The Mutational Landscape of the Adult Healthy Parous and Nulliparous Human Breast

Cereser et al. Nature Communications 14, 5136, 2023.

Studies spanning over half a century have consistently shown that the age at which a woman has her first child, and the timing of pregnancy are risk factors for developing breast cancer. Recent research takes these findings further and shows an age-dependent accumulation of somatic mutations in specific cancer-relevant genes in healthy mammary cells. Older first-time mothers may have a greater chance of harmful mutations, about 15 per year, in their breast cells. Pregnancy may induce a rapid expansion of breast cells with specific mutations and could promote breast cancer. In brief, the age of first childbirth and the timing of pregnancies could influence breast cancer risk due to genetic and other factors.
https://pubmed.ncbi.nlm.nih.gov/37673861/

Exome Sequencing Identifies Breast Cancer Susceptibility Genes and Defines the Contribution of Coding Variants to Breast Cancer Risk

Wilcox et al. Nature Genetics 55, 1435-1439, 2023.

Current cancer genetic tests cover only a handful of genes associated with genetic risk, and there is clear room to unearth undiscovered genes. An international collaborative study using data from 26,368 women with breast cancer and 217,673 control group without breast cancer from 8 different countries (i.e., Netherlands, Spain, Germany, France, Malaysia, Singapore, Cyprus, and the United Kingdom) has unveiled an association of breast cancer with genomic alterations in four new genes (MAP3K1, BARD1, LZTR1 and ATR; with prior known association with cancer) and hinted about 90 more such genes. These findings offer the potential of developing additional risk prediction genes for screening and improved clinical management.
https://pubmed.ncbi.nlm.nih.gov/37592023/

Changes in Methylation-based Aging in Women Who Do and Do Not Develop Breast Cancer.

Kresovich et al. Journal of the National Cancer Institute,
https://doi.org/10.1093/jnci/djad117, 2023

A study involving 417 women from the Sister Study cohort analyzed DNA methylation data from paired blood samples collected approximately 7.7 years apart, calculating three epigenetic metrics of biological aging. Half of the women (n=190) were diagnosed and treated for breast cancer between blood draws, while the other half (n=227) remained cancer-free. After accounting for covariates and baseline biological aging metrics, women diagnosed and treated for breast cancer had higher biological aging at the second blood draw than cancer-free women. Case-only analyses revealed that radiation therapy showed strong positive associations with biological aging. In conclusion, breast cancer diagnosis and treatment may be associated with accelerated biological aging.
https://pubmed.ncbi.nlm.nih.gov/37467056/

Molecular Portraits of Cell Cycle Checkpoint Kinases in Cancer Evolution, Progression, and Treatment Responsiveness.

Oropeza et al. Sci Adv. 9(26):eadf2860, 2023.

The study analyzed somatic and germline mutation frequencies in cell cycle checkpoint kinase genes using data from several breast cancer studies, including the Cancer Genome Atlas and the International Cancer Genome Consortium. The authors identified correlative connections between specific gene mutations, breast cancer subtypes, and prognostic patterns. The authors highlighted specific gene mutations linked to the development or progression of ER-positive/HER2-negative breast cancer in pre-and post-menopausal women and treatment-resistant forms of the ER-positive/HER2-positive subtype in younger women. In addition, the authors found specific alterations associated with advanced, treatment-resistant forms of the ER-positive/HER2-positive subtype exclusively in younger women. The study provides new candidate molecules for improving breast cancer subtypes.
https://pubmed.ncbi.nlm.nih.gov/37390209

Impact of Breast Cancer and Germline BRCA Pathogenic Variants on Fertility Preservation in Young Women.

Prokurotaite et al., Life (Basel). 2023;13(4):930. doi: 10.3390/life13040930.

To further clarify the impact of pathogenic BCRA variants on the preservation of fertility in carrier women, the authors evaluated the number of mature oocytes in 85 young women aged with a mean age of 32.2 ± 3.9 years. The authors observed no significant change in the number of collected mature oocytes upon follicular stimulation in the experimental and control groups.
https://pubmed.ncbi.nlm.nih.gov/37109459/

Obesity Promotes Breast Epithelium DNA Damage In Women Carrying A Germline Mutation In BRCA1 Or BRCA2.

Bhardwaj et al., Science Translational Medicine 15(684): Eade1857, 2023

Although obesity and germline BRCA mutations are widely considered risk factors for breast cancer, the molecular relationship between these two risk factors remains unclear. This study demonstrated a positive correlation between body mass index and levels of DNA damage, as well as metabolic pathways in normal breast epithelium in women with mutant BRCA carriers. Interestingly, breast adipose tissues from women with BRCA mutations also exhibited upregulation of estrogen biosynthesis components. These results provide evidence for an aggressive action of these adipose-derived molecules on nearby breast epithelial cells and in turn, breast cancer oncogenesis in breast epithelium with BRCA mutations.
https://pubmed.ncbi.nlm.nih.gov/36812344/

Using Publicly Available Datasets To Identify Population-Based Transcriptomic Landscape Contributing To The Aggressiveness Of Breast Cancer In Young Women

Tabbal et al., Frontiers in Genetics 13:1039037, 2023.

The study explored the genomic basis of invasiveness associated with early onset of breast cancer. Using functional genomic analytical tools and public databases, alterations in gene expression patterns were assessed in various patient populations divided into two age groups: ≤45 and 45–65 years. The authors observed an increased expression of genes involved in pathways that are suggestive of basal The study explored the genomic basis of invasiveness associated with early onset of breast cancer. Using functional genomic analysis tools and public databases, alterations in gene expression patterns were assessed in various patient populations divided into two age groups: ≤45 and 45–65 years. The authors observed an increased expression of genes involved in pathways that are suggestive of basal tumors in young African patients and luminal A in young Asian patients. This study reinforced the notion of the papulation-associated genomic basis of tumor biology and resulting behaviors; however, it remains unclear if this could be translated into therapeutic strategies for BCYW.
https://pubmed.ncbi.nlm.nih.gov/36685821/

Impact Of Anti-HER2 Therapy Alone And With Weekly Paclitaxel On The Ovarian Reserve Of Young Women With HER2-Positive Breast Cancer.

Lambertini, et al., Journal of National Comprehensive Cancer Network 21(1):33- 41.e16, 2023.

The study examined the status of gonad toxicity after using anti-HER2 and taxane agents and assessed the levels of the biomarker anti-müllerian hormone in HER2-positive early-breast-cancer premenopausal women (n = 130). The results indicated a significant decline in the AMH levels during the mense period, leading to surgery. A larger decline in AMH levels was observed after the combined treatment with paclitaxel and anti-HER2 therapy. This study concluded that anti-HER2 therapies alone had limited gonad toxicity, but the addition of paclitaxel resulted in a marked decline in AMH levels with possible negative effects on ovarian function and fertility.
https://pubmed.ncbi.nlm.nih.gov/36634607/

Young Black Women May Be More Likely To Have First Mammogram Cancers: A New Perspective In Breast Cancer Disparities.

Wilkerson et al., Annals of Surgical Oncology, doi: 10.1245/s10434-022-12995-y, 2023.

This study confirmed that Black women were significantly more likely to be diagnosed with first mammogram cancer than White women and those from other racial groups. Factors such as delay in mammographic screening, race, and lack of private insurance were primarily associated with an increased likelihood of cancer detection on the first mammogram. The results suggested that Black women, particularly those with elevated lifetime risk, may benefit from starting mammography at an earlier age.
https://pubmed.ncbi.nlm.nih.gov/36602665/

Survival Benefit Of Chemotherapy According To 21-Gene Recurrence Score In Young Women With Breast Cancer.

Nash et al., Annals of Surgical Oncology, doi: 10.1245/s10434-022-12699-3, 2023

The authors explored the benefit of chemotherapy according to the recurrence score (RS) from Oncotype DX in younger women (aged 40–50 years) diagnosed with HR-positive, HER2-negative patients. Overall, 45.3% of the 15,422 patients receiving chemotherapy were associated with a higher RS; higher-stage, higher-grade tumors, and tumors that were PR-negative. RS was observed to be of prognostic value for overall survival (OS) regardless of the nodal status. The study concluded that the decision to chemotherapy could be especially preference-sensitive in women aged 40–50 years with intermediate RS. , as it may not provide the survival benefit for many women.
https://pubmed.ncbi.nlm.nih.gov/36611067/

Early Breast Cancer In Women Aged 35 Years Or Younger: A Large National Multicenter French Population-Based Case Control-Matched Analysis.

Dufour et al., Breast 68:163-172, 2023.

In support of the notion that early breast cancer is usually associated with a poor outcome, a recent analysis of multicenter French datasets (involving 556 and 5925 patients with breast cancer aged ≤35 and 36–50 years, respectively) confirmed the presence of high-grade, invasive tumors in the younger cohort and provided the associated aggressive treatment regimen.

https://pubmed.ncbi.nlm.nih.gov/36774756/

Application Of Novel Breast Biospecimen Cell Type Adjustment Identifies Shared DNA Methylation Alterations In Breast Tissue And Milk With Breast Cancer Risk Factors.

Muse et al., Cancer Epidemiol Biomarkers & Prevention pii: EPI-22-0405, 2023.

Over the years, alterations in the methylation pattern have evolved as an epigenomic biomarker in predicting early breast transformation. However, very few studies have directly compared the methylation patterns of breast tissues and breast milk. In this context, a recent study on DNA methylation involving 48 specimens of breast milk and 95 specimens of breast tumors suggested the presence of shared hypermethylated CpG loci among breast tissue and breast milk. The study emphasized the value of using breast milk as a noninvasive diagnostic approach.
https://pubmed.ncbi.nlm.nih.gov/36780234/

Genomic Characterization Of Hormone Receptor-Positive Breast Cancer Arising In Very Young Women.

Luen et al., Annals of Oncology,https://doi.org/10.1016/j.annonc.2023.01.009, 2023..

A recent genomic study highlighted the usefulness of genomic subgrouping in developing effective targeted treatment strategies for BCYW. The authors confirmed a high rate of prevalence of mutations in GATA3 (a marker for ductal and lobular and ER+ breast tumors). They provided indications for homologous recombination deficient phenotypes (indicative of defective repair of DNA double-strand breaks in ER-positive/HER2-negative breast tumors in younger women (<40 years, n = 359) compared with older women (≥40 years, n = 917). These molecular variables were further linked with poor overall survival and distant recurrence-free interval
https://pubmed.ncbi.nlm.nih.gov/36709040/

Association Of Body Mass Index With 21-Gene Recurrence Score Among Women With Estrogen Receptor-Positive, ERBB2-Negative Breast Cancer.

Lee at al., JAMA Network Open 5(11):e2243935, 2022.

Although body mass index (BMI) is associated with various clinical disorders, its relationship with genomic alterations in young women with ER-positive and HER2-negative breast cancer remains unclear. In this study, 776 Korean women aged < or >45 years with ER-positive, HER2-negative breast cancer were included. The cases with the known status of the Oncotype Dx 21-gene data and recurrence score were considered, and these endpoints were correlated with the BMI score. The study suggested that a BMI of 25 or higher is associated with a higher Oncotype Dx score in younger patients with ER-positive and HER2-negative breast tumors, implying a recommendation for chemotherapy after breast surgery.
https://pubmed.ncbi.nlm.nih.gov/36441548/

Mammary Collagen Is Under Reproductive Control With Implications For Breast Cancer.

Guo, et al., Matrix Biology 105:104-126, 2022.

High breast density as detected by mammography is a generally accepted risk factor for breast cancer. Fibrillar collagen is one of the key components of breast density. The authors demonstrated that the expression of collagen is regulated in a dynamic manner during pregnancy, lactation, and weaning phase of the mammary glands in a rat model and in human breast tissues. The authors further described a collagen signature involving 48 genes, which is generally noted in postpartum-associated breast cancer, and its association with poor survival of patients with breast cancer including younger women with ER-negative breast tumors.
https://pubmed.ncbi.nlm.nih.gov/34839002/

Somatic And Germline Genomic Alterations In Very Young Women With Breast Cancer.

Waks et al., Clinical Cancer Research 28(11):2339-2348, 2022.

The authors examined the biological basis of poor prognosis of breast cancer in young women compared with older women by studying the genomic differences between breast tumors in young versus older women. Whole-exome sequencing of tumor and germline was performed in 92 patients (52.7% tumors were ER- positive/HER2-negative; 28.0% were HER2-positive, and 16.1% were triple-negative) with a median age of 32.5 years, and the data were compared with TCGA genomic data in older women (≥45 years old, median age 61 years). The study reported a higher prevalence of genomic alterations in GATA3 and ARID1A in young patients, which also carried a pathogenic BRCA germline variant.
https://pubmed.ncbi.nlm.nih.gov/35101884/

Delineation Of Pathogenomic Insights Of Breast Cancer In Young Women.

Paul et al., Cells 11(12):1927, 2022.

Using the publicly available TCGA and Metabric breast cancer datasets, this study reported dysregulation of intrinsic breast cancer subtype-specific genes in breast cancer in younger women aged <40 years, compared with the matched normal or normal breast tissues. The study further correlated the expression patterns with the overall survival (OS) or relapse-free survival (RFS) of patients with breast cancer. Interestingly, several dysregulated genes in BCYW were also detected in the secreted exosomes and body fluids, implying the usefulness of body-fluid-based, noninvasive biomarkers in developing noninvasive strategies for screening a larger segment of the age-appropriate group of younger women.
https://pubmed.ncbi.nlm.nih.gov/35741056/

Germline Genetic Carriers Versus Noncarriers.

Lewinsohn et al., Clinical Breast Cancer S1526-8209(22)00290-7, 2022.

This study reported that among young women with breast cancer, carriers of germline genetic pathogenic variants and non-carriers had similar desires for having biological children and similar concerns about infertility post-treatment. However, carriers were more likely to report concerns about the heritability of cancer risk, and this impacted some carriers’ decisions not to pursue future pregnancies. The study highlighted the importance of counseling regarding strategies to prevent the transmission of cancer risk to offspring.
https://pubmed.ncbi.nlm.nih.gov/36628811/