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Purpose: Limited 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. Methods: Peripheral 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. Results: The 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%). Conclusion: The 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. [ABSTRACT FROM AUTHOR]

Breast cancer is a global health problem. It is an age-dependent disease, but cases of early-onset breast cancer (eBC) are gradually increasing. There are many unresolved questions regarding eBC risk factors, mechanisms of development and screening. Only 10% of eBC cases are due to mutations in the BRCA1/BRCA2 genes, and 90% have a more complex genetic background. This poses a significant challenge to timely cancer detection in young women and highlights the need for research and awareness. Therefore, identifying genetic risk factors for eBC is essential to solving these problems. This study represents an association analysis of 144 eBC cases and 163 control participants to identify genetic markers associated with eBC risks in Kazakh women. We performed a two-stage approach in association analysis to assess genetic predisposition to eBC. First-stage genome-wide association analysis revealed two risk intronic loci in the CHI3L2 gene (p = 5.2 × 10−6) and MGAT5 gene (p = 8.4 × 10−6). Second-stage exonic polymorphisms haplotype analysis showed significant risks for seven haplotypes (p < 9.4 × 10−4). These results point to the importance of studying medium- and low-penetrant genetic markers in their haplotype combinations for a detailed understanding of the role of detected genetic markers in eBC development and prediction. [ABSTRACT FROM AUTHOR]

Background: Approximately 27% of female breast cancer patients are diagnosed before the age of 55, a group often comprising mothers with young children. Maternal psychosocial well-being significantly impacts these children’s psychosocial well-being. This study assesses the well-being of children with mothers who have early-onset breast cancer. Methods: We examined the eldest child (up to 15 years old) of women with nonmetastatic breast cancer (

Abstract Background Early-onset breast cancer (EOBC) is a specific condition that affects women under the age of 45. BRCA pathogenic/likely pathogenic (P/LP) germline variants have been demonstrated to be harbored in a subgroup of EOBC individuals, and BRCA-positive genetic result offers an option to ensure more specified therapeutic implications. Establishing comprehensive BRCA1/2 genetic testing, including both the detection of small-scale mutations and large genomic rearrangements (LGRs), is needed for risk assessment and clinical management. In this study, we described a Turkish EOBC cohort along with their clinico-pathological characteristics and BRCA1/2 mutational profiles. A total of 67 unrelated patients were enrolled. Both next-generation sequencing (NGS)-based gene panel and multiplex ligation-dependent probe amplification (MLPA) were performed for BRCA1/2 variant identification. Patients' family medical history and hormone receptor status of the tumors were also recorded. Results 14 (20.90%) patients were found to carry BRCA P/LP germline variants. (Nine were BRCA2-positive, and five were BRCA1-positive.) Two novel BRCA2 variants were detected. No significant differences were found between BRCA-positive vs. BRCA-negative or BRCA1-positive vs. BRCA2-positive for hormonal status and family history. Conclusions BRCA1/2 genes represent a predominant part of the genetic landscape of EOBC. Our results expand the spectrum of BRCA1/2 variants and provide knowledge of the BRCA1/2 variant prevalence in our cohort.

Background: Approximately 27% of female breast cancer patients are diagnosed before the age of 55, a group often comprising mothers with young children. Maternal psychosocial well-being significantly impacts these children's psychosocial well-being. This study assesses the well-being of children with mothers who have early-onset breast cancer. Methods: We examined the eldest child (up to 15 years old) of women with nonmetastatic breast cancer (<55 years old, mean age: 40) enrolled in the mother–child rehab program 'get well together'. Using maternal reports on children's well-being (the Strengths and Difficulties Questionnaire; SDQ), we describe the prevalence of abnormally high SDQ scores and identify protective and risk factors via linear regression. Results: The mean SDQ scores of 496 children (4–15 years old, mean age: 8) fell below the thresholds, indicating psychosocial deficits. However, most SDQ scores deviated negatively from the general population, especially for emotional problems, with one in ten children displaying high and one in five displaying very high deficits. Female sex, more siblings, a positive family environment and maternal psychosocial well-being were protective factors for children's psychosocial well-being. Conclusions: Children of mothers with breast cancer may benefit from improved maternal well-being and family support. Further research is needed to identify appropriate interventions. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this study was to identify the mean age at which breast cancer (BC) was first diagnosed in 2010 or 2022, and to evaluate whether there were any changes in age groups at first BC diagnosis. Methods: This retrospective cross-sectional study included adult women (18 years or older) who were diagnosed with BC (ICD-10: C50) for the first time in 2010 or 2022 in office-based practices in Germany (in 300 general practices or 95 gynecological practices). We examined the mean age at diagnosis and the percentage of patients in three age groups (18–49, 50–65, and > 65) for both 2010 and 2022. The average age difference between 2010 and 2022 was analyzed using Wilcoxon rank tests, and the proportions of the three age groups were analyzed using chi-squared tests. These analyses were performed separately for patients in general and gynecological practices. Results: The mean age at which BC was initially diagnosed in 2022 was found to be significantly greater than that in 2010 for both general practices (66.9 years vs. 64.0 years p < 0.001) and gynecological practices (62.2 years vs. 60.3 years, p < 0.001). Early-onset BC decreased from 15.6 to 12.0% in general practices and from 23.2 to 18.2% in gynecological practices between 2010 and 2022. The proportion of new BC diagnoses in the age group 50–65 increased from 36.6 to 40.9% in gynecological practices, but did not increase in general practices. Conclusion: The study found that BC was diagnosed at an older age in 2022 than in 2010. In addition, the proportion of early-onset BC cases decreased, while the proportion of cases in the age group 50–65 increased in gynecological practices in Germany. [ABSTRACT FROM AUTHOR]

Background: Early-onset breast cancer (EOBC) is a specific condition that affects women under the age of 45. BRCA pathogenic/likely pathogenic (P/LP) germline variants have been demonstrated to be harbored in a subgroup of EOBC individuals, and BRCA-positive genetic result offers an option to ensure more specified therapeutic implications. Establishing comprehensive BRCA1/2 genetic testing, including both the detection of small-scale mutations and large genomic rearrangements (LGRs), is needed for risk assessment and clinical management. In this study, we described a Turkish EOBC cohort along with their clinico-pathological characteristics and BRCA1/2 mutational profiles. A total of 67 unrelated patients were enrolled. Both next-generation sequencing (NGS)-based gene panel and multiplex ligation-dependent probe amplification (MLPA) were performed for BRCA1/2 variant identification. Patients' family medical history and hormone receptor status of the tumors were also recorded. Results: 14 (20.90%) patients were found to carry BRCA P/LP germline variants. (Nine were BRCA2-positive, and five were BRCA1-positive.) Two novel BRCA2 variants were detected. No significant differences were found between BRCA-positive vs. BRCA-negative or BRCA1-positive vs. BRCA2-positive for hormonal status and family history. Conclusions: BRCA1/2 genes represent a predominant part of the genetic landscape of EOBC. Our results expand the spectrum of BRCA1/2 variants and provide knowledge of the BRCA1/2 variant prevalence in our cohort. [ABSTRACT FROM AUTHOR]

The risk of early‐onset (EO) breast cancer is known to be increased in relatives of EO breast cancer patients, but less is known about the familial risk of other EO cancers. We assessed familial risks of EO cancers (aged ≤40 years) other than breast cancer in 54 753 relatives of 5562 women with EO breast cancer (probands) by using a population‐based cohort from Finland. Standardized incidence ratios (SIRs) and 95% confidence intervals (CI) were estimated by using gender‐, age‐ and period‐specific cancer incidences of the general population as reference. The risk of any cancer excluding breast cancer in first‐degree relatives was comparable to population cancer risk (SIR 0.99, 95% CI: 0.84‐1.16). Siblings' children of women with EO breast cancer were at an elevated risk of EO testicular and ovarian cancer (SIR = 1.74, 95% CI: 1.07‐2.69 and 2.69, 95% CI: 1.08‐5.53, respectively). The risk of EO pancreatic cancer was elevated in siblings of the probands (7.61, 95% CI: 1.57‐22.23) and an increased risk of any other cancer than breast cancer was observed in children of the probands (1.27, 95% CI: 1.03‐1.55). In conclusion, relatives of women with EO breast cancer are at higher familial risk of certain discordant EO cancers, with the risk extending beyond first‐degree relatives. What's new? Family members of early‐onset breast cancer patients are at a higher risk of early‐onset breast cancer. However, it is unclear whether the familial risk is limited to early‐onset cancer of the same site. Here, the authors estimate the familial risks of discordant early‐onset cancers in relatives of female early‐onset breast cancer patients, using an extensive, prospective population‐based cohort. The findings suggest that the familial risk extends to discordant early‐onset cancers, including ovarian, testicular and pancreatic cancers, as well as beyond first‐degree relatives. [ABSTRACT FROM AUTHOR]

Simple Summary: Epidemiologic studies have observed higher risks of breast cancer recurrence and death in women diagnosed <40 years of age compared to ≥40 years. There is ongoing clinical debate as to whether this is due to the overrepresentation of advanced and aggressive disease features or unique disease biology. Younger women are more likely to be diagnosed with more aggressive subtypes, including triple-negative breast cancer. Herein, we conduct a systematic review and meta-analysis of studies assessing the association between age <40 years at diagnosis and clinical outcomes in triple-negative breast cancer. We present pooled risk estimates for recurrence-free survival, breast cancer-specific and overall survival, and pathological complete response. Our findings highlight the prognostic significance of age in triple-negative breast cancer and may point to a need for tailored local and systemic treatment strategies in women of younger ages. Early-onset diagnosis, defined by age <40 years, has historically been associated with inferior outcomes in breast cancer. Recent evidence suggests that this association is modified by molecular subtype. We performed a systematic review and meta-analysis of the literature to synthesize evidence on the association between early-onset diagnosis and clinical outcomes in triple-negative breast cancer (TNBC). Studies comparing the risk of clinical outcomes in non-metastatic TNBC between early-onset patients and later-onset patients (≥40 years) were queried in Medline and EMBASE from inception to February 2023. Separate meta-analyses were performed for breast cancer specific survival (BCSS), overall survival (OS), and disease-free survival (DFS), locoregional recurrence-free survival (LRRFS), distant recurrence-free survival (DRFS), and pathological complete response (pCR). In total, 7581 unique records were identified, and 36 studies satisfied inclusion criteria. The pooled risk of any recurrence was significantly greater in early-onset patients compared to later-onset patients. Better BCSS and OS were observed in early-onset patients relative to later-onset patients aged >60 years. The pooled odds of achieving pCR were significantly higher in early-onset patients. Future studies should evaluate the role of locoregional management of TNBC and the implementation of novel therapies such as PARP inhibitors in real-world settings, and whether they improve outcomes. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common cancer among women worldwide. BRCA1/2 are responsible for 16–20% of the risk for hereditary BC. Other susceptibility genes have been identified; Fanconi Anemia Complementation Group M (FANCM) being one of these. Two variants in FANCM, rs144567652 and rs147021911, are associated with BC risk. These variants have been described in Finland, Italy, France, Spain, Germany, Australia, the United States, Sweden, Finnish, and the Netherlands, but not in the South American populations. Our study evaluated the association of the SNPs rs144567652 and rs147021911 with BC risk in non-carriers of BRCA1/2 mutations from a South American population. The SNPs were genotyped in 492 BRCA1/2-negative BC cases and 673 controls. Our data do not support an association between FANCM rs147021911 and rs144567652 SNPs and BC risk. Nevertheless, two BC cases, one with a family history of BC and the other with sporadic early-onset BC, were C/T heterozygotes for rs144567652. In conclusion, this is the first study related contribution of FANCM mutations and BC risk in a South American population. Nevertheless, more studies are necessary to evaluate if rs144567652 could be responsible for familial BC in BRCA1/2-negatives and for early-onset non-familial BC in Chilean BC cases. [ABSTRACT FROM AUTHOR]

Background: Few studies have focused specifically on prognostic factors and optimal surgical intervention for early-onset triple-negative breast cancer (eTNBC), which is characterized by high malignancy and poor prognosis. Methods: We performed a cohort study with a median follow-up of 31 months using Surveillance, Epidemiology, and End Results (SEER) data of patients diagnosed with stages I-III eTNBC between 2010 and 2016. In addition, we collected cases between 2006 and 2016 from our center as an external validation set. Clinical features, pathologic characteristics and oncologic outcomes were analyzed. Prognostic factors for overall survival (OS) and breast cancer-specific survival (BCSS) were determined by Cox proportional hazards analyses and were incorporated into the prognostic nomogram. Subgroup analysis based on propensity score matching method was conducted to explore the subset of patients that would benefit from breastconserving therapy (BCT). Results: Based on SEER dataset, patients with eTNBC were more likely to undergo mastectomy than BCT. On multivariable analysis, patients with better survival outcomes were those not married, uninsured, had higher T and N stage, and had histological type of mixed invasive ductal and lobular carcinoma. The prognostic nomogram based on these variables successfully predicted the 3- and 5-year BCSS (C-index in training cohort, 0.774; in validation cohort from SEER, 0.768; in validation cohort from our center, 0.723). Subgroup analysis illustrated that patients with T1N0M0 or T2-4N+M0 tumors who underwent BCT achieved longer overall survival than those who underwent mastectomy (for T1N0M0, P = 0.022; for T2-4N+M0, P = 0.003); however, the type of surgery did not influence OS among patients with T1N+M0 or T2-4N0M0 tumors (for T1N+M0, P = 0.305; for T2-4N0M0, P = 0.317). Conclusions: The prognosis of patients with eTNBC is mainly affected by marital status, insurance status, T stage, N stage and histological type. The prognostic nomogram based on these factors is quite reliable. Subgroup analysis suggested that BCT may be a superior option for patients with eTNBC, especially those with T1N0M0 and T2-4N+M0 tumors. [ABSTRACT FROM AUTHOR]

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.

Breast cancer during pregnancy (PrBC) is a rare tumor with only a little information on its immune landscape. Here, we sought to characterize the cellular composition of the tumor microenvironment (TME) of PrBC and identify its differences from early-onset breast cancer (EOBC) in non-pregnant women. A total of 83 PrBC and 89 EOBC were selected from our Institutional registry and subjected to tumor-infiltrating lymphocytes (TILs) profiling and immunohistochemistry for CD4, CD8, forkhead box P3 (FOXP3), and programmed death-ligand 1 (PD-L1) (clone 22C3). A significantly lower frequency of hormone receptor (HR)-positive tumors was observed in PrBC. The prevalence of low/null PD-L1 and CD8+TILs was higher in PrBC than in the controls, specifically in HR+/HER2– breast cancers. PrBC had a significantly higher risk of relapse and disease-related death, compared to EOBC. The presence of TILs and each TIL subpopulation were significantly associated with disease relapse. Moreover, the death rate was higher in PrBC with CD8+ TILs. The TME of PrBC is characterized by specific patterns of TIL subpopulations with significant biological and prognostic roles. Routine assessment of TILs and TILs subtyping in these patients would be a valid addition to the pathology report that might help identify clinically relevant subsets of women with PrBC. [ABSTRACT FROM AUTHOR]

Purpose of Review: Early-onset breast cancer presents various challenges in regard to reproductive health. This review examines the current data pertaining to issues such as fertility preservation, preimplantation genetics, the impact of chemotherapy and endocrine therapy, contraception, and pregnancy in the young breast cancer population. Recent Findings: Many breast cancer treatments such as chemotherapy and endocrine therapy can be gonadotoxic or teratogenic. Multiple fertility preservation options are now available to young breast cancer patients, including embryo and oocyte preservation, ovarian tissue preservation, and ovarian suppression with GnRH agonists. In patients with known cancer germline mutations, preimplantation genetic testing is an option. Summary: Fertility preservation and other reproductive services are expanding and offer great promise to the early-onset breast cancer community. Providers must be knowledgeable about the various options in order to better empower patients. [ABSTRACT FROM AUTHOR]

Introduction: Perceived breast cancer risk predicts screening behaviors. However, perceived risk is often inaccurate, notably in Black women, who often underestimate their risk despite having higher disease-specific mortality rates. We examined predictors of perceived breast cancer risk, and its impact on surveillance.Methods: We used baseline data from a randomized trial targeting unaffected women recruited by relatives with early-onset breast cancer. Data collection occurred between 2012 and 2013. Accuracy of perceived risk was assessed by comparing perceived risk to objective lifetime breast cancer risks, calculated with the Gail and Claus models. A multivariate mixed model regression examined predictors of accuracy of perceived risk. The impact of perceived risk on breast cancer surveillance was assessed with one-way ANOVAS comparing Black to White women.Results: Among participants, 21.4% self-identified as Black and 78.6% as White. Overall, 72.9% (n=247/339), 16.2% (n=55/339), and 10.9% (n=37/339) of participants overestimated, accurately perceived, and underestimated, respectively, their lifetime breast cancer risk. Race did not predict the accuracy of risk perception. Younger participants were more likely to overestimate their risk (β=-.455; CI [-.772, -.138]; P=.005). MRI utilization was predicted by a higher objective risk (F 1,263 [= 30.271]; P<.001) and more accurate risk perception (P=.010; Fisher's exact test).Conclusions: Most women with a family history of early-onset breast cancer inaccurately perceived their risk for developing the disease. Younger women were more likely to overestimate their risk. Findings can guide the development of tailored interventions to improve adherence to breast cancer surveillance recommendations. [ABSTRACT FROM AUTHOR]

Abstract Background This study is to explore the relationship between the ZBRK1/ZNF350 (Zinc finger and BRCA1-interacting protein with KRAB domain-1; also known as zinc-finger protein 350) gene polymorphism and early-onset breast cancer. Methods The ZBRK1/ZNF350 gene exon detection analysis was performed with the direct sequencing and Snapshot methods in 80 cases of breast cancer (aged ≤ 40 years old) and 240 healthy subjects (aged ≤ 40 years old). Results Totally 9 sequence variants were detected, including 5 missense mutations and 4 synonymous mutations, located at EXON3, EXON4 and EXON5, respectively. The rs4987241 and rs3764538 variants were published for the first time, while the remaining variants had been reported before. There were significant differences in the frequency distribution of family history between the breast cancer and control groups. Moreover, there were significant differences in the CT genotype frequency at the rs138898320 locus between the breast cancer and healthy control groups. Compared with the carriers of CC wild genotype at rs138898320, the risk of breast cancer was reduced by 88.3% in the CT mutant genotype carriers, with significant difference. In the stratification with no family history, compared with the carriers of CC wild genotype at rs138898320, significant differences were observed for the CT mutant genotype carriers. In the stratification with family history, there was no significant difference in the variation of rs138898320. Conclusion The rs138898320 CT mutation genotype of ZBRK1/ZNF350 may reduce the risk of breast cancer, and the protecting effect would be increased in the stratification with no family history. Trial registration Not applicable.

Breast cancer (BC) is the most prevalent malignancy in women with Li-Fraumeni syndrome (LFS). The literature on BC in LFS is limited due to its rarity worldwide. A TP53 founder pathogenic variant (c.1010G>A; p.R337H) is responsible for the higher prevalence of this syndrome among women of Brazilian ancestry. Purpose: The aim of the study was to describe the BC phenotype expressed by Brazilian female LFS carriers and compare the data between p.R337H and other TP53 germline pathogenic/likely pathogenic variants (non-p.R337H carriers). Methods: We searched for cases of TP53 germline pathogenic/likely pathogenic variant carriers affected by BC included between 2015 and 2020 in the BLiSS (Brazilian Li-Fraumeni Study) registry at the Sírio-Libanês Hospital. Results: Among 163 adult female carriers from the registry, 91 (56%) had received a BC diagnosis, including 72 p.R337H carriers. BC was the first cancer diagnosed in 90% of cases. Early onset BC (age ≤45 years) was diagnosed in 78.2% of cases (11.5% <31 years; 66.7% 31–45 years; 21.8% >45 years). The median age of BC diagnosis for p.R337H carriers was 39.5 years (range 20–69 years) compared to 34 years (range 21–63 years) for non-p.R337H carriers (p = 0.009). In total, 104 breast tumors were observed in 87 women. Bilateral BC was observed in 29.3% of cases. Histology was available for 96 tumors, comprising 69 invasive breast carcinomas, which were mostly invasive ductal carcinomas (95.6%), 25 ductal in situ carcinomas and 2 soft-tissue sarcomas. Overall, 90.5% of invasive breast carcinomas were hormone receptor (HR)-positive, 39.5% were human epidermal growth factor receptor 2 (HER2)-positive, and 32.8% showed HR and HER2 co-expression. In addition, 55.4% of patients opted for contralateral prophylactic mastectomy after a first BC diagnosis. There were no significant differences in the risk of developing contralateral BC or in the immunohistochemical profile between p.R337H and non-p.R337H groups. Conclusions: The expressed phenotype of p.R337H is similar to that of other TP53 pathogenic/likely pathogenic variants, except for an average older age at the onset of disease; however, this is still younger than the general population. [ABSTRACT FROM AUTHOR]

Background: BRCA1‐associated RING Domain 1 (BARD1) is an important gene related to breast cancer development. However, the role of BARD1 mutations in breast cancer remains inconclusive. This study is to investigate the relationship between exon mutations of BARD1 gene and the risk of early‐onset breast cancer. Methods: Totally, 60 cases of early‐onset breast cancer patients (age 30–40 years) and 240 healthy women (age 30–40 years) were enrolled. Exon mutations of BARD1 were detected and analyzed by direct sequencing and SNaPshot. Results: The risk of breast cancer was increased by 3.475 times in carriers with deletion mutation at rs28997575 site of BARD1 (aOR1 = 3.475, 95%CI = 1.302–9.276) (p = 0.013). The risk of breast cancer in carriers with GC genotype at rs2229571 site of BARD1 was reduced by 72.6% (aOR1 = 0.274, 95%CI = 0.134–0.562) (p = 0.001), and that in carriers with CC genotype was reduced by 82.8% (aOR1 = 0.172, 95%CI = 0.076–0.392) (p = 0.001). After stratification with family history, the difference of rs2229571 site mutation genotype was statistically significant (OR = −2.169, 95%CI = 0.016–0.828, p = 0.032). Additionally, the frequency distribution of breast cancer family history in the case group (15%) was significantly more than that in the control group (6.7%) (p = 0.037). Conclusion: The deletion mutation at rs28997575 locus of the BARD1 gene can significantly increase the risk of breast cancer. The mutation genotype of rs2229571 locus can significantly reduce the risk of breast cancer. Family history is associated with BARD1 gene polymorphism. A family history of breast cancer may be a risk factor for breast cancer. [ABSTRACT FROM AUTHOR]

Introduction: The CHEK2 gene is known to be an important signal transducer involved in DNA repair, apoptosis, or cell cycle arrest in response to DNA damage. The mutations in this gene have been associated with a wide range of cancers, both sporadic and hereditary. Germline CHEK2 mutations are linked to an increased risk of breast cancer. Therefore, the aim of this study was to identify the prevalence of CHEK2 variants in BRCA1/2- and PALB2-negative early-onset patients with breast cancer and/or ovarian cancer in a Turkish population for the first time. Methods: The study included 95 patients with BRCA1/2- and PALB2-negative early-onset breast cancer and/or ovarian cancer and also 60 unaffected women. All the intron/exon boundaries and coding exons of CHEK2 were subjected to mutational analysis by heteroduplex analysis and DNA sequencing. Results: A total of 16 CHEK2 variants were found in breast cancer patients within the Turkish population. CHEK2 c.1100delC mutation most frequently studied in the CHEK2 gene was not detected in our study. The prevalence of variants of uncertain significance in CHEK2 was found to be 7.3% (n = 7) in BRCA1/2 and PALB2 mutation-negative Turkish patients with early-onset breast and/or ovarian cancer. Conclusion: The present study may shed light on alternative variations that could be significant for understanding the prevalence and clinical suitability of the CHEK2 gene. [ABSTRACT FROM AUTHOR]

Abstract Background BRCA1‐associated RING Domain 1 (BARD1) is an important gene related to breast cancer development. However, the role of BARD1 mutations in breast cancer remains inconclusive. This study is to investigate the relationship between exon mutations of BARD1 gene and the risk of early‐onset breast cancer. Methods Totally, 60 cases of early‐onset breast cancer patients (age 30–40 years) and 240 healthy women (age 30–40 years) were enrolled. Exon mutations of BARD1 were detected and analyzed by direct sequencing and SNaPshot. Results The risk of breast cancer was increased by 3.475 times in carriers with deletion mutation at rs28997575 site of BARD1 (aOR1 = 3.475, 95%CI = 1.302–9.276) (p = 0.013). The risk of breast cancer in carriers with GC genotype at rs2229571 site of BARD1 was reduced by 72.6% (aOR1 = 0.274, 95%CI = 0.134–0.562) (p = 0.001), and that in carriers with CC genotype was reduced by 82.8% (aOR1 = 0.172, 95%CI = 0.076–0.392) (p = 0.001). After stratification with family history, the difference of rs2229571 site mutation genotype was statistically significant (OR = −2.169, 95%CI = 0.016–0.828, p = 0.032). Additionally, the frequency distribution of breast cancer family history in the case group (15%) was significantly more than that in the control group (6.7%) (p = 0.037). Conclusion The deletion mutation at rs28997575 locus of the BARD1 gene can significantly increase the risk of breast cancer. The mutation genotype of rs2229571 locus can significantly reduce the risk of breast cancer. Family history is associated with BARD1 gene polymorphism. A family history of breast cancer may be a risk factor for breast cancer.

Breast cancer (BC) is the most prevalent malignancy in women with Li-Fraumeni syndrome (LFS). The literature on BC in LFS is limited due to its rarity worldwide. A TP53 founder pathogenic variant (c.1010G>A; p.R337H) is responsible for the higher prevalence of this syndrome among women of Brazilian ancestry.PurposeThe aim of the study was to describe the BC phenotype expressed by Brazilian female LFS carriers and compare the data between p.R337H and other TP53 germline pathogenic/likely pathogenic variants (non-p.R337H carriers).MethodsWe searched for cases of TP53 germline pathogenic/likely pathogenic variant carriers affected by BC included between 2015 and 2020 in the BLiSS (Brazilian Li-Fraumeni Study) registry at the Sírio-Libanês Hospital.ResultsAmong 163 adult female carriers from the registry, 91 (56%) had received a BC diagnosis, including 72 p.R337H carriers. BC was the first cancer diagnosed in 90% of cases. Early onset BC (age ≤45 years) was diagnosed in 78.2% of cases (11.5% 45 years). The median age of BC diagnosis for p.R337H carriers was 39.5 years (range 20–69 years) compared to 34 years (range 21–63 years) for non-p.R337H carriers (p = 0.009). In total, 104 breast tumors were observed in 87 women. Bilateral BC was observed in 29.3% of cases. Histology was available for 96 tumors, comprising 69 invasive breast carcinomas, which were mostly invasive ductal carcinomas (95.6%), 25 ductal in situ carcinomas and 2 soft-tissue sarcomas. Overall, 90.5% of invasive breast carcinomas were hormone receptor (HR)-positive, 39.5% were human epidermal growth factor receptor 2 (HER2)-positive, and 32.8% showed HR and HER2 co-expression. In addition, 55.4% of patients opted for contralateral prophylactic mastectomy after a first BC diagnosis. There were no significant differences in the risk of developing contralateral BC or in the immunohistochemical profile between p.R337H and non-p.R337H groups.ConclusionsThe expressed phenotype of p.R337H is similar to that of other TP53 pathogenic/likely pathogenic variants, except for an average older age at the onset of disease; however, this is still younger than the general population.

Background: 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., Patients and Methods: 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., Results: 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., Conclusion: 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., (© The Author(s) 2024. Published by Oxford University Press.)

Background: Chemotherapy-induced premature menopause leads to some consequences, including infertility. We initiated this randomized phase III trial to determine whether a cyclophosphamide-free adjuvant chemotherapy regimen would increase the likelihood of menses resumption and improve survival outcomes.Methods: Young women with operable estrogen receptor-positive HER2-negative breast cancer after definitive surgery were randomly assigned to receive adjuvant epirubicin and cyclophosphamidefollowed by weekly paclitaxel (EC-wP) or epirubicin and paclitaxel followed by weekly paclitaxel (EP-wP). All patients received at least 5-year adjuvant endocrine therapy after chemotherapy. Two coprimary endpoints were the rate of menstrual resumption at 12 months after chemotherapy and 5-year disease-free survival in the intention-to-treat population. This study is registered at ClinicalTrials.gov (NCT01026116). All statistical tests were 2-sided.Results: Between January 2011 and December 2016, 521 patients (median age = 34 years; interquartile range = 31-38 years) were enrolled, with 261 in the EC-wP group and 260 in the EP-wP group. The rate of menstrual resumption at 12 months after chemotherapy was 48.3% in EC-wP (95% confidence interval [CI] = 42.2% to 54.3%) and 63.1% in EP-wP (95% CI = 57.2% to 68.9%), with an absolute difference of 14.8% (95% CI = 6.37% to 23.2%, P < .001). The posthoc exploratory analysis by patient-reported outcome questionnaires indicated that pregnancy might occur in fewer women in the EC-wP group than in the EP-wP group. At a median follow-up of 62 months, the 5-year disease-free survival was 78.3% (95% CI = 72.2% to 83.3%) in EC-wP and 84.7% (95% CI = 79.3% to 88.8%) in EP-wP (stratified log-rank P = .07). The safety data were consistent with the known safety profiles of relevant drugs.Conclusions: The cyclophosphamide-free chemotherapy regimen might be associated with a higher probability of menses resumption. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common malignancy occurring during gestation. In early-stage breast cancer during pregnancy (PrBC), breast-conserving surgery (BCS) with delayed RT is a rational alternative to mastectomy, for long considered the standard-of-care. Regrettably, no specific guidelines on the surgical management of these patients are available. In this study, we investigated the feasibility and safety of BCS during the first trimester of pregnancy in women with early-stage PrBC. All patients with a diagnosis of PrBC during the first trimester of pregnancy jointly managed in two PrBC-specialized Centers were included in this study. All patients underwent BCS followed by adjuvant radiotherapy to the ipsilateral breast after delivery. Histopathological features and biomarkers were first profiled on pre-surgical biopsies. The primary outcome was the isolated local recurrence (ILR). Among 168 PrBC patients, 67 (39.9%) were diagnosed during the first trimester of gestation. Of these, 30 patients (age range, 23-43 years; median=36 years; gestational age, 2-12 weeks; median=7 weeks; median follow-up time=6.5 years) met the inclusion criteria. The patients that were subjected to radical surgery (n=14) served as controls. None of the patients experienced perioperative surgical complications. No ILR were observed within three months (n=30), 1 year (n=27), and 5 years (n=18) after surgery. Among the study group, 4 (12.3%) patients experienced ILR or new carcinomas after 6-13 years, the same number (n=4) had metastatic dissemination after 3-7 years. These patients are still alive and disease-free after 14-17 years of follow-up. The rate of recurrences and metastasis in the controls were not significantly different. The findings provide evidence that BCS in the first trimester PrBC is feasible and reasonably safe for both the mother and the baby.

Breast cancer is the most common malignancy occurring during gestation. In early-stage breast cancer during pregnancy (PrBC), breast-conserving surgery (BCS) with delayed RT is a rational alternative to mastectomy, for long considered the standard-of-care. Regrettably, no specific guidelines on the surgical management of these patients are available. In this study, we investigated the feasibility and safety of BCS during the first trimester of pregnancy in women with early-stage PrBC. All patients with a diagnosis of PrBC during the first trimester of pregnancy jointly managed in two PrBC-specialized Centers were included in this study. All patients underwent BCS followed by adjuvant radiotherapy to the ipsilateral breast after delivery. Histopathological features and biomarkers were first profiled on pre-surgical biopsies. The primary outcome was the isolated local recurrence (ILR). Among 168 PrBC patients, 67 (39.9%) were diagnosed during the first trimester of gestation. Of these, 30 patients (age range, 23-43 years; median=36 years; gestational age, 2-12 weeks; median=7 weeks; median follow-up time=6.5 years) met the inclusion criteria. The patients that were subjected to radical surgery (n=14) served as controls. None of the patients experienced perioperative surgical complications. No ILR were observed within three months (n=30), 1 year (n=27), and 5 years (n=18) after surgery. Among the study group, 4 (12.3%) patients experienced ILR or new carcinomas after 6-13 years, the same number (n=4) had metastatic dissemination after 3-7 years. These patients are still alive and disease-free after 14-17 years of follow-up. The rate of recurrences and metastasis in the controls were not significantly different. The findings provide evidence that BCS in the first trimester PrBC is feasible and reasonably safe for both the mother and the baby. [ABSTRACT FROM AUTHOR]

The study investigated the association between single nucleotide polymorphisms (SNPs) of BRCA1-interacting protein C-terminal helicase 1 (BACH1) gene and early-onset breast cancer in Uygur and Han women in Xinjiang. SNPs of BACH1 gene exons were detected by direct sequencing and snapshot technique in 80 Uygur and 80 Han patients with breast cancer and 240 healthy Uygur and 240 healthy Han women (all younger than 40 years old). In Uygur and Han breast cancer patients, the variant C allele of rs4986764 SNP can reduce the risk of breast cancer. The protective effect of this locus is more obvious in Han breast cancer patients without tumor family history (P = 0.001, OR = 0.079). In Uygur breast cancer patients, the GG genotype of rs4986765 (OR = 5.617) and the G genotypes (AG + GG) in the dominant model (OR = 4.254) and the AG of c.587A > G SNP (OR = 7.590) and G genotypes (AG + GG) in the dominant model (OR = 7.590) significantly increased the risk of breast cancer. However, they did not significantly increase the risk of breast cancer in Han population. The present study demonstrates that the rs4986764 mutation of BACH1 gene may reduce the risk of early-onset breast cancer in Uygur and Han populations in Xinjiang. The protective effect was more obvious in Han population without family history of cancer. The change of rs4986765 and c.587A > G sites both increased the risk of breast cancer for Uygur. However, there was no significant correlation with early-onset breast cancer in Han population.

Breast cancer during pregnancy (PrBC) is a rare tumor with only a little information on its immune landscape. Here, we sought to characterize the cellular composition of the tumor microenvironment (TME) of PrBC and identify its differences from early-onset breast cancer (EOBC) in non-pregnant women. A total of 83 PrBC and 89 EOBC were selected from our Institutional registry and subjected to tumor-infiltrating lymphocytes (TILs) profiling and immunohistochemistry for CD4, CD8, forkhead box P3 (FOXP3), and programmed death-ligand 1 (PD-L1) (clone 22C3). A significantly lower frequency of hormone receptor (HR)-positive tumors was observed in PrBC. The prevalence of low/null PD-L1 and CD8+TILs was higher in PrBC than in the controls, specifically in HR+/HER2– breast cancers. PrBC had a significantly higher risk of relapse and disease-related death, compared to EOBC. The presence of TILs and each TIL subpopulation were significantly associated with disease relapse. Moreover, the death rate was higher in PrBC with CD8+ TILs. The TME of PrBC is characterized by specific patterns of TIL subpopulations with significant biological and prognostic roles. Routine assessment of TILs and TILs subtyping in these patients would be a valid addition to the pathology report that might help identify clinically relevant subsets of women with PrBC.

Background: This study is to explore the relationship between the ZBRK1/ZNF350 (Zinc finger and BRCA1-interacting protein with KRAB domain-1; also known as zinc-finger protein 350) gene polymorphism and early-onset breast cancer. Methods: The ZBRK1/ZNF350 gene exon detection analysis was performed with the direct sequencing and Snapshot methods in 80 cases of breast cancer (aged ≤ 40 years old) and 240 healthy subjects (aged ≤ 40 years old). Results: Totally 9 sequence variants were detected, including 5 missense mutations and 4 synonymous mutations, located at EXON3, EXON4 and EXON5, respectively. The rs4987241 and rs3764538 variants were published for the first time, while the remaining variants had been reported before. There were significant differences in the frequency distribution of family history between the breast cancer and control groups. Moreover, there were significant differences in the CT genotype frequency at the rs138898320 locus between the breast cancer and healthy control groups. Compared with the carriers of CC wild genotype at rs138898320, the risk of breast cancer was reduced by 88.3% in the CT mutant genotype carriers, with significant difference. In the stratification with no family history, compared with the carriers of CC wild genotype at rs138898320, significant differences were observed for the CT mutant genotype carriers. In the stratification with family history, there was no significant difference in the variation of rs138898320. Conclusion: The rs138898320 CT mutation genotype of ZBRK1/ZNF350 may reduce the risk of breast cancer, and the protecting effect would be increased in the stratification with no family history. Trial registration Not applicable. [ABSTRACT FROM AUTHOR]

Abstract Background Early-onset breast cancer (EOBC) affects about one in 300 women aged 40 years or younger and is associated with worse outcomes than later onset breast cancer. This study explored novel serum proteins as surrogate markers of prognosis in patients with EOBC. Methods Serum samples from EOBC patients (stages 1–3) were analysed using agnostic high-precision quantitative proteomics. Patients received anthracycline-based chemotherapy. The discovery cohort (n = 399) either had more than 5-year disease-free survival (DFS) (good outcome group, n = 203) or DFS of less than 2 years (poor outcome group, n = 196). Expressed proteins were assessed for differential expression between the two groups. Bioinformatics pathway and network analysis in combination with literature research were used to determine clinically relevant proteins. ELISA analysis against an independent sample set from the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) cohort (n = 181) was used to validate expression levels of the selected target. Linear and generalized linear modelling was applied to determine the effect of target markers, body mass index (BMI), lymph node involvement (LN), oestrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 status on patients’ outcome. Results A total of 5346 unique proteins were analysed (peptide FDR p ≤ 0.05). Of these, 812 were differentially expressed in the good vs poor outcome groups and showed significant enrichment for the insulin signalling (p = 0.01) and the glycolysis/gluconeogenesis (p = 0.01) pathways. These proteins further correlated with interaction networks involving glucose and fatty acid metabolism. A consistent nodal protein to these metabolic networks was resistin (upregulated in the good outcome group, p = 0.009). ELISA validation demonstrated resistin to be upregulated in the good outcome group (p = 0.04), irrespective of BMI and ER status. LN involvement was the only covariate with a significant association with resistin measurements (p = 0.004). An ancillary in-silico observation was the induction of the inflammatory response, leucocyte infiltration, lymphocyte migration and recruitment of phagocytes (p < 0.0001, z-score > 2). Survival analysis showed that resistin overexpression was associated with improved DFS. Conclusions Higher circulating resistin correlated with node-negative patients and longer DFS independent of BMI and ER status in women with EOBC. Overexpression of serum resistin in EOBC may be a surrogate indicator of improved prognosis.

Identification of candidate genes associated with susceptibility of breast cancer can have a significant impact at a cancer management national healthcare systems level, making genetic testing more affordable and cost‐effective. We have previously shown that the major histocompatibility complex class I‐related chain A (MICA) was related to breast cancer and plays an important role in modulating immune response mechanisms through NKG2D receptor activation. Compared to our previous study, in this work, we recruited a new cohort composed of 354 unrelated Tunisian women affected by breast cancer and 380 age‐matched women as controls, all genotyped for MICA‐129 Met/Val (rs 1051792). Subsequently, we exanimated the distribution of this polymorphism in ten families. As a result, an association was found between the Val allele and Val/Val genotype and the risk of breast cancer (p = 2.5 × 10–15; OR = 2.40; p = 6.5 × 10–13; OR = 3.03, respectively). Stratified analysis with age and family history of cancer revealed an association between the Val/Val genotype and younger patients <40 years (p =.003; OR = 2.03). Among those patients having a family history of cancer, 68% had a Val/Val genotype (p =.02; OR = 1.82). In the family study, an analyse of pedigrees revealed that the majority of families showed the development of breast cancer at a young age. Moreover, all patients diagnosed with early‐onset breast cancer had a Val/Val genotype. Our results lead us to propose that this polymorphism may be an inherited genetic biomarker contributing to an increased breast cancer risk in Tunisian women. [ABSTRACT FROM AUTHOR]

The study investigated the association between single nucleotide polymorphisms (SNPs) of BRCA1-interacting protein C-terminal helicase 1 (BACH1) gene and early-onset breast cancer in Uygur and Han women in Xinjiang. SNPs of BACH1 gene exons were detected by direct sequencing and snapshot technique in 80 Uygur and 80 Han patients with breast cancer and 240 healthy Uygur and 240 healthy Han women (all younger than 40 years old). In Uygur and Han breast cancer patients, the variant C allele of rs4986764 SNP can reduce the risk of breast cancer. The protective effect of this locus is more obvious in Han breast cancer patients without tumor family history (P = 0.001, OR = 0.079). In Uygur breast cancer patients, the GG genotype of rs4986765 (OR = 5.617) and the G genotypes (AG + GG) in the dominant model (OR = 4.254) and the AG of c.587A > G SNP (OR = 7.590) and G genotypes (AG + GG) in the dominant model (OR = 7.590) significantly increased the risk of breast cancer. However, they did not significantly increase the risk of breast cancer in Han population. The present study demonstrates that the rs4986764 mutation of BACH1 gene may reduce the risk of early-onset breast cancer in Uygur and Han populations in Xinjiang. The protective effect was more obvious in Han population without family history of cancer. The change of rs4986765 and c.587A > G sites both increased the risk of breast cancer for Uygur. However, there was no significant correlation with early-onset breast cancer in Han population. [ABSTRACT FROM AUTHOR]

The burden and experiences that come with a breast cancer diagnosis in a family impact how women perceive personal cancer risk and pursue preventive strategies and/or early detection screening. Hence, this study sought to understand how Filipino women incorporate their experiences living with a sister diagnosed with early-onset breast cancer to their personal perceived risk and screening behavior. Guided by phenomenological approach of inquiry, a face-to-face, semi-structured interview was conducted with 12 purposively sampled women with a female sibling diagnosed with breast cancer before age 50. Transcripts were analyzed using thematic analysis. Results revealed that the respondents tend to compare themselves with their sister when constructing views of personal cancer vulnerability. The subjective risk is also shaped by their beliefs regarding cancer causation such as personalistic causes, personal theory of inheritance, and locus of control. Their sisters' cancer diagnoses serve as a motivation for them to perform breast self-examination. However, clinical breast examination and screening mammography are underutilized due to perceived barriers such as difficulty allotting time to medical consultation, fear, and lack of finances. Overall, cancer risk perception and screening behavior are important factors that must be addressed during cancer genetic counseling consultations. Better understanding of these factors will aid in the formulation of an effective management plan for at-risk women. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) is the most common type of cancer among women in Kazakhstan. To date, little data are available on the spectrum of genetic variation in Kazakh women with BC. We aimed to identify population-specific genetic markers associated with the risk of developing early-onset BC and test their association with clinical and prognostic factors. The study included 224 Kazakh women diagnosed with BC (≤40 age). Entire coding regions (>1700 exons) and the flanking noncoding regions of 94 cancer-associated genes were sequenced from blood DNA using MiSeq platform. We identified 38 unique pathogenic variants (PVs) in 13 different cancer-predisposing genes among 57 patients (25.4%), of which 6 variants were novel. In total, 12 of the 38 distinct PVs were detected recurrently, including BRCA1 c.5266dup, c.5278-2del, and c.2T>C, and BRCA2 c.9409dup and c.9253del that may be founder in this population. BRCA1 carriers were significantly more likely to develop triple-negative BC (OR = 6.61, 95% CI 2.44-17.91, p = 0.0002) and have family history of BC (OR = 3.17, 95% CI 1.14-8.76, p = 0.03) compared to non-carriers. This study allowed the identification of PVs specific to early-onset BC, which may be used as a foundation to develop regional expertise and diagnostic tools for early detection of BC in young Kazakh women.

Abstract Breast cancers arising in women carrying a germline mutation in BRCA1 are typically high-grade, early-onset and have distinct morphological features (BRCA1 -like). However, the majority of early-onset breast cancers of this morphological type are not associated with germline BRCA1 mutations or constitutional BRCA1 promoter methylation. We aimed to assess DNA methylation across the genome for associations with the " BRCA1 -like" morphology. Genome-wide methylation in blood-derived DNA was measured using the Infinium HumanMethylation450K BeadChip assay for women under the age of 40 years participating in the Australian Breast Cancer Family Study (ABCFS) diagnosed with: i) BRCA1 -like breast cancer (n = 30); and ii) breast cancer without BRCA1 -like morphological features (non BRCA1- like; n = 30), and age-matched unaffected women (controls; n = 30). Corresponding tumour-derived DNA from 43 of the affected women was also assessed. Methylation of blood-derived DNA was found to be elevated across 17 consecutive marks in the BRCA1 promoter region and decreased at several other genomic regions (including TWIST2 and CTBP1) for 7 women (23%) diagnosed with BRCA1 -like breast cancer compared with women in the other groups. Corresponding tumour-derived DNA available from 5 of these 7 women had elevated methylation within the BRCA1 and SPHK2 promoter region and decreased methylation within the ADAP1 , IGF2BP3 and SPATA13 promoter region when compared with the other breast tumours. These methylation marks could be biomarkers of risk for BRCA1 -like breast cancer, and could be responsible in part for their distinctive morphological features and biology. As such, they may assist with prevention and targeted therapies for this cancer subtype. Highlights • Some young women have widespread blood derived DNA methylation at the BRCA1 promoter • These women also have reduced blood derived DNA methylation at TWIST2 and CTBP1 • Corresponding tumour DNA from these women have elevated methylation at BRCA1 • These tumours also have other DMR when compared to other breast cancer molecular subtypes. [ABSTRACT FROM AUTHOR]

Key Clinical Message: We used a multi‐gene panel testing to identify the germline variants in a mother‐daughter pair with early‐onset breast cancer, and detected one pathogenic protein‐truncating variant in BRCA2. Our results highlight the importance of genetic testing in identifying the pathogenic mutation running in cancer families. [ABSTRACT FROM AUTHOR]

Background: Early-onset breast cancer (EOBC) affects about one in 300 women aged 40 years or younger and is associated with worse outcomes than later onset breast cancer. This study explored novel serum proteins as surrogate markers of prognosis in patients with EOBC.Methods: Serum samples from EOBC patients (stages 1-3) were analysed using agnostic high-precision quantitative proteomics. Patients received anthracycline-based chemotherapy. The discovery cohort (n = 399) either had more than 5-year disease-free survival (DFS) (good outcome group, n = 203) or DFS of less than 2 years (poor outcome group, n = 196). Expressed proteins were assessed for differential expression between the two groups. Bioinformatics pathway and network analysis in combination with literature research were used to determine clinically relevant proteins. ELISA analysis against an independent sample set from the Prospective study of Outcomes in Sporadic versus Hereditary breast cancer (POSH) cohort (n = 181) was used to validate expression levels of the selected target. Linear and generalized linear modelling was applied to determine the effect of target markers, body mass index (BMI), lymph node involvement (LN), oestrogen receptor (ER), progesterone receptor and human epidermal growth factor receptor 2 status on patients' outcome.Results: A total of 5346 unique proteins were analysed (peptide FDR p ≤ 0.05). Of these, 812 were differentially expressed in the good vs poor outcome groups and showed significant enrichment for the insulin signalling (p = 0.01) and the glycolysis/gluconeogenesis (p = 0.01) pathways. These proteins further correlated with interaction networks involving glucose and fatty acid metabolism. A consistent nodal protein to these metabolic networks was resistin (upregulated in the good outcome group, p = 0.009). ELISA validation demonstrated resistin to be upregulated in the good outcome group (p = 0.04), irrespective of BMI and ER status. LN involvement was the only covariate with a significant association with resistin measurements (p = 0.004). An ancillary in-silico observation was the induction of the inflammatory response, leucocyte infiltration, lymphocyte migration and recruitment of phagocytes (p < 0.0001, z-score > 2). Survival analysis showed that resistin overexpression was associated with improved DFS.Conclusions: Higher circulating resistin correlated with node-negative patients and longer DFS independent of BMI and ER status in women with EOBC. Overexpression of serum resistin in EOBC may be a surrogate indicator of improved prognosis. [ABSTRACT FROM AUTHOR]

To study the potential contribution of genes other than BRCA1/ 2, PTEN, and TP53 to the biological and clinical characteristics of multiple early-onset cancers in Norwegian families, including early-onset breast cancer, Cowden-like and Li-Fraumeni-like syndromes (BC, CSL and LFL, respectively). The Hereditary Cancer Biobank from the Norwegian Radium Hospital was used to identify early-onset BC, CSL or LFL for whom no pathogenic variants in BRCA1/ 2, PTEN, or TP53 had been found in routine diagnostic DNA sequencing. Forty-four cancer susceptibility genes were selected and analyzed by our in-house designed TruSeq amplicon-based assay for targeted sequencing. Protein- and RNA splicing-dedicated in silico analyses were performed for all variants of unknown significance (VUS). Variants predicted as the more likely to affect splicing were experimentally analyzed by minigene assay. We identified a CSL individual carrying a variant in CHEK2 (c.319+2T>A, IVS2), here considered as likely pathogenic. Out of the five VUS ( BRCA2, CDH1, CHEK2, MAP3K1, NOTCH3) tested in the minigene splicing assay, only NOTCH3 c.14090C>T (p.Ser497Leu) showed a significant effect on RNA splicing, notably by inducing partial skipping of exon 9. Among 13 early-onset BC, CSL and LFL patients, gene panel sequencing identified a potentially pathogenic variant in CHEK2 that affects a canonical RNA splicing signal. Our study provides new information on genetic loci that may affect the risk of developing cancer in these patients and their families, demonstrating that genes presently not routinely tested in molecular diagnostic settings may be important for capturing cancer predisposition in these families. [ABSTRACT FROM AUTHOR]

Objective To explore the imaging characteristics of ultrasonography for early-onset breast cancer（ EOBC） ，and evaluate the application value of ultrasonography in diagnosis of EOBC. Methods From January2014 to December 2015，30 cases of breast cancer patients pathologically confirmed were divided into two groupsaccordingtoage，15 cases in each group. A group of patients aged 35 years old or less， were as observation group; Group B patients aged > 35 years old， were set to the control group. Two groups of patients were given with preoperative conventional ultrasound and contrast-enhanced ultrasound examination and the ultrasonographic characteristics were compared. Results Patients in group A had obvious differences with group B in the focal uneven width， aspect ratio， internal echo， contrast enhancement presence of filling defect， enhancement and fade time characteristics， there were statistically significant difference （P<0.05）ConclusionContrast-enhanced ultrasound in the diagnosis of early onset breast cancer has the characteristic performance in the image， has important diagnostic value for early-onset breast cancer， and has a certain clinical application prospect [ABSTRACT FROM AUTHOR]

This year's 18th St. Gallen (SG) consensus conference on the treatment of early breast cancer (SGBCC: St. Gallen International Breast Cancer Conference) focused on practice-oriented questions. The individual situation and risk-benefit assessment were discussed in great detail. As in previous years, a German working group of leading breast cancer experts presented the results of the international SGBCC 2023 against the background of German treatment recommendations - especially the updated treatment recommendations of the Arbeitsgemeinschaft Gynäkologische Onkologie e. V. (AGO) - for everyday clinical practice in Germany. The German treatment recommendations of AGO are based on the current evidence. The comparison with the clinical approach in Germany has proven useful, as the SGBCC panel consists of experts from different countries and disciplines. That is why country-specific characteristics can be incorporated into the SGBCC recommendations., Competing Interests: Conflict of Interest/Interessenkonflikt Prof. Michael Untch, MD: All remuneration to the AG/institution (referent and consultant activity): Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Lilly, MSD Merck, Myriad Genetics, Pfizer, Roche, Pierre Fabre, Novartis, Molecular Health, Agendia, GSK, Seagen, Gilead, Medac, Stemline Genzyme. Maggie Banys-Paluchowski, MD, Associate Professor, received remuneration from: Roche, Novartis, Pfizer, pfm, Eli Lilly, Onkowissen, Seagen, AstraZeneca, Eisai, Amgen, Samsung, Canon, MSD, GSK, Daiichi Sankyo, Gilead, Sirius Pintuition, Pierre Fabre, ExactSciences, Syantra, Stemline, and study support from: EndoMag, Mammotome, MeritMedical, Gilead, Hologic, ExactSciences, Sirius Medical. Prof. Sara Y. Brucker, MD, received remuneration from AstraZeneca, Roche, Novartis, Medtronic, Sanofi, Lilly, MSD, and Hologic. Prof. Wilfried Budach, MD, received remuneration from Merck, BMS, Jörg Eickeler Veranstaltungen, medpublico. Prof. Carsten Denkert, MD, received remuneration from Novartis, Roche, MSD Oncology, Daiichi Sankyo, AstraZeneca, Merck, Molecular Health and study support from the European Commission, German Cancer Aid, BMBF, GBG, Myriad, and Roche. He is involved in patents for digital pathology (VMscope digital pathology software) and biomarker signatures (patents WO2015114146A1 and WO2010076322A1). Prof. Nina Ditsch, MD, received remuneration from AstraZeneca, Daiichi Sankyo, Gilead Sciences, Lilly, Merit Medical, Molecular Health, MSD, Novartis, Onkowissen, Pfizer, pfm medical, Roche, Seagen, Teva. Prof. Peter A. Fasching, MD, received grants from Biontech, Pfizer, Cepheid, and remuneration from Novartis, Pfizer, Daiichi Sankyo, AstraZeneca, Esai, Merck Sharp & Dohme, Lilly, Pierre Fabre, SeaGen, Roche, Agendia, Sanofi Aventis, Gilead, Mylan, and Menarini. Renate Haidinger has no conflicts of interest. Prof. Dr. med. Jörg Heil has no conflicts of interest. Prof. Dr. med. Christian Jackisch received remuneration from AstraZeneca, Lilly, Celgene, MSD; Eisai, Novartis, Pfizer, Gilead, Daiichi Sankyo, Medupdate, Streamed Up, Roche, and research support from Exact Sciences. Prof. Dr. med. Wolfgang Janni received remuneration from AstraZeneca, Celgene, Chugai, Daiichi Sankyo, Eisai, ExactScience, GSK, Janssen, Lilly, Menarini, MSD, Novartis, Sanofi-Aventis, Roche, Pfizer, Seagen, Gilead, Inivata. Hans-Christian Kolberg, MD, Associate Professor, received remuneration from Pfizer, Novartis, Seagen, Roche, Genomic Health/Exact Sciences, Amgen, AstraZeneca, Riemser, Carl Zeiss Meditec, Teva, Theraclion, Janssen-Cilag, GSK, LIV Pharma, Lilly, SurgVision, Onkowissen, Gilead, Daiichi Sankyo, and MSD, as well as travel support from Carl Zeiss Meditec, LIV Pharma, Novartis, Amgen, Pfizer, Daiichi Sankyo, Tesaro, and owns shares in Theraclion SA and Phaon Scientific GmbH. David Krug, MD, Associate Professor, received remuneration from Merck Sharp & Dohme, med update, onkowissen, and Pfizer, as well as research support from Merck KGaA. Prof. Dr. med. Sibylle Loibl did not receive any remuneration. The following companies granted support and remuneration to the GBG: Abbvie, Amgen; AZ; Celgene/BMS, Daiichi Sankyo, Gilead, GSK, Incyte, Lilly, MSD, Merck KG, Medupdate, Streamedup, Novartis, Olema, Pfizer; Relay, Sanofi, Seagen, Roche. Prof. Diana Lüftner, MD, received remuneration from Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Eli Lilly, Gilead, GSK, high5md, Loreal, Novartis, onkowissen, Pfizer, Roche, Teva. Marion van Mackelenbergh, MD, Associate Professor, received remuneration from Amgen, AstraZeneca, Daiichi Sankyo, GenomicHealth, Gilead, GSK, Lilly, Molecular Health, MSD, Mylan, Novartis, Pfizer, PierreFabre, Roche, Seagen, and travel fees from Daiichi Sankyo, Gilead, Lilly. Prof. Julia Radosa, MD, received remuneration from Pfizer, Eisai, MSD, Medac GmbH, Roche, Novartis, Gedeon Richter, Lilly, Pierre Fabre, Daiichi Sankyo, Seagen, Theramex. Prof. Toralf Reimer received remuneration from AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, Myriad, Novartis, Pfizer, and Roche. Manfred Welslau, MD, received remuneration from Amgen, Astellas, AstraZeneca, Celgene, Gilead, Hexal, Janssen, Lilly, Novartis, Roche, Sanofi and has consulted and reviewed for Amgen, Bristol-Myers Squibb, Celgene, Gilead, Hexal, Janssen, Lilly, Medac, Novartis, Roche, Sanofi, AstraZeneca. Rachel Würstlein, MD, Associate Professor, received remuneration from Agendia, Amgen, Aristo, Astra Zeneca, Celgene, Clovis Oncology, Daiichi Sankyo, Eisai, Exact Sciences, Gilead, GlaxoSmithKline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Mylan, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PINK, PumaBiotechnology, Riemser, Roche, Sandoz/Hexal, Sanofi Genzyme, Seattle Genetics/Seagen, Stemline, Tesaro Bio, Teva, Veracyte, Viatris, FOMF, Aurikamed, Clinsol, Pomme Med, medconcept, MCI. Prof. Nadia Harbeck, MD, received remuneration from Amgen, AstraZeneca, Daiichi Sankyo, Gilead, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Sandoz, Sanofi, Seagen, Viatris, Zuelligpharma. Prof. Jens Huober, MD, received research support from Celgene, Novartis, Hexal, and Lilly. Remuneration for lectures from Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Celgene, Eisai, Abbvie, Seagen, Gilead, and Daiichi Sankyo. Consultancy fees from Lilly, Novartis, Roche, Pfizer, Hexal, AstraZeneca, MSD, Celgene, Abbvie, Daiichi, Gilead. Travel fees from Roche, Pfizer, Novartis, Celgene, Daiichi Sankyo, and Gilead. / Prof. Dr. med. Michael Untch: Alle Honorare an den AG/Institution (Referenten- und Beratertätigkeit): Amgen, AstraZeneca, Daiichi Sankyo, Eisai, Lilly, MSD Merck, Myriad Genetics, Pfizer, Roche, Pierre Fabre, Novartis, Molecular Health, Agendia, GSK, Seagen, Gilead, Medac, Stemline Genzyme. PD Dr. med. Maggie Banys-Paluchowski erhielt Honorar von: Roche, Novartis, Pfizer, pfm, Eli Lilly, Onkowissen, Seagen, AstraZeneca, Eisai, Amgen, Samsung, Canon, MSD, GSK, Daiichi Sankyo, Gilead, Sirius Pintuition, Pierre Fabre, ExactSciences, Syantra, Stemline, und Studienunterstützung von: EndoMag, Mammotome, MeritMedical, Gilead, Hologic, ExactSciences, Sirius Medical. Prof. Dr. med. Sara Y. Brucker erhielt Honorar von AstraZeneca, Roche, Novartis, Medtronic, Sanofi, Lilly, MSD und Hologic. Prof. Dr. med. Wilfried Budach erhielt Honorar von Merck, BMS, Jörg Eickeler Veranstaltungen, medpublico. Prof. Dr. med. Carsten Denkert erhielt Honorar von Novartis, Roche, MSD Oncology, Daiichi Sankyo, AstraZeneca, Merck, Molecular Health und Studienunterstützung von der Europäischen Kommission, der Deutschen Krebshilfe, dem BMBF, der GBG, Myriad und Roche. Er ist an Patenten zur digitalen Pathologie (VMscope digital pathology software) und zu Biomarkersignaturen beteiligt (Patent WO2015114146A1 und WO2010076322A1). Prof. Dr. med. Nina Ditsch erhielt Honorar AstraZeneca, Daiichi Sankyo, Gilead Sciences, Lilly, Merit Medical, Molecular Health, MSD, Novartis, Onkowissen, Pfizer, pfm medical, Roche, Seagen, Teva. Prof. Dr. med. Peter A. Fasching erhielt Zuschüsse von Biontech, Pfizer, Cepheid sowie Honorar von Novartis, Pfizer, Daiichi Sankyo, AstraZeneca, Esai, Merck Sharp & Dohme, Lilly, Pierre Fabre, SeaGen, Roche, Agendia, Sanofi Aventis, Gilead, Mylan und Menarini. Renate Haidinger hat keine Interessenkonflikte. Prof. Dr. med. Jörg Heil hat keine Interessenkonflikte. Prof. Dr. med. Christian Jackisch erhielt Honorar von AstraZeneca, Lilly, Celgene, MSD; Eisai, Novartis, Pfizer, Gilead, Daiichi Sankyo, Medupdate, Streamed Up, Roche und Forschungsunterstützung von Exact Sciences. Prof. Dr. med. Wolfgang Janni erhielt Honorar von AstraZeneca, Celgene, Chugai, Daiichi Sankyo, Eisai, ExactScience, GSK, Janssen, Lilly, Menarini, MSD, Novartis, Sanofi-Aventis, Roche, Pfizer, Seagen, Gilead, Inivata. PD Dr. med. Hans-Christian Kolberg erhielt Honorar von Pfizer, Novartis, Seagen, Roche, Genomic Health/Exact Sciences, Amgen, AstraZeneca, Riemser, Carl Zeiss Meditec, Teva, Theraclion, Janssen-Cilag, GSK, LIV Pharma, Lilly, SurgVision, Onkowissen, Gilead, Daiichi Sankyo und MSD sowie Reisekostenunterstützung von Carl Zeiss Meditec, LIV Pharma, Novartis, Amgen, Pfizer, Daiichi Sankyo, Tesaro und besitzt Anteile von Theraclion SA and Phaon Scientific GmbH. PD Dr. med. David Krug erhielt Honorar von Merck Sharp & Dohme, med update, onkowissen und Pfizer sowie Forschungsunterstützung von Merck KGaA. Prof. Dr. med. Sibylle Loibl erhielt keine persönlichen Honorare. Unterstützung und Honorare an die GBG wurde von folgenden Firmen gewährt: Abbvie, Amgen; AZ; Celgene/BMS, Daiichi Sankyo, Gilead, GSK, Incyte, Lilly, MSD, Merck KG, Medupdate, Streamedup, Novartis, Olema, Pfizer; Relay, Sanofi, Seagen, Roche. Prof. Dr. med. Diana Lüftner erhielt Honoraria von Amgen, AstraZeneca, Celgene, Daiichi Sankyo, Eli Lilly, Gilead, GSK, high5md, Loreal, Novartis, onkowissen, Pfizer, Roche und Teva. PD Dr. med. Marion van Mackelenbergh erhielt Honorar von Amgen, AstraZeneca, Daiichi Sankyo, GenomicHealth, Gilead, GSK, Lilly, Molecular Health, MSD, Mylan, Novartis, Pfizer, PierreFabre, Roche, Seagen sowie Reisekostenunterstützung von Daiichi Sankyo, Gilead, Lilly. Prof. Dr. med. Julia Radosa erhielt Honorar von Pfizer, Eisai, MSD, Medac GmbH, Roche, Novartis, Gedeon Richter, Lilly, Pierre Fabre, Daiichi Sankyo, Seagen, Theramex. Prof. Toralf Reimer erhielt Honorar von AstraZeneca, Daiichi Sankyo, Eli Lilly, Gilead, Myriad, Novartis, Pfizer und Roche. Dr. med. Manfred Welslau erhielt Honorar von Amgen, Astellas, AstraZeneca, Celgene, Gilead, Hexal, Janssen, Lilly, Novartis, Roche, Sanofi und hat Beratungs- bzw. Gutachtertätigkeit bei Amgen, Bristol-Myers Squibb, Celgene, Gilead, Hexal, Janssen, Lilly, Medac, Novartis, Roche, Sanofi, AstraZeneca. PD Dr. med. Rachel Würstlein erhielt Honorar von Agendia, Amgen, Aristo, AstraZeneca, Celgene, Clovis Oncology, Daiichi Sankyo, Eisai, Exact Sciences, Gilead, GlaxoSmithKline, Hexal, Lilly, Medstrom Medical, MSD, Mundipharma, Mylan, Nanostring, Novartis, Odonate, Paxman, Palleos, Pfizer, Pierre Fabre, PINK, PumaBiotechnology, Riemser, Roche, Sandoz/Hexal, Sanofi Genzyme, Seattle Genetics/Seagen, Stemline, Tesaro Bio, Teva, Veracyte, Viatris, FOMF, Aurikamed, Clinsol, Pomme Med, medconcept, MCI. Prof. D. med. Nadia Harbeck erhielt Honorar von Amgen, AstraZeneca, Daiichi Sankyo, Gilead, Lilly, MSD, Novartis, Pierre Fabre, Pfizer, Roche, Sandoz, Sanofi, Seagen, Viatris, Zuelligpharma. Prof. Dr. med. Jens Huober erhielt Forschungsunterstützung von Celgene, Novartis, Hexal, Lilly. Honorar für Vortragstätigkeiten von Lilly, Novartis, Roche, Pfizer, AstraZeneca, MSD, Celgene, Eisai, Abbvie, Seagen, Gilead, Daiichi Sankyo. Honorar für Beratertätigkeit von Lilly, Novartis, Roche, Pfizer, Hexal, AstraZeneca, MSD, Celgene, Abbvie, Daiichi, Gilead. Reisekostenunterstützung von Roche, Pfizer, Novartis, Celgene, Daiichi Sankyo, Gilead., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution-NonDerivative-NonCommercial License, permitting copying and reproduction so long as the original work is given appropriate credit. Contents may not be used for commecial purposes, or adapted, remixed, transformed or built upon. ( https://creativecommons.org/licenses/by-nc-nd/4.0/ ).)

The PALB2 gene, has been accepted as a moderate-penetrance gene associated with breast cancer susceptibility and this gene product is involved in the DNA damage repair pathway via co-localization with BRCA2. Germline PALB2 mutations are associated with an increased breast cancer risk. However, the prevalence of the diverse types of PALB2 variants depend on the population. Thus, the aim of the present study was to determine, for the first time, the prevalence of PALB2 variants in a Turkish population of BRCA1/BRCA2-negative early-onset patients with breast cancer. In total, 223 Turkish patients with BRCA1/BRCA2 negative early-onset breast cancer and 60 unaffected women were included in the study. All the coding exons and intron/exon boundaries of PALB2 were subjected to mutational analysis by heteroduplex analysis (HDA)and DNA sequencing. Eighteen PALB2 variants were found in breast cancer patients within the Turkish population. Three variants (c.271G>A, c.404C>A and c.2981T>A) have not been previously reported. In addition, nine intronic variants were described, and this study is the first to describe the c.1685-44T>A intronic variant. The prevalence of possible pathogenic PALB2 variants was found to be 4.03 % in BRCA1/2-negative Turkish patients with early-onset breast cancer. Different variants of PALB2 have been reported in the literature, and the prevalence of these variants could different for each population. This is the first study to investigate the prevalence of PALB2 variants in Turkish patients with early-onset breast cancer. [ABSTRACT FROM AUTHOR]

Background: Variant ATM heterozygotes have an increased risk of developing cancer, cardiovascular diseases, and diabetes. Costs and time of sequencing and ATM variant complexity make large-scale, general population screenings not cost-effective yet. Recently, we developed a straightforward, rapid, and inexpensive test based on p53 mitotic centrosomal localization (p53-MCL) in peripheral blood mononuclear cells (PBMCs) that diagnoses mutant ATM zygosity and recognizes tumor-associated ATM polymorphisms. Methods: Fresh PBMCs from 496 cancer patients were analyzed by p53-MCL: 90 cases with familial BRCA1/2- positive and -negative breast and/or ovarian cancer, 337 with sporadic cancers (ovarian, lung, colon, and post-menopausal breast cancers), and 69 with breast/thyroid cancer. Variants were confirmed by ATM sequencing. Results: A total of seven individuals with ATM variants were identified, 5/65 (7.7 %) in breast cancer cases of familial breast and/or ovarian cancer and 2/69 (2.9 %) in breast/thyroid cancer. No variant ATM carriers were found among the other cancer cases. Excluding a single case in which both BRCA1 and ATM were mutated, no p53-MCL alterations were observed in BRCA1/2-positive cases. Conclusions: These data validate p53-MCL as reliable and specific test for germline ATM variants, confirm ATM as breast cancer susceptibility gene, and highlight a possible association with breast/thyroid cancers. [ABSTRACT FROM AUTHOR]

Recent cancer studies have suggested that the faciogenital dysplasia 1 (FGD1) gene may play a role in the development of tumor cells. Somatic alterations in the FGD1 gene and increased Fgd1 protein expression have been observed in many breast tumor cases. The present study sequenced the FGD1 gene in tumor DNA from 46 breast cancer patients using Ion Torrent sequencing. Three synonymous polymorphisms and one missense polymorphism were detected with next-generation sequencing; however, no somatic mutations were observed. The Thr697 variant was identified in 18 patients with an average age at diagnosis of 55 years, which was a lower average age than patients without the polymorphism. In addition, a higher frequency of Thr697 was observed in African-American patients. The Pro712 was observed in 15 breast cancer patients with an average age of 58 years, and was observed as a haplotype with the Thr697 variant in 28% of the breast cancer patients studied. The missense polymorphism (Ala226Thr) was identified in a 40-year-old female patient who had a recurrence of cancer. These polymorphisms (Ala226Thr, Thr697 and Pro712) may be associated with an earlier onset of breast cancer. [ABSTRACT FROM AUTHOR]

All women in the South Sweden Health Care Region with breast cancer diagnosed aged less than 41 during the period between 1990 and 1995 were contacted in 1996 and offered germline mutation analysis of the BRCA1 and BRCA2 genes. Mutation carriers ( n = 20) were compared with noncarriers ( n = 201) for overall survival (OS) and risk of contralateral breast cancer (CBC). Mutation carriers were younger at diagnosis and more likely to have ER-negative, PgR-negative and grade III tumors. Median follow-up was 19 years. The 5-, 10-, 15-, and 20-year OS were 60, 45, 39, and 39 % for mutation carriers and 82, 70, 59, and 53 % for noncarriers, respectively (5-year log-rank P = 0.013; 10-year P = 0.008; 15-year P = 0.020; and 20-year P = 0.046). In univariable analysis, there was a trend for an inferior OS for mutation carriers (HR 1.8; 95 % CI 1.0-3.3). When stratified for use of (neo)adjuvant chemotherapy, an inferior OS was significant only for the subgroup of patients who did not receive chemotherapy (HR 3.0; 95 % CI 1.2-7.7). In multivarible analysis, BRCA1/2 mutation status was a significant predictor of OS when adjusting for tumor stage, age, and use of chemotherapy, but not when ER status was also included in the model. The 15-year cumulative risk of CBC was 53 % for mutation carriers and 10 % for noncarriers (HR 5.9; 95 % CI 1.9-18.6); among the noncarriers the risks were 5, 22, and 30 % for patients without close relatives having breast cancer, with second-degree relatives having breast cancer, and with firstdegree relatives with breast cancer, respectively. In conclusion, the poor prognosis of young BRCA1/2 mutation carriers with breast cancer is mainly explained by the prevalent occurrence of negative prognostic factors rather than mutation status per se, and can to at least some extent be abrogated by the use of chemotherapy. [ABSTRACT FROM AUTHOR]