BRCA genes related to the development of hereditary breast and ovarian cancer syndrome in patients of Northeast Mexico. Methods: This is a multicenter study that recruited patients from two reference oncology centers in Nuevo Leon, Mexico: the CECIL (The CUCC Early Cancer Detection Clinic) Hereditary Cancer Registry and Hereditary Cancer Program from Tec Salud. From March of 2016 to March of 2023, a total of 872 patients meeting NCCN criteria were evaluated by Medical Geneticists from both centers and were tested with NGS multigene cancer panels. Results: A total of 665 (76.26%) patients with a clinical diagnosis of HBOC (Hereditary Breast Hereditary Cancer Syndrome) were included. We found 310 (46.6%) patients had at least one variant, 180 (58%) with at least one pathogenic variant, and 130 (41%) with a VUS (a variant of uncertain significance). BRCA1 was found in 79 (43.8%) and BRCA2 in 32 (17.7%) of all PV. Non-BRCA PV were found in 69 (38.3%) patients: 4 ATM, 2 BLM, 3 BRIP1, 22 CHEK2, 4 CDKN2A, 5 MUTYH, 10 PALB2, 4 RAD51C, 2 SDHA, 2 TP53, 2 WRN, CDH1, CDK4, DICER, MSH3, NBN, PTEN, RAD50, USH2A one of each. Is remarkable that 19 of the 22 patients with CHEK2 and 5 of the 10 patients with PALB2 had the recurrent PV c.707T&amp;gt;C and c.2167_2168del, respectively. Conclusions: Non-BRCA PV in Northern Mexico corresponds to one-third of the BC and OC cases, including HRD (homologous recombination deficiency) genes. HDR patient carriers are potential targets of iPARP therapies. This project reinforces the fact that multigene panels should be employed to ensure a complete diagnosis in hereditary cancer patients. Citation Format: Carlos H. Burciaga-Flores, Diana C. Perez-Ibave, Maria L. Garza-Rodriguez, Oscar Vidal-Gutierrez, Cynthia M. Villarreal-Garza, Dione Aguilar y Mendez. Non-BRCA variants in hereditary breast and ovarian cancer patients in the Northern Mexico population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3947.

Abstract 3929: Comparative genomics of breast cancer in indigenous African and western populations first results from the E-Predict study

Abstract Breast cancer (BC) stands as the foremost female malignancy globally and is the most prevalent cancer in numerous developing countries, particularly in sub-Saharan Africa (SSA). Over the past decade, significant strides in comprehending the pathobiology of the disease and tumour dynamics have greatly enhanced treatment options, particularly in industrialized nations. Regrettably, SSA countries have witnessed only marginal, if any, improvements, with mortality rates surpassing incidence rates. Unfavourable outcome, early onset and high-grade tumours are predominant in SSA. Despite these challenging clinical phenotypes, there is currently a limited understanding of the primary molecular drivers, primarily due to a dearth of reliable data. Furthermore, there is a paucity of research conducted in, and pertinent to, the challenges of the disease in low-income countries (LICs), despite a rising incidence and higher mortality-to-incidence ratios. We thus established an international translational cancer research consortium in five distinct African countries. This initiative has contributed to the creation of a high-quality repository of biomaterials. Additionally, we have conducted whole exome sequencing on the initial 100 cases of breast cancer, comparing the molecular architecture of these tumors with data from The Cancer Genome Atlas (TCGA). We examining and compared the clinical disease phenotypes between indigenous African women and Western patients. A higher proportion of grade III tumors was observed in African patients aged between 30 to 59 years as compared to other patients within the same age group. In comparative molecular analyses, we found a significantly elevated tumor mutational burden in African patients (median of &amp;gt;15/MB) in contrast to other populations within the TCGA (median ~ 0.7/MB). Gene sets featuring co-occurring mutations, predicted to be associated with survival using the TCGA dataset, showed high mutation rates in the African cohort. Notably, co-occurring mutations between PIK3CA and genes linked to genomic instability, such as BIRC6 (HR: 11.7, p = 2.7e-05), KMT2C (HR: 4.7, p = 4.01e-04), NEB (HR: 3.84, p = 0.48), and PCLO (HR: 4.9, p = 0.016), among others, strongly correlated with poor overall survival and were highly mutated within the African cohort. Interestingly, within the TCGA, patients with early breast cancer onset exhibit twice as many mutations in KMT2C, a gene known for its association with DNA damage repair, genomic instability, and showed an improved response to immune checkpoint inhibition. These initial findings suggest that breast cancer genomics in indigenous African populations may exhibit substantial differences, potentially warranting consideration for distinct therapeutic modalities for these patients. Citation Format: Smiths Sengkwawoh Lueong, Pamela Derliche Tonouo Derliche Tonouo, Arnol Auvaker Tiofack, Rovaldo Nguims Kenfack, Jules Roger Kuiate, Esther Dina Mbassi, Sidonie Noa Ananga, Etienne Okobalemba Atenguena, Gustave Simo, Abdel Jelil Njouendou, Walters Ndaka, Zacharie Sando, Emmanuella Mayemi, Rachel Tayou, Gilles Gael Aghoagni, Anne Sango, Benjamin Pokam, Augustin Tozoula Bambara, Jens T. Siveke. Comparative genomics of breast cancer in indigenous African and western populations first results from the E-Predict study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3929.