Early-onset Breast Cancer Research Articles

Proteogenomic analysis dissects early-onset breast cancer patients with prognostic relevance.

Early-onset breast cancer is known for its aggressive clinical characteristics and high prevalence in East Asian countries, but a comprehensive understanding of its molecular features is still lacking. In this study, we conducted a proteogenomic analysis of 126 treatment-naïve primary tumor tissues obtained from Korean patients with young breast cancer (YBC) aged ≤40 years. By integrating genomic, transcriptomic, and proteomic data, we identified five distinct functional subgroups that accurately represented the clinical characteristics and biological behaviors of patients with YBC. Our integrated approach could be used to determine the proteogenomic status of HER2, enhancing its clinical significance and prognostic value. Furthermore, we present a proteome-based homologous recombination deficiency (HRD) analysis that has the potential to overcome the limitations of conventional genomic HRD tests, facilitating the identification of new patient groups requiring targeted HR deficiency treatments. Additionally, we demonstrated that protein-RNA correlations can be used to predict the late recurrence of hormone receptor-positive breast cancer. Within each molecular subtype of breast cancer, we identified functionally significant protein groups whose differential abundance was closely correlated with the clinical progression of breast cancer. Furthermore, we derived a recurrence predictive index capable of predicting late recurrence, specifically in luminal subtypes, which plays a crucial role in guiding decisions on treatment durations for YBC patients. These findings improve the stratification and clinical implications for patients with YBC by contributing to the optimal adjuvant treatment and duration for favorable clinical outcomes.

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.

Informing Psychosocial Care for Young Couples Coping with Early-Onset Breast Cancer: A Cross-Sectional Examination of Unmet Service Needs and Their Association with Psychological Distress in the First Year Post-Diagnosis.

Objective: Young women diagnosed with breast cancer report greater psychological and physical morbidity than both older women and healthy peers. Similarly, young partners experience elevated cancer-related distress. Psychosocial oncology programs are not frequently attuned to the needs of young adult patients and may exclude their social networks. This marks a critical gap in psychosocial care delivery. The study investigated unmet service needs, psychological distress, and care preferences of young couples managing breast cancer in the first year post-diagnosis. Methods: Forty dyads (n = 80) of women aged 18-45 and their partners completed measures of anxiety (Generalized Anxiety Disorder-7), depression (Patient Health Questionnaire-9), and a service use questionnaire adapted from previously published Adolescent and Young Adult (AYA) literature. The resulting 25 items assessed perceived care needs and service utilization across three domains: informational, emotional/supportive, and practical issues. Descriptive statistics, cross-tabulations, and bivariate correlations were computed. Actor and partner effects of unmet needs on mental health outcomes were investigated with generalized estimating equations (GEE). Results: Patients and partners were in their late thirties, mostly non-Hispanic White, married, highly educated, and employed. Approximately 60% of patients and 43%-66% of partners presented one or more unmet service needs, which correlated with greater distress. Unmet needs about information related to exercise, recurrence, nutrition, and symptom management were prevalent. Unmet supportive service needs of both patients and partners included age-appropriate programs, sexual health, and family counseling. Women reported practical needs for work/school accommodations, integrative care, financial issues and health coverage; while financial concerns, health insurance, and caregiving demands were priorities for partners. Conclusion: Young couples facing early-onset breast cancer experience large proportions of unmet service needs. These challenges were exacerbated by the lack of developmentally targeted psychosocial programs pertaining to informational, supportive, and practical care needs. Enhancing providers' understanding of the psychosocial issues affecting young couples' well-being, and the implementation of systematic procedures to detect and respond to their distress, is urgently needed.

PALB2 analysis in the diagnostic process of breast cancer: An Italian monocentric experience.

The clinical utility of germline BRCA1 and BRCA2 testing is well established in patients with family history suggestive for hereditary breast and ovarian cancer syndrome. Recently, germline PALB2 pathogenic variants were also associated with an increased risk of breast and other cancers and, in the Italian population, it has been described in few studies without a systematic germline analysis of BRCA1, BRCA2 and PALB2. In this study, we described ASST Sette Laghi cancer genetic counselling services' experience in the analysis of 402 patients with suspected breast and ovarian cancer syndrome, by using BRCA1, BRCA2 and PALB2 germline genetic test. The frequency of PALB2 pathogenic variants was 1.2% compared to 3.5% and 3.2% for BRCA1 and BRCA2, respectively, whereas class 3 variants were detected in 0.3% and 0.5% of the BRCA1 and BRCA2 investigated patients, respectively. PALB2 pathogenic variants were identified in patients with a strong family history for breast cancer. Moreover, PALB2 variants were significantly associated with a younger age of breast cancer onset (mean age, 40.25 years) compared to wild-type patients (mean age 51.2 years, p-value = 0.0331). Similar to BRCA-associated breast cancer, the majority of PALB2 breast cancers were identified at an advanced clinical stage. Pedigree analysis revealed a family history of breast and ovarian cancer syndrome in all PALB2 pathogenic variants carriers (early breast cancer onset, bilateral breast cancer and ovarian cancer). In conclusion, the germline analysis of BRCA1, BRCA2 and PALB2 should be included in breast cancer clinical practice as a not negligible number of PALB2 carriers could be identified and referred to specific surveillance protocols.

Breast Cancer Prognosis in Young BRCA1/BRCA2 Mutation Carriers: A Retrospective Hospital-based Cohort Study

AimStudies 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 noncarriers. Materials and methodsThis 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. ResultsTwenty-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). ConclusionIn 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.

Increasing rates of early-onset Luminal A breast cancers correlate with binge drinking patterns

BackgroundBreast cancer (BC) rates have been increasing in young women in the U.S. Alcohol is an established risk factor for breast cancer and has been consistently associated with hormone receptor positive cancers, the type of breast cancer that has been increasing the fastest in young women. Given these trends, we conducted an ecological study to examine whether alcohol consumption, and specifically binge drinking trends, were correlated with female breast cancer diagnosed under 40 years of age using breast cancer data from the Surveillance, Epidemiology, and End Results (SEER) Cancer Registry. We accounted for a latent period before cancer diagnosis by using exposure 10 years before the outcome (lag model); we also conducted a separate cumulative analysis of 10-year aggregate exposure.FindingsModerate (Incidence Rate Ratio (IRR) = 1.05, 95% Confidence Interval (CI) = 1.02–1.07) and heavy (IRR = 1.05, 95% CI = 1.02–1.07)(≥ 1 and ≥ 2 drinks/day, respectively) alcohol consumption were each associated with Luminal A breast cancer but not the other molecular subtypes. Binge drinking was associated with an increased rate of early-onset Luminal A BC in both the 10-year lag model (IRR = 1.06, 95% CI = 1.02 to 1.11) and the cumulative model (IRR = 1.05, 95% CI = 1.02–1.07). Binge drinking was also associated with early-onset Luminal B BC in the cumulative model (IRR = 1.04, 95% CI = 1.01–1.07), but not associated with ERBB2-enriched or triple negative early-onset BC in either model.ConclusionThese trends support the hypothesis that one reason for the increase in early-onset breast cancer is from increased alcohol intake including binge drinking.

Development of a novel prediction model for carriage of BRCA1/2 pathogenic variant in Japanese patients with breast cancer based on Japanese organization of hereditary breast and ovarian cancer registry data.

With the increasing demand for BRCA genetic testing, most existing prediction models were developed using data from individuals of European descent. This study aimed to identify clinicopathological factors of hereditary breast and ovarian cancer (HBOC) syndrome and develop the first Japanese-specific prediction model for BRCA pathogenic variant carriers in Japan. We utilized data from 3072 Japanese patients with breast cancer aggregated by the Japanese Organization of Hereditary Breast and Ovarian Cancer registry. Prediction models were developed using 70% of the overall dataset and validated using the remaining 30%. Factors associated with the BRCA pathogenic variant status were identified using logistic univariate analysis, and significant factors were further analyzed using logistic multivariate analysis to develop prediction models for BRCA1/2 (BRCA1 and/or BRCA2), BRCA1, and BRCA2 pathogenic variants. BRCA1 showed associations with aggressive clinicopathological factors such as triple-negative breast cancer and nuclear grade 3. Moreover, the prediction model showed a high area under the curve (AUC) of 0.879. By contrast, BRCA2 exhibited fewer characteristic associated factors, and the AUC of the model was 0.669. Common factors shared by BRCA1/2, BRCA1, and BRCA2 were the age at diagnosis of breast cancer and the youngest age of relatives with breast cancer. Consistent with previous research, early-onset breast cancer appeared to be strongly associated with HBOC. We successfully developed prediction models for BRCA1/2, BRCA1, and BRCA2 pathogenic variants. By accurately stratifying patients' risk and guiding targeted screening and preventative interventions, these models will contribute to improved management and outcomes of HBOC.

Exposure to ambient polycyclic aromatic hydrocarbons and early-onset female breast cancer in a case-control study in Ontario, Canada.

Ambient polycyclic aromatic hydrocarbons (PAHs) are a class of toxicologically important and understudied air pollutants. Epidemiologic evidence suggests that chronic exposure to PAHs increases breast cancer risk; however, there are few studies in nonoccupational settings that focus on early-onset diagnoses. The relationship between residentially-based ambient PAH concentrations and female breast cancer, among those 18-45 years of age, was characterized in the Ontario Environment and Health Study (OEHS). The OEHS was a population-based case-control study undertaken in Ontario, Canada between 2013 and 2015. Primary incident breast cancers were identified within 3 months of diagnosis, and a population-based series of controls were recruited. Concentrations of ambient PAHs, using fluoranthene as a surrogate, were derived using a chemical transport model at a 2.5 km spatial resolution. These estimates were assigned to participants' residences at the time of the interview and 5 years prior. Logistic regression was used to estimate odds ratios (ORs) and their 95% confidence intervals (CIs) based on a quartile categorization of fluoranthene exposure while adjusting for a series of individual- and area-level risk factors. The shape of the exposure-response trend was evaluated using cubic splines. Median fluoranthene exposure for cases and controls was 0.0017 µg/m3 and 0.0014 µg/m3, respectively. In models adjusted for a parsimonious set of risk factors, the highest quartile of exposure was associated with an increased risk of breast cancer (OR = 2.16; 95% CI = 1.22, 3.84). Restricted spline analyses revealed nonlinear dose-response patterns. These findings support the hypothesis that ambient PAH exposures increases the risk of early-onset breast cancer.

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&lt;0.01) in BC and from 23% to 30% (Ptrend&lt;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

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.

Genetic Risk, Health-Associated Lifestyle, and Risk of Early-onset Total Cancer and Breast Cancer.

Early-onset cancer (diagnosed under age 50) generally manifests as an aggressive disease phenotype. The association between healthy lifestyle and early-onset cancer and whether it varies by common genetic variants remains unclear. We analyzed a prospective cohort of 66,308 participants who were under age 50 and free of cancer at baseline in the UK Biobank. Using Cox regression, we estimated Hazard ratios (HRs) and 95% confidence intervals (CIs) for early-onset total and breast cancer based on sex-specific composite total cancer polygenic risk scores (PRSs), a breast cancer-specific PRS, and sex-specific health-associated lifestyle scores (HLSs). 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 females (HR, 95% CI: 1.83, 1.49-2.26) and males (2.03, 1.51-2.73) as well as early-onset breast cancer in females (3.06, 2.20-4.26). An unfavorable lifestyle (highest vs lowest category of HLS) was associated with higher risk of total cancer and breast cancer in females across genetic risk categories; the association with total cancer and breast cancer was stronger in the highest genetic risk category than the lowest: HRs (95% CIs) were 1.55 (1.12, 2.14) and 1.69 (1.11, 2.57) in the highest genetic risk category and 1.03 (0.64, 1.67) and 0.81 (0.36, 1.85) in the lowest. Genetic and lifestyle factors were independently associated with early-onset total and breast cancer risk. Individuals with a high genetic risk may benefit more from adopting a healthy lifestyle in preventing early-onset cancer.

BRCA1/2 mutations and outcomes among Middle Eastern patients with early-onset breast cancer in Oman.

High prevalence of early-onset breast cancer (EOBC) has been reported in Middle Eastern populations. For example, in Oman more than 50% of patients with breast cancer (BC) are under age 45 at diagnosis. Causes for this high incidence are unknown. Germline BRCA gene mutations have been associated with EOBC, however, prevalence of these mutations and how they relate to EOBC in Oman has not been assessed. Clinical data were collected for patients with BC treated at Royal Hospital, Oman between 2010 and 2022. Germline BRCA1/2 gene mutations were identified using sequencing and MLPA. Correlation and Kaplan-Meier survival analyses were performed to test relationships among clinico-pathological features, gene mutations, and outcomes. Total of 1336 Middle Eastern patients with BC were included; 611 were aged <45 at diagnosis (45.7%). No significant correlation was found between BRCA1/2 mutation status and EOBC (P = .229), and the majority of EOBC cases had no family history of BC. EOBC tumors did, however, differ in clinicopathological features; EOBCs were significantly larger (P < .0001), of higher grade (P < .0001), and included more HER2-enriched, and triple negative subtypes (P = .018) compared with later onset cases. Accordingly, survival analyses revealed that EOBC had significantly worse disease-free survival (P = .002). BRCA gene variants showed a distinct range of mutations including, in BRCA2, 3 previously unreported mutations and 4 potential founder recurrent mutations. Our findings showed that germline BRCA1/2 mutations were not over-represented in EOBC cases in Oman, and therefore are unlikely to be responsible for high EOBC rates.

Rare Germline Variants in DNA Repair Genes Detected in BRCA-Negative Finnish Patients with Early-Onset Breast Cancer.

Breast cancer is the most common malignancy, with a mean age of onset of approximately 60 years. Only a minority of breast cancer patients present with an early onset at or before 40 years of age. An exceptionally young age at diagnosis hints at a possible genetic etiology. Currently, known pathogenic genetic variants only partially explain the disease burden of younger patients. Thus, new knowledge is warranted regarding additional risk variants. In this study, we analyzed DNA repair genes to identify additional variants to shed light on the etiology of early-onset breast cancer. Germline whole-exome sequencing was conducted in a cohort of 63 patients diagnosed with breast cancer at or before 40 years of age (median 33, mean 33.02, range 23-40 years) with no known pathogenic variants in BRCA genes. After filtering, all detected rare variants were sorted by pathogenicity prediction scores (CADD score and REVEL) to identify the most damaging genetic changes. The remaining variants were then validated by comparison to a validation cohort of 121 breast cancer patients with no preselected age at cancer diagnosis (mean 51.4 years, range 28-80 years). Analysis of novel exonic variants was based on protein structure modeling. Five novel, deleterious variants in the genes WRN, RNF8, TOP3A, ERCC2, and TREX2 were found in addition to a splice acceptor variant in RNF4 and two frameshift variants in EXO1 and POLE genes, respectively. There were also multiple previously reported putative risk variants in other DNA repair genes. Taken together, whole-exome sequencing yielded 72 deleterious variants, including 8 novel variants that may play a pivotal role in the development of early-onset breast cancer. Although more studies are warranted, we demonstrate that young breast cancer patients tend to carry multiple deleterious variants in one or more DNA repair genes.

Prospective metabolome-wide association study suggests environmental chemicals cause early-onset breast cancer through disruption of nutrient sensing mechanisms

Prospective metabolome-wide association study suggests environmental chemicals cause early-onset breast cancer through disruption of nutrient sensing mechanisms

Hereditary breast cancer next-generation sequencing panel evaluation in the south region of Brazil: A novel BRCA2 candidate pathogenic variant is reported.

In this article, we delineate a loosely selected cohort comprising patients with a history of early-onset breast cancer and/or a familial occurrence of cancer. The aim of this study was to gain insights into the presence of breast cancer-related gene variants in a population from a micro-region in southern Brazil, specifically the Metropolitan Region of Curitiba. This area exhibits a highly genetically mixed population, mirroring the general characteristics of the Brazilian people. Comprehensive next-generation sequencing (NGS) multigene panel testing was conducted on 12 patients from the region, utilizing three different library preparation methods. Two pathogenic variants and one candidate pathogenic variant were identified: BRCA2 c.8878C>T, p.Gln2960Ter; CHEK2 c.1100del, p.Thr367Metfs15, and BRCA2 c.3482dup, p.Asp1161Glufs3. BRCA2 c.3482dup, a novel candidate pathogenic variant, previously unpublished, is reported. The prevalence of pathogenic variants in this small cohort is similar to that described in the literature. All different library preparation methods were equally proficient in enabling the detection of these variants.

Obesity and Early-Onset Breast Cancer and Specific Molecular Subtype Diagnosis in Black and White Women

Epidemiologic data suggest an association of obesity with breast cancer (BC); however, obesity's contribution to early onset and risk of diagnosis with specific molecular subtypes by race is uncertain. To examine the race-specific association of body mass index with early onset and diagnosis of specific molecular subtypes. This retrospective cohort study included patients with BC diagnosed between October 1, 2017, and March 31, 2022, at 3 University of South Alabama Mitchell Cancer Institute clinics. Participants were also prospectively enrolled for serum leptin measurement. The primary outcome was age at BC onset and specific subtype diagnosis. The secondary outcome was race-specific differences. Odds ratios (ORs) for associations of body mass index with age at onset and subtype were estimated using the Fisher exact test. Race was self-reported. Of the 1085 study patients, 332 (30.6%) were Black with a median age of 58 (IQR, 50-66) years, and 753 (69.4%) were White with a median age of 63 (IQR, 53-71) years. A total of 499 patients (46.0%) had obesity, with Black women with obesity receiving more frequent BC diagnosis than their White counterparts (OR, 2.40; 95% CI, 1.87-3.15; P < .001). In addition, Black women had a significantly higher incidence of early-onset disease (OR, 1.95; 95% CI, 1.33-2.86; P = .001) than White women, and obesity increased this risk significantly in Black women (OR, 2.92; 95% CI, 1.35-6.22; P = .006). Black women with obesity also had a significantly higher risk of luminal A BC (OR, 2.53; 95% CI, 1.81-3.56; P < .001) and triple-negative BC (TNBC) (OR, 2.48; 95% CI, 1.43-4.22; P = .002) diagnosis than White counterparts. Black women, with or without BC, had significantly higher serum leptin levels (median [IQR], 55.3 [40.3-66.2] ng/mL and 29.1 [21.1-46.5] ng/mL, respectively, P < .001) than White women (median [IQR], 33.4 [18.9-47.7] ng/mL and 16.5 [10.0-22.9] ng/mL, respectively), which was associated with higher odds of luminal A disease (OR, 5.25; 95% CI, 1.69-14.32, P = .003). Higher odds of early-onset disease (OR, 3.50; 95% CI, 0.43-23.15; P = .33 for trend), and TNBC diagnosis (OR, 6.00; 95% CI, 0.83-37.27; P = .14 for trend) were also seen, although these outcomes were not statistically significant. In this cohort study of patients with BC, obesity and high serum leptin levels were associated with an enhanced risk of early-onset BC and diagnosis of luminal A and TNBC subtypes in Black women. These findings should help in developing strategies to narrow the existing disparity gaps.

Somatic and germline aberrations in homologous recombination repair genes among Chinese high-risk breast cancer patients by multi-gene next-generation sequencing.

Recently, genes involved in homologous recombination repair (HRR) pathway have been extensively studied. However, the landscapes of HRR gene mutations remain poorly defined in Chinese high-risk breast cancer (BC) patients. Our study aims to identify the status of germline and somatic HRR gene mutations and their association with clinicopathological features in these patients. A total of 100 high-risk BC patients from our institution who underwent paired peripheral blood germline and BC tissues somatic 26 genes next-generation sequencing (NGS) from January 2018 to July 2023 were enrolled for retrospective analysis. Out of 100 high-risk BC patients, 55 (55%) had at least one germline or somatic mutation in HRR genes. Among them, 22% carried germline pathogenic variants (19 BRCA1/2 and 3 non-BRCA genes), 9% harbored somatic pathogenic mutations (3 BRCA1/2 and 6 non-BRCA genes). Among high-risk factors, family history and early onset BC showed a correlation with HRR gene mutations (p < 0.05). BRCA1 germline and HRR gene somatic mutations showed a correlation with TNBC, but BRCA2 germline mutations were associated with Luminal B/HER2-negative BC (p < 0.05). Patients with HRR gene somatic pathogenic variant more likely had a lympho-vascular invasion and distant metastasis (p < 0.05). The prevalence of HRR gene germline and somatic mutations were higher in Chinese BC patients with high risk factors. We strongly recommend that these high-risk BC patients receive comprehensive gene mutation testing, especially HRR genes, which are not only related to genetic consultation for BC patients and provide a theoretical basis for necessary prevention and individualized treatment.

Genetic Testing of Breast Cancer Patients with Very Early-Onset Breast Cancer (≤30 Years) Yields a High Rate of Germline Pathogenic Variants, Mainly in the BRCA1, TP53, and BRCA2 Genes.

Early-onset breast cancer constitutes a major criterion for genetic testing referral. Nevertheless, studies focusing on breast cancer patients (≤30 years) are limited. We investigated the contribution and spectrum of known breast-cancer-associated genes in 267 Greek women with breast cancer ≤30 years while monitoring their clinicopathological characteristics and outcomes. In this cohort, a significant proportion (39.7%) carried germline pathogenic variants (PVs) distributed in 8 genes. The majority, namely 36.7%, involved BRCA1, TP53, and BRCA2. PVs in BRCA1 were the most prevalent (28.1%), followed by TP53 (4.5%) and BRCA2 (4.1%) PVs. The contribution of PVs in CHEK2, ATM, PALB2, PTEN, and RAD51C was limited to 3%. In the patient group ≤26 years, TP53 PVs were significantly higher compared to the group 26-30 years (p = 0.0023). A total of 74.8% of TP53 carriers did not report a family history of cancer. Carriers of PVs receiving neoadjuvant chemotherapy showed an improved event-free survival (p < 0.0001) compared to non-carriers. Overall, many women with early-onset breast cancer carry clinically actionable variants, mainly in the BRCA1/2 and TP53 genes. The inclusion of timely testing of TP53 in these patients provides essential information for appropriate clinical management. This is important for countries where reimbursement involves the cost of genetic analysis of BRCA1/2 only.

Spectrum and characteristics of germline PALB2 pathogenic variants in 1556 early-onset breast cancer patients in China

PurposeLimited data are available regarding the partner and localizer of BRCA2 (PALB2) in Chinese patients with early breast cancer. This study aimed to assess the spectrum and characteristics of germline PALB2 pathogenic variants in this population.MethodsPeripheral blood samples were collected from 1556 patients diagnosed with BRCA1/2-negative early-onset breast cancer. All coding regions and exon‒intron boundaries of the PALB2 genes were screened through next-generation sequencing.ResultsThe prevalence of PALB2 pathogenic variants was approximately 0.77% in the cohort. Eleven PALB2 pathogenic variants were identified in twelve participants, including five frameshift mutations and six nonsense mutations. All other variants were detected once, except for PALB2 c.1056_1057del (detected twice). Two PALB2 carriers (2/12, 16.7%) have documented family history of breast cancer and/or ovarian cancer. Patients with a positive family history exhibited a threefold higher possibility of being identified as PALB2 carriers than those without a family history (2% vs. 0.69%), although the difference was not statistically significant (p = 0.178). Compared to non-carriers, PALB2 carriers has a tendency to appear in younger age (≤ 30 years) (25% vs 14.4%), human epidermal growth factor receptor-2 (HER2)-negative status (83.3% vs. 70.2%), and diagnosed with invasive micropapillary carcinoma (16.7% vs 3.1%).ConclusionThe prevalence of the germline PALB2 pathogenic variants was approximately 0.77% in Chinese patients with BRCA1/2-negative early-onset breast cancer. Our findings is crucial for understanding population-specific genetic risks and offering insights that can enhance genetic counseling and genetic testing strategies in this population.

Histopathological phenotyping of cancers in PTEN Hamartoma Tumor Syndrome for improved recognition: A single-center study.

PTEN hamartoma tumor syndrome (PHTS) has a broad clinical spectrum including various benign and malignant tumors at varying age of diagnosis. Many patients remain unrecognized, unaware of their increased cancer risk. We aimed to describe the cancer spectrum, age of onset and histopathological cancer characteristics to assess whether specific cancer characteristics could improve PHTS recognition. Genetic testing results and pathology reports were collected for patients tested for germline PTEN variants between 1997 and 2020 from the diagnostic laboratory and the Dutch nationwide pathology databank (Palga). The cancer spectrum and age of onset were assessed in patients with (PTENpos) and without (PTENneg) a germline PTEN variant. Histopathological cancer characteristics were assessed in a nested cohort. 341 PTENpos patients (56% females) and 2882 PTENneg patients (66% females) were included. PTENpos patients presented mostly with female breast (BC, 30%), endometrial (EC, 6%), thyroid (TC, 4%) or colorectal cancer (4%). PTENpos were significantly younger at cancer onset (43 vs. 47 years) and had more often (46% vs. 18%) a second BC than PTENneg. PTEN detection rates were highest for BC <40 years (9%), TC <20 years (15%) and EC <50 years (28%), and dropped to 6%, 4%, and 15% by age 60. Histopathological characteristics were similar between groups. No histopathological cancer characteristics were distinctive for PHTS. However, PTENpos were significantly younger at cancer onset. Therefore early-onset BC, EC, or TC warrants consideration of PHTS diagnostics either through a pre-screen for other PHTS features or direct germline testing.