Early-onset Breast Research Articles

Hormone Receptor Positive Breast Cancer in Young Women: A Review.

The global incidence of hormone-positive breast cancer (HR+ BC) in young women is rising, though the underlying reasons remain unclear. HR+ disease in younger women appears to represent a distinct clinical entity compared to that in older women, exhibiting distinct clinicopathological characteristics, outcomes and responses to treatment. Despite these differences, there is a paucity of large-volume data focusing on young women with HR+ in contemporary literature. Hormone receptor positive breast cancer in young women is associated with poorer prognoses compared to older women. Additionally, early age onset breast cancer presents unique challenges, including concerns related to fertility, the toxic effects of therapeutic agents, and specific surgical considerations. The purpose of this review is to report the existing literature on HR+ disease in young women.

Financial burden within first year of diagnosis for privately-insured patients with early-onset breast or colorectal cancer.

9 Background: Rising incidence of early-onset (E-O) cancers has been observed globally. E-O breast cancer (BC) are patients (pts) diagnosed ages 18 to 44 and E-O colorectal cancer (CRC) are aged 18 to 49. Because many E-O cancers are among pts who do not meet screening eligibility criteria by age, they are often diagnosed at advanced stage, which is also more expensive to treat. Younger pts may also have lower incomes and fewer assets, increasing risk of financial burden for pts with E-O cancers. We estimated the financial burden for pts and private payors for E-O BC and CRC, compared to non-elderly pts with BC and CRC diagnosed between the age of 45 to 64 and 50 to 64 (older-onset), respectively. Methods: We applied a claims-based algorithm to identify pts with incident BC and CRC diagnosed between 2014 and 2021 from MarketScan Commercial Claims and Encounters Data and required 12-month continuous enrollment before and after the index diagnosis for completeness of claims. Financial burden was quantified as total and out-of-pocket (OOP) payments, calculated as the sum of deductibles, copayments, and coinsurance. We used generalized linear models and quantile regressions to compare differences in mean and median costs, respectively, between pts with E-O vs. older onset cancer, adjusting for comorbidity, region, insurance plan type, sex (for CRC) and year. Results: Study cohort included 58,419 pts with BC and 11,251 pts with CRC. The proportion of E-O increased from 15% in 2014 to 17% in 2022 (Ptrend<0.01) in BC and from 23% to 30% (Ptrend<0.01) in CRC. Higher percentage of E-O pts were enrolled in high-deductible plans (BC: 25% v22%; CRC: 24% vs. 21%) and received systemic therapy (BC: 61% v 49%; CRC: 57% vs. 43%). Higher percent of surgery (93% v 89%) was observed in E-O BC and radiation (21% v 16%) in E-O CRC. Pts with E-O BC and CRC had significantly higher adjusted mean and median total and OOP payments (Table). Conclusions: E-O BC and CRC result in substantial costs to payors and moderately higher OOP payments. OOP maximums in private insurance may offer some financial protection for pts. E-O Older onset Difference 95% CIBC: BC: Mean total pay $182,770 $128,640 $54,130 $50445, $57817 Median total pay 143,351 93,317 50,034 47691, 52377 Mean OOP 6,014 5,063 951 817, 1085 Median OOP 5,142 4,258 884 791, 978 CRC: Mean total pay $153,446 $123,449 $29,998 $24244, $35752 Median total pay 119,747 89,340 30,406 25216, 35597 Mean OOP 5,429 4,791 638 428, 848 Median OOP 4,452 4,015 437 266, 607

Breast cancer prognosis in young BRCA1/BRCA2 mutation carriers: a retrospective hospital-based cohort study

Studies evaluating the prognostic impact of germline BRCA1/2 mutations (gBRCAm) in patients with breast cancer report conflicting results. Therefore, we aimed to investigate outcomes of patients with gBRCA mutations and early onset of breast cancer (< 30 years) compared with those of non-carriers. This retrospective study included 149 patients recruited between 2005 and 2019. The outcomes were overall survival (OS) and disease-free survival (DFS), which were defined as the time from the first diagnosis to death from any cause and the first recurrence, second cancer, or death from any cause, respectively. Key patient data, Kaplan–Meier plots, and outcomes were described according to the BRCA mutation status. Hazard ratios (HR) were calculated using the Cox proportional hazards model. Twenty-eight patients (28/149; 18.8 %) were gBRCAm carriers. The OS median follow-up was 8.2 years. OS was 89.3% [70.4-96.4] in carriers vs 99.2% [95% CI 94.3–99.9] in non-carrier patients at 2 years; 85.2% [65.2-94.2] vs 93.0% [86.5–96.5] at 5 years, and 76.5% [54.7-88.8] vs 85.2% [75.7-91.2] at 10 years. There was no difference in OS between groups in multivariable analysis (HR=1.90 [0.69-5.23], p=0.22). The DFS median follow-up was 6.6 years. Similar results were observed for DFS (HR=1.39 [0.63-3.08], p=0.42). In this large hospital-based cohort of patients with very early onset breast cancer, we found no clear evidence that gBRCA1/2m significantly affects OS after adjusting for known prognostic factors.

The Association Between Breast Cancer Predisposing Genetic Variants and Multifocal, Multicentric Breast Cancer.

Breast-conserving surgery is often discouraged in BRCA gene carriers with early onset breast cancer. The genetic variant carrier breast cancers are more likely to be multifocal or multicentric (MFMC). This retrospective study includes newly diagnosed patients with breast cancer undergoing genetic testing between 2010 and 2021 within the Johns Hopkins Regional Health System. After excluding patients who received neoadjuvant chemotherapy or stage IV breast cancers, patients were divided into two groups: those who tested positive for a variant recognized by the National Comprehensive Cancer Network as predisposing the patient to breast cancer (ATM, BRCA1, BRCA2, CHEK2, NF1, PALB2, RAD51C, RAD51D, and TP53) and those who tested negative. Pathologic features of the tumors were compared, focusing on evidence for MFMC disease, defined as more than one malignant foci more than 5mm apart. Among the 282 eligible cases, 69 (24%) were positive for a genetic variant. The variant carriers were younger at diagnosis (p < 0.001), more likely to have invasive ductal carcinoma (p = 0.03), more likely to have undergone mastectomy (p = 0.03), and more likely to have a grade 3 cancer (p = 0.003). Variant carriers were not more likely to have MFMC disease (28% vs. 22%, p = 0.4). A positive genetic variant was not a predictor of MFMC within the entire cohort [odds ratio (OR):1.3, 95% confidence interval (CI) 0.6-2.6, p = 0.5). Genetic variant carrier cancers are not more likely to be MCMF than sporadic cancers.

Abstract PO1-08-01: Identifying a founder BRCA1 variant in the Qatari population With unique genotype – phenotype correlations

Abstract PURPOSE: Hereditary breast and ovarian cancer syndrome (HBOC) is the most common cause of hereditary breast &amp; ovarian cancers in Qatar and worldwide which is caused by pathogenic variants in the BRCA1&amp; BRCA2 genes. The aim of this retrospective study is to describe a common recurrent founder pathogenic variant in the BRCA1 gene that was observed in the native Qatari population with unique genotype-phenotype correlations. METHODS: Medical records of Qatari patients (affected &amp; unaffected) with personal and/or family history of breast &amp; ovarian cancers who carry pathogenic/likely pathogenic mutations in the BRCA1 &amp; BRCA2 genes were reviewed between 2013- 2020. Epidemiological information and clinical data were reviewed including age, gender, ethnic background, personal history of cancer, tumour characteristics and family history. We used frequencies and proportions to describe the data and used Kaplan-Meier curves and log-rank analysis to compare survival rates. For the analysis, we used Stata Corp. 2015. Stata Statistical Software: Release 14, College Station, TX: Stata Corp LP. Result: Our result confirms the presence of a common recurrent pathogenic variant in BRCA1 gene [(c.4787 C&amp;gt;A) (p. Ser 1596*)] among Qatari patients who belong to 8 consanguineous large families followed by BRCA1[ c.4065_4068delTCAA]. BRCA1 c.4787 variant is highly associated with early onset breast cancer specifically Invasive ductal carcinoma (IDC) triple negative breast cancer (stage I, grade III), rather than ovarian cancer. In addition, the c.4787 C&amp;gt;A was found to be highly penetrant in families for young onset breast cancer. Conclusion: We showed that BRCA1 c.4787 C&amp;gt;A pathogenic variant is a highly recurrent variant among Qatari consanguineous families and contributes to the early onset breast cancer in Qatar. Early identification of this variant can aide to improve patient’s survival &amp; guide early personalized treatment and prevention. Citation Format: Salha Al-Bader, Hind Habish, Reem Al Sulaiman, Hajer Al-Mulla, Hafedh Ghazouani. Identifying a founder BRCA1 variant in the Qatari population With unique genotype – phenotype correlations [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO1-08-01.

Abstract NG02: Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers

Abstract NG02: Distinct genomic and immunologic tumor evolution in germline TP53-driven breast cancers

Classification of Early Breast Cancer using Convolutional Neural Networks

Breast cancer is a life-threatening disease that impacts millions of people worldwide, necessitating heightened awareness and effective early detection strategies. Current methods for determining the presence and type of breast cancer in a clinical breast exam conducted by healthcare providers may be inaccurate, imprecise, and prone to error. The goal of this research project is to offer a second opinion for physicians to predict whether or not a patient has early onset breast cancer through a machine learning model developed from an image dataset, to significantly reduce the error in breast cancer staging, making the process more efficient in healthcare. Early detection is crucial for successful treatments of breast cancer, as treatment options in late-stage diagnosis of breast cancer can have a much worse prognosis. In the US, 240,000 cases of breast cancer are diagnosed per year in both men and women with a mortality rate of approximately 42,000 per year. [1] To approach this problem, I have tested an MLP Classifier, Logistic Regression, Ridge Classifier, Random Forest Classifier, Decision Tree Classifier, Support Vector Classifier, and trained a Convolutional Neural Network to compare various results and determine the best accuracy. The Convolutional Neural Network yielded impressive outcomes, reaching up to 79% testing accuracy and 98% training accuracy. The final model exhibits the capability to identify early signs of breast cancer and differentiate between malignant and benign tumours with relatively high accuracy showing the potential of AI in combination with medical imaging that can assist medical staff in diagnosis.

Sequencing-based functional assays for classification of BRCA2 variants in mouse ESCs

Sequencing of genes, such as BRCA1 and BRCA2, is recommended for individuals with a personal or family history of early onset and/or bilateral breast and/or ovarian cancer or a history of male breast cancer. Such sequencing efforts have resulted in the identification of more than 17,000 BRCA2 variants. The functional significance of most variants remains unknown; consequently, they are called variants of uncertain clinical significance (VUSs). We have previously developed mouse embryonic stem cell (mESC)-based assays for functional classification of BRCA2 variants. We now developed a next-generation sequencing (NGS)-based approach for functional evaluation of BRCA2 variants using pools of mESCs expressing 10-25 BRCA2 variants from a given exon. We use this approach for functional evaluation of 223 variants listed in ClinVar. Our functional classification of BRCA2 variants is concordant with the classification reported in ClinVar or those reported by other orthogonal assays.

Global trends in incidence, death, burden and risk factors of early-onset cancer from 1990 to 2019

ObjectiveThis study aimed to explore the global burden of early-onset cancer based on the Global Burden of Disease (GBD) 2019 study for 29 cancers worldwid.Methods and analysisIncidence, deaths, disability-adjusted life...

Somatic mutations in tumor-adjacent normal breast tissue in young women with high risk family history.

576 Background: It’s incompletely understood why some women without germline breast cancer predisposing mutations develop early onset breast cancer. Breast cancer in young women is often more aggressive, with high histologic grade, worse prognosis, and higher risk of recurrence. We hypothesize that these women have somatic mutations in the normal breast tissue that contribute to breast cancer tumorigenesis. Methods: Whole exome sequencing (WES) data was analyzed from normal tissue adjacent to breast tumor and compared to matched peripheral blood (n=28). All patients were &lt;50yo, had high risk family history as per NCCN guidelines, and had negative Ambry Genetics panel testing. FFPE sections were reviewed by two pathologists to identify normal breast tissue furthest away from tumor. WES was performed on Illumina HS4000 using 100-base pair paired-end reads. Samples were mapped to the human reference genome (vGRCh38). PCR duplicates were marked (Picard), and indel regions were adjusted (GATK). High-quality germline variants (HaplotypeCaller), somatic mutations (Mutect), and indels (IndelGenotyper) were called. Low-quality variants were filtered out. The classification and number of mutations per gene per sample were extracted and analyzed. Results: Majority of patients were white (86%), median age 45, with invasive ductal carcinoma (86%), ER+/PR+/HER2- (100%). Median somatic variants per sample were 97 (range: 45-285), all single nucleotide variants, mostly missense mutations, C&gt;T conversions were seen in 45% of mutations. This suggests cytidine deaminase (APOBEC) involvement. All samples had alterations in at least one of the top ten affected genes which include transcription factors in zinc finger family (listed below). Zinc finger proteins play a key role in tumorigenesis, cancer progression and metastasis in a variety of cancers. Upregulation of zinc finger proteins has been associated with worse prognosis in breast cancer. Conclusions: We describe novel somatic mutations in zinc finger proteins in normal breast tissue adjacent to tumor that may contribute to early onset breast cancer in patients with high risk family history. [Table: see text]

Abstract 1000: Associations of parity and body mass index with NanoString digital spatial protein profiling in early onset breast cancer

Abstract Purpose: Young women’s breast cancers (YBCs), defined herein as breast cancer (BC) diagnosed at age ≤ 40 years, are etiologically and biologically distinct from postmenopausal BCs, demonstrating a higher proportion of estrogen receptor (ER) negative subtypes and a worse prognosis. Studies have not assessed whether risk factors such as recent parity and body mass index (BMI) are linked to protein expression profiles in YBCs. Accordingly, we examined protein expression assessed with GeoMx® Digital Spatial Profiling (DSP) in 640 YBCs prepared as tissue microarrays (TMAs) in the Young Women’s BC Study (YWBCS). Methods: The YWBCS is a multi-institutional cohort of 1,297 women with incident BC diagnosed at age &amp;lt;40 years identified through medical record review, with risk factor data collected via questionnaires. TMAs including 1,505 cores of 640 YBCs that were collected prior to therapy and were suitable for molecular analysis were evaluated for 72 markers with NanoString GeoMx DSP. Associations of log-transformed biomarker expression with BMI and time from last live birth to BC diagnosis were carried out using linear mixed modeling approaches, accounting for multiple tumor tissue cores per individual. Results: Mean age at BC was 35.5 years (range 17-40). Tumor subtypes based on clinical immunostaining were the following: luminal B 46%; luminal A 36%; triple negative 12% and HER2+ 6%. Of 72 biomarkers tested, 53 (74%) were evaluable after QC and normalization. GeoMx ER and PR protein levels were higher in luminal A and luminal B YBCs than in HER2+ and TNBC (p=2x10-94 and 2x10-52, respectively), supporting the accuracy of the GeoMx assay. Compared to nulliparas or those with most recent birth &amp;gt; 3 years before BC, those who gave birth ≤ 3 years prior to BC had tumors with higher expression of PR (8x10-6) and ER (p=0.006), and lower expression of BCL-2 (p=0.006). In contrast, women with last birth ≥ 6 years prior to BC had higher expression of CD8 (p=0.006) and PD-1 (p=0.001) than nulliparas and those with more recent births. Compared to women with BMI between 18.5 and 29.9, those with higher or lower BMIs had higher expression of CD34 (p=0.0003), CD4 (p=0.0009) and CD14 (p=0.001). BCL-2 expression was higher among women with BMI &amp;lt; 18.5 compared to those with higher values (p=0.005). Women with BMI of 30+ had higher β2-microglobulin levels than those with lower BMIs (p=0.003). Inverse dose-response associations (with higher BMI related to lower levels) were observed for expression of ER (p=0.01), pan cytokeratin (p=0.004) and four proteins in the p13K/AKT signaling pathway (p ≤ 0.01 for each). Conclusions: Preliminarily, we identify differences in hormonal and immune markers in YBCs in relation to timing of births and BMI, suggesting that these factors may contribute to etiologic heterogeneity. Multivariate modeling is ongoing to incorporate molecular subtype and other risk factors. Citation Format: Robert A. Vierkant, Laura M. Pacheco-Spann, Stacey J. Winham, Jennifer M. Kachergus, Ji Shi, Craig Snow, Fergus J. Couch, Janet E. Olson, Chen Wang, Derek C. Radisky, Amy C. Degnim, E. Aubrey Thompson, Laura C. Collins, Kathryn J. Ruddy, Ann H. Partridge, Mark E. Sherman. Associations of parity and body mass index with NanoString digital spatial protein profiling in early onset breast cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 1000.

Abstract P6-02-16: Breast cancer prognosis of germline BRCA1/BRCA2 mutation carriers of young women: a retrospective hospital-based cohort

Abstract Background Studies evaluating prognostic impact of germline BRCA1/2 mutations (gBRCAm) on breast cancer patients reported controversial results. The primary aim of this study was to investigate outcomes of young gBRCAm patients with very early onset of breast cancer (&amp;lt; 30 years) compared with noncarriers. Methods In this retrospective study, 149 patients 30 years aged or younger at early breast cancer diagnosis between 2005 and 2019 were included in Oscar Lambret Center. Outcomes were overall survival (OS) and disease-free survival (DFS), defined as time from first diagnosis to first recurrence, second cancer or death from any cause, at 2 years, 5 years, and 10 years. Key patient data, kaplan-meier plots and outcomes were described by BRCA mutation status. Hazard ratios (HR) were calculated using Cox proportional-hazards models. Results Twenty-eight (18.8%) patients were gBRCAm carriers. The median follow-up was 6.5 years (IQR 0.25-16.5). Twenty-three deaths, 41 recurrences and 2 second cancers were reported. OS was 89.3% [70.4–96.4] in gBRCAm patients vs 99.1% [95% CI 93.9–99.9] in non-carriers patients at 2 years; 85.0% [64.7–94.1] vs 92.3% [85.1–96.1] at 5 years and 75.3% [52.5–88.3] vs 80.2% [66.6–88.7] at 10 years. There was no difference in OS between groups in multivariable analysis (HR=1.63 [0.55–4.77], p=0.37). Similar results were noted when comparing disease-free survival (HR=1.42 [0.64–3.11], p=0.38). Conclusions In this cohort of 149 patients with very early onset breast cancer, outcomes of gBRCAm mutation carriers did not differ from non-carriers when adjusted for others prognostic factors. Citation Format: Florent HEGO, Maël BARTHOULOT, Charles PIERARD, Audrey Mailliez. Breast cancer prognosis of germline BRCA1/BRCA2 mutation carriers of young women: a retrospective hospital-based cohort [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 P6-02-16.

Abstract P4-03-42: Evaluating the Impact of Race and Body Mass Index on the Diagnosis and Prognosis of Early Onset Breast Cancer

Abstract Background: Early-onset breast cancer is typically defined as a diagnosis of disease before age 40-45. Prior studies have shown interesting associations between race and obesity on the incidence and prognosis of breast cancer. Data from the SEER program at the National Cancer Institute has shown increased mortality amongst African American women (0.2%) compared to Non-Hispanic White (NHW) women (0.1%) who were diagnosed with breast cancer at age 45 years or younger. This is despite a similar risk of diagnosis between racial groups of this age range (1.27%, 1.27%). Other large studies have shown that African American patients tended to present with more advanced disease had worse clinical outcomes. Our study sought to determine the impact of race and obesity on the diagnosis and prognosis of early onset breast cancer amongst the patient population at Georgetown University Hospital (GUH). Methods: We compiled a database of all new patients, 652 in total, seen at Lombardi Cancer Center at Medstar GUH from 10/2020- 6/2022. We reviewed patient charts in the EMR and documented age at diagnosis, race, ethnicity, stage at diagnosis, and BMI. The BMI was categorized by underweight (BMI &amp;lt; 18.5), healthy weight (BMI 18.5-24.9), overweight (BMI 25-25.9), obese (BMI 30-34.9), and morbidly obese (BMI ≥ 35). Stage at diagnosis was determined by comparing the pathology report with the NCCN guidelines version 4.2022. We identified 136 patients who were diagnosed at GUH at age 45 years old or younger and compared our findings to SEER data from 2017-2019. Results: Out of 136 patients who met our age criteria, 131 had racial data available: 29 AA (0.22), 68 NHW (0.52), 4 Hispanic (0.03), 30 Other (0.23). Out of the 34 patients with advanced disease (stage 3 and 4) 16 were NHW (0.47), 4 were AA (0.12), 2 were Hispanic (0.06) and 12 were Other (0.35). 131 patients had BMI data available: 5 underweight (0.04), 56 healthy weight (0.43), 41 overweight (0.31), 21 obese (0.16), and 8 morbidly obese (0.06). 18 patients with advanced disease were overweight or obese, out of which 11 were NHW (0.61), 3 were AA (0.16), 3 were Other (0.16), and 1 was Hispanic (0.06). Conclusion: In contrast with the SEER data, our study found that the patient population at GUH had a much higher proportion of Non-Hispanic White (NHW) patients who were diagnosed with advanced disease compared to African American (AA) patients. It also found a higher proportion of NHW patients amongst those who were diagnosed with advanced stage disease and were overweight or obese compared to AA patients. This data suggests that in our patient population, Non-Hispanic White women who were overweight or obese at the time of diagnosis of early onset breast cancer (≤ 45 years old) were more likely to be diagnosed with advanced stage disease than women in other demographic groups. It is possible that this discrepancy is related to racial variations in receptor status. Further investigation is required to correlate these associations in clinical practice with other known demographic variables and disease-specific risk factors in order to better understand how they impact the diagnosis and prognosis of early-onset breast cancer. Citation Format: Austin Kordic, Amanda Reyes, Nadia Ashai. Evaluating the Impact of Race and Body Mass Index on the Diagnosis and Prognosis of Early Onset Breast Cancer [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 P4-03-42.

The "extreme phenotype approach" applied to male breast cancer allows the identification of rare variants of ATR as potential breast cancer susceptibility alleles.

In oncogenetics, some patients could be considered as "extreme phenotypes", such as those with very early onset presentation or multiple primary malignancies, unusually high numbers of cancers of the same spectrum or rare cancer types in the same parental branch. For these cases, a genetic predisposition is very likely, but classical candidate gene panel analyses often and frustratingly remains negative. In the framework of the EX2TRICAN project, exploring unresolved extreme cancer phenotypes, we applied exome sequencing on rare familial cases with male breast cancer, identifying a novel pathogenic variant of ATR (p.Leu1808*). ATR has already been suspected as being a predisposing gene to breast cancer in women. We next identified 3 additional ATR variants in a cohort of both male and female with early onset and familial breast cancers (c.7762-2A>C; c.2078+1G>A; c.1A>G). Further molecular and cellular investigations showed impacts on transcripts for variants affecting splicing sites and reduction of ATR expression and phosphorylation of the ATR substrate CHEK1. This work further demonstrates the interest of an extended genetic analysis such as exome sequencing to identify very rare variants that can play a role in cancer predisposition in extreme phenotype cancer cases unexplained by classical cancer gene panels testing.

Clinicopathologic characteristics of early-onset breast cancer: a comparative analysis of cases from across Ghana

BackgroundBreast cancer is the commonest cancer diagnosed globally and the second leading cause of cancer-related mortality among women younger than 40 years. This study comparatively reviewed the demographic, pathologic and molecular features of Early-Onset Breast Cancer (EOBC) reported in Ghana in relation to Late Onset Breast Cancer (LOBC).MethodsA descriptive, cross-sectional design was used, with purposive sampling of retrospective histopathology data from 2019 to 2021. Reports of core or incision biopsy, Wide Local Excision or Mastectomy with or without axillary lymph node dissection specimen and matched immunohistochemistry reports were merged into a single file and analysed with SPSS v. 20.0. Descriptive statistics of frequencies and percentages were used to describe categorical variables. Cross-tabulation and chi-square test was done at a 95% confidence interval with significance established at p < 0.05.ResultsA total of 2418 cases were included in the study with 20.2% (488 cases) being EOBCs and 79.8% (1930 cases) being LOBCs. The median age at diagnosis was 34.66 (IQR: 5.55) in the EOBC group (< 40 years) and 54.29 (IQR: 16.86) in the LOBC group (≥ 40 years). Invasive carcinoma—No Special Type was the commonest tumour type with grade III tumours being the commonest in both categories of patients. Perineural invasion was the only statistically significant pathologic parameter with age. EOBC was associated with higher DCIS component (24.8% vs 21.6%), lower hormone-receptor-positive status (52.30% vs 55.70%), higher proliferation index (Ki-67 > 20: 82.40% vs 80.30%) and a higher number of involved lymph nodes (13.80% vs 9.00%). Triple-Negative Breast cancer (26.40% vs 24.30%) was the most predominant molecular subtype of EOBC.ConclusionEOBCs in our setting are generally more aggressive with poorer prognostic histopathological and molecular features when compared with LOBCs. A larger study is recommended to identify the association between relevant pathological features and early onset breast cancer in Ghana. Again, further molecular and genetic studies to understand the molecular genetic drivers of the general poorer pathological features of EOBCs and its relation to patient outcome in our setting is needed.

Vitamin D Receptor Microsatellite Repeats in the 3’untranslated region: Relation to Early Onset Breast Cancer among Pakistani Women

Vitamin D Receptor Microsatellite Repeats in the 3’untranslated region: Relation to Early Onset Breast Cancer among Pakistani Women

Reproductive risk factors associated with breast cancer in young women by molecular subtype

BackgroundFew studies have examined detailed features of pregnancy and the postpartum period as potential risk factors for early onset breast cancer (BC) by molecular subtype. These data may have value for improving risk assessment and prevention. MethodsWe surveyed parous enrollees in the prospective Mayo Clinic Breast Disease Registry (MCBDR) who had been diagnosed with BC at age <55 years between 2015 and 2020. Summary statistics were used to describe survey responses and reproductive risk factors by BC subtype (defined by estrogen/progesterone receptors and human epidermal growth factor receptor expression, nurse-abstracted from the medical record). Associations were assessed with Kruskal-Wallis and Chi-Square tests, followed by age-adjusted linear and logistic regression models. We compared results from this parous cohort to those from a separate cohort of nulliparous MCBDR participants with BC diagnosed at age <55 years. ResultsIn 436 parous respondents with subtype data abstracted, we identified a higher frequency of BRCA1 mutation, earlier age at diagnosis, and lower BI in patients with triple negative BC. Comparing parous to nulliparous young women with breast cancer, the proportion with TNBC was larger in the latter (12.2% vs. 15.1%, p = 0.03). ConclusionsEarly age at diagnosis and deleterious BRCA1 mutation were more frequent among TNBC patients. In addition, parous young women with TNBC had a lower BI than those with other BC subtypes, a hypothesis-generating finding that supports the need for additional research on the cycle of pregnancy-lactation-postpartum involution and BC etiology.

A novel germline mutation of the &lt;i&gt;PALB&lt;/i&gt; gene in a young Yakut breast cancer woman

Background. Breast cancer (BC) is the most common female malignancy worldwide. partner and localizer of BRCA2 gene (PALB2) is directly involved in DNA damage response. germline mutation in PALB2 has been identified in breast cancer and familial pancreatic cancer cases, accounting for approximately 1–2% and 3–4%, respectively. the goal of this report was to describe new PALB2 mutation in a young Yakut breast cancer patient with family history of cancer. Material and methods. Genomic DNA were isolated from blood samples and used to prepare libraries using a capture-based target enrichment kit, Hereditary Cancer Solution™ (SOPHIA GENETICS, Switzerland), covering 27 genes (ATM, APC, BARD1, BRCA1, BRCA2, BRIP1, CDH1, CHEK2, EPCAM, FAM175A, MLH1, MRE11A, MSH2, MSH6, MUTYH, NBN, PALB2, PIK3CA, PMS2, PMS2CL, PTEN, RAD50, RAD51C, RAD51D, STK11, TP53 and XRCC2). paired-end sequencing (2 × 150 bp) was conducted using NextSeq 500 system (Illumina, USA). Results. Here we describe a case of a never-before-reported mutation in the PALB gene that led to the early onset breast cancer. We report the case of a 39-year-old breast cancer Yakut woman with a family history of pancreatic cancer. Bioinformatics analysis of the NGS data revealed the presence of the new PALB2 gene germinal frameshift deletion (NM_024675:exon1:c.47dela:p.K16fs). in accordance with dbPubMed ClinVar, new mutation is located in codon of the PALB2 gene, where the likely pathogenic donor splice site mutation (NM_024675.3:c.48+1delG) associated with hereditary cancer-predisposing syndrome has been earlier described. Conclusion. We found a new never-before-reported mutation in PALB2 gene, which probably associated with early onset breast cancer in Yakut indigenous women with a family history of pancreatic cancer.

Abstract 1451: BRCA1 and BRCA2 germline mutational spectrum in Algerian triple negative breast cancer (TNBC) patients

Abstract Background: Breast cancer is currently the leading cause of cancer morbidity and mortality among Algerian women. To date, triple negative breast cancer (TNBC) shows substantial overlap with basal type cancer and it is associated with aggressive tumor behavior, poor prognosis and BRCA1 mutations. In the present study, we screened for the prevalence of BRCA1 and BRCA2 germline mutations in a cohort of 169 TNBC patients using PCR-Sanger sequencing and NGS with a cancer panel of 30 hereditary cancer genes or BRCA1/BRCA2 genetic test. Materials and Methods: 169 TNBC patients and their relatives were referred trough several public hospitals from six years (2013-2019). BRCA1 germline mutation was screened using PCR-Sanger sequencing in 66 TNBC patients with strong family history of breast and ovarian cancer and 103 sporadic TNBC patients including all exons where a mutation was previously found in Algerian population (exons 2, 3, 4, 10, 17 and 19). BRCA2 germline mutation was screened using PCR-Sanger sequencing in 24 TNBC patients with strong family history of breast cancer including all exons where a mutation was previously found in Algerian patients (exons 10 and 22). In addition, nine (9) TNBC patients with strong family history of breast and ovarian cancer were analyzed by NGS using BRCA1 and BRCA2 test or a cancer panel of 30 hereditary genes (Colors genomics). Results: The analysis of the genomic DNA samples of 169 TNBC patients revealed that 15 patients carried pathogenic germline variants in BRCA1 gene and three patients carried pathogenic variants in BRCA2 gene (10.65%). Eight distinct germline mutations in BRCA1 have been detected in this study: c.83_84delTG, c.181T&amp;gt;G, c.798_799delTT, c.505C&amp;gt;T, c.923_924delGC, c.2125_2126insA, c.5257A&amp;gt;G and deletion of exon 15. Interestingly, the recurrent and specific mutation c.83_84delTG has been detected in 4 unrelated TNBC patients. The pathogenic variant c.2125_2126insA has been detected in three unrelated families and also in the first relatives of 2 patients. The rare likely pathogenic variant BRCA1 c.5257A&amp;gt;G/p.Arg1753Gly has been detected in young female TNBC patient. The Del exon 15 in BRCA1 has been detected in two unrelated patients. Three distinct germline mutations in BRCA2 have been detected in three TNBC patients: c.1813dupA, c.7654dupA and c.8485C&amp;gt;T. Interestingly, these three mutations are reported for the first time in Algerian population. The c.1813dupA and c.8485C&amp;gt;T pathogenic variants have been detected in two young female TNBC patients with a family history of male breast cancer. Conclusions: In the current study, we detected recurrent germline mutations in BRCA1 gene in early onset TNBC patients. BRCA2 pathogenic variants have also been detected in young female TNBC patients. TNBC immunophenotype should be considered as an additional criterion for genetic counselling and testing of BRCA genes in Algerian women with early onset breast cancer. Citation Format: Farid Cherbal, Chiraz Mehemmai, Hadjer Gaceb, Hassen Mahfouf, Kada Boualga. BRCA1 and BRCA2 germline mutational spectrum in Algerian triple negative breast cancer (TNBC) patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1451.

Germline CHEK2 and ATM Variants in Myeloid and Other Hematopoietic Malignancies

An intact DNA damage response is crucial to preventing cancer development, including in myeloid and lymphoid malignancies. Deficiencies in the homologous recombination (HR) pathway can lead to defective DNA damage responses, and this can occur through inherited germline mutations in HR pathway genes, such as CHEK2 and ATM. We now understand that germline mutations can be identified frequently (~ 5-10%) in patients with myeloid and lymphoid malignancies, and among the most common of these are CHEK2 and ATM. We review the role that deleterious germline CHEK2 and ATM variants play in the development of hematopoietic malignancies, and how this influences clinical practice, including cancer screening, hematopoietic stem cell transplantation, and therapy choice. In recent large cohorts of patients diagnosed with myeloid or lymphoid malignancies, deleterious germline loss of function variants in CHEK2 and ATM are among the most common identified. Germline CHEK2 variants predispose to a range of myeloid malignancies, most prominently myeloproliferative neoplasms and myelodysplastic syndromes (odds ratio range: 2.1-12.3), and chronic lymphocytic leukemia (odds ratio 14.83). Deleterious germline ATM variants have been shown to predispose to chronic lymphocytic leukemia (odds ratio range: 1.7-10.1), although additional studies are needed to demonstrate the risk they confer for myeloid malignancies. Early studies suggest there may also be associations between deleterious germline CHEK2 and ATM variants and development of clonal hematopoiesis. Identifying CHEK2 and ATM variants is crucial for the optimal management of patients and families affected by hematopoietic malignancies. OPENING CLINICAL CASE: "A 45year-old woman presents to your clinic with a history of triple-negative breast cancer diagnosed five years ago, treated with surgery, radiation, and chemotherapy. About six months ago, she developed cervical lymphadenopathy, and a biopsy demonstrated small lymphocytic leukemia. Peripheral blood shows a small population of lymphocytes with a chronic lymphocytic leukemia immunophenotype, and FISH demonstrates a complex karyotype: gain of one to two copies of IGH and FGFR3; gain of two copies of CDKN2C at 1p32.3; gain of two copies of CKS1B at 1q21; tetrasomy for chromosome 3; trisomy and tetrasomy for chromosome 7; tetrasomy for chromosome 9; tetrasomy for chromosome 12; gain of one to twocopies of ATM at 11q22.3; deletion of chromosome 13 deletion positive; gain of one to two copies of TP53 at 17p13.1). Given her history of two cancers, you arrange for germline genetic testing using DNA from cultured skin fibroblasts, which demonstrates pathogenic variants in ATM [c.1898 + 2T > G] and CHEK2 [p.T367Metfs]. Her family history is significant for multiple cancers. (Fig.1)." Fig. 1 Representative pedigree from a patient with germline pathogenic ATM and CHEK2 variants who was affected by early onset breast cancer and chronic lymphocytic leukemia. Arrow indicates proband. Colors indicate cancer type/disease: purple, breast cancer; blue, lymphoma; brown, melanoma; yellow, colon cancer; and green, autoimmune disease.