Premenopausal Breast Cancer Research Articles

Abstract B012: Pedigree and multi-omics analyses implicate nucleotide excision repair genes, XPA, ERCC6, and ERCC8, in susceptibility to breast cancer

Abstract Background: The majority of low- and moderate-risk [odds ratios (OR) ≤ 3] susceptibility genes for peri- and post-menopausal breast cancer (≥50 years of age), particularly those with minor allele frequency (MAF) of <30%, have not yet been identified and/or validated. We used a hypothesis-driven integrative approach to identify breast cancer susceptibility genes by analyzing pedigree and multi-omics (genomics, transcriptomics, mutation landscape) data. Methods: We conducted pedigree analysis in 31 families with DNA repair disorders, xeroderma pigmentosum (XP), trichothiodystrophy (TTD), Cockayne syndrome (CS), XP/TTD and XP/CS. These disorders can be caused by mutations in genes involved in the nucleotide excision repair (NER) pathway such as XPA-XPG, ERCC6 and ERCC8. We estimated the frequency of hereditary breast cancer, defined as the presence of at least two cases of premenopausal breast cancer (diagnosed <50 years of age) or one case of premenopausal breast cancer and one case of ovarian cancer in one side of the family, in our study. Furthermore, we conducted individual analysis of four genome-wide association studies (GWAS) datasets (totaling 2961 cases and 4335 controls), individual and meta-analysis of two gene expression microarray datasets (98 cases and 163 controls), and targeted analysis of The Cancer Genome Atlas (TCGA) (522 breast cancers). All analyses involved invasive ductal breast carcinoma in women diagnosed at ≥50 years of age. Results: In an XP family with causative mutations in XPA, there were four cases of premenopausal breast cancer (including heterozygote mutation carriers), one case of ovarian cancer, and one case of prostate cancer. Comprehensive sequencing failed to identify a BRCA1 or BRCA2 mutation in this family. Overall, 7 of 31 (22.6%) families with DNA repair disorders had a family history that was compatible with hereditary breast cancer. Hence, we selected a panel of NER genes as candidates for association studies with breast cancer. Our candidate-gene association analysis of GWAS datasets suggested an increased risk of breast cancer with ERCC6 (main effect:1.29 ≤ OR ≤ 2.91, 0.005 ≤ p ≤ 0.04, 11.8 ≤ MAF ≤ 29.7%) and implicated its interaction with ERCC8 (joint effect:3.03 ≤ OR ≤ 5.31, 0.01 ≤ pinteraction ≤ 0.03). Our transcriptomics analysis identified significant upregulation of ERCC6 (p=7.95 × 10–6) and ERCC8 (p=4.67 × 10–6) in breast cancer. Our analysis of TCGA breast tumor data showed similar mutation frequency of ERCC6 (1.8%) and ERCC8 (0.3%) as known breast cancer susceptibility genes such as BLM (1.9%) and LSP1 (0.3%). Conclusion: Our integrative analyses suggest that ERCC6 may be a previously unreported low- to moderate-risk breast cancer susceptibility gene, which may also interact with ERCC8. ERCC6 and ERCC8 code for the main components of the transcription-coupled (TC) repair sub-pathway of the NER. TC-NER protects against genotoxic agents, such as free radicals and reactive oxygen species. Our results provide a deeper biologic insight and leads for prevention of common breast cancer. Citation Format: Roxana Moslehi, Amiran Dzutsev. Pedigree and multi-omics analyses implicate nucleotide excision repair genes, XPA, ERCC6, and ERCC8, in susceptibility to breast cancer [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: DNA Damage Repair: From Basic Science to Future Clinical Application; 2024 Jan 9-11; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2024;84(1 Suppl):Abstract nr B012.

Identification of genes and pathways associated with menopausal status in breast cancer patients using two algorithms

BackgroundMenopausal status has a known relationship with the levels of estrogen, progesterone, and other sex hormones, potentially influencing the activity of ER, PR, and many other signaling pathways involved in the initiation and progression of breast cancer. However, the differences between premenopausal and postmenopausal breast cancer patients at the molecular level are unclear.MethodsWe retrieved eight datasets from the Gene Expression Omnibus (GEO) database. Differentially expressed genes (DEGs) associated with menopausal status in breast cancer patients were identified using the MAMA and LIMMA methods. Based on these validated DEGs, we performed Gene Ontology (GO) functional enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Protein–protein interaction (PPI) networks were constructed. We used DrugBank data to investigate which of these validated DEGs are targetable. Survival analysis was performed to explore the influence of these genes on breast cancer patient prognosis.ResultsWe identified 762 DEGs associated with menopausal status in breast cancer patients. PPI network analysis indicated that these genes are primarily involved in pathways such as the cell cycle, oocyte meiosis and progesterone-mediated oocyte maturation pathways. Notably, several genes played roles in multiple signaling pathways and were associated with patient survival. These genes were also observed to be targetable according to the DrugBank database.ConclusionWe identified DEGs associated with menopausal status in breast cancer patients. The association of these genes with several key pathways may promote understanding of the complex characterizations of breast cancer. Our findings offer valuable insights for developing new therapeutic strategies tailored to the menopausal status of breast cancer patients.

Health-related quality of life of premenopausal young breast cancer survivors undergoing endocrine therapy

PurposeThe incidence of breast cancer in premenopausal women in South Korea is higher compared to the West. This study aimed to identify factors associated with the health-related quality of life (HRQoL) among survivors with premenopausal young breast cancer undergoing endocrine therapy by examining the effects of menopausal symptoms, social support, and resilience on HRQoL. MethodsCross-sectional study was used to select survivors with breast cancer undergoing endocrine therapy. The study instruments used included a basic information questionnaire, Menopause Rating Scale, Multidimensional Scale of Perceived Social Support, Connor–Davidson Resilience Scale, and Health-Related Quality of Life Instrument with 8 items. Researchers utilized independent t-tests, one-way analysis of variance, Pearson's correlation coefficients, and multiple linear regression to analyze the data. The data were collected from August to September 2021, and the questionnaire was administered via a link posted on a bulletin board of an online breast cancer survivors community. Finally, 133 questionnaires were included in the final analysis. ResultsAmong 150 participants, 133 completed the questionnaires. HRQoL was higher in the groups with a monthly income of ≥5 million KRW (β = 0.231, p = .011), fewer menopausal symptoms (β = −0.399, p < .001), and higher social support (β = 0.170, p = .038), and lower in the group receiving endocrine therapy and OFS (β = −0.192, p = .010). The explanatory power for HRQoL of premenopausal young breast cancer survivors undergoing endocrine therapy was 38.3% (F = 10.634, p < .001). ConclusionBreast cancer survivors should be supported to participate in economic activity, utilize rehabilitation and intervention programs to alleviate menopausal symptoms, and benefit from a social support network formed by the hospital, community, and government.

International Pooled Analysis of Leisure-Time Physical Activity and Premenopausal Breast Cancer in Women From 19 Cohorts.

There is strong evidence that leisure-time physical activity is protective against postmenopausal breast cancer risk but the association with premenopausal breast cancer is less clear. The purpose of this study was to examine the association of physical activity with the risk of developing premenopausal breast cancer. We pooled individual-level data on self-reported leisure-time physical activity across 19 cohort studies comprising 547,601 premenopausal women, with 10,231 incident cases of breast cancer. Multivariable Cox regression was used to estimate hazard ratios (HRs) and 95% CIs for associations of leisure-time physical activity with breast cancer incidence. HRs for high versus low levels of activity were based on a comparison of risk at the 90th versus 10th percentiles of activity. We assessed the linearity of the relationship and examined subtype-specific associations and effect modification across strata of breast cancer risk factors, including adiposity. Over a median 11.5 years of follow-up (IQR, 8.0-16.1 years), high versus low levels of leisure-time physical activity were associated with a 6% (HR, 0.94 [95% CI, 0.89 to 0.99]) and a 10% (HR, 0.90 [95% CI, 0.85 to 0.95]) reduction in breast cancer risk, before and after adjustment for BMI, respectively. Tests of nonlinearity suggested an approximately linear relationship (Pnonlinearity = .94). The inverse association was particularly strong for human epidermal growth factor receptor 2-enriched breast cancer (HR, 0.57 [95% CI, 0.39 to 0.84]; Phet = .07). Associations did not vary significantly across strata of breast cancer risk factors, including subgroups of adiposity. This large, pooled analysis of cohort studies adds to evidence that engagement in higher levels of leisure-time physical activity may lead to reduced premenopausal breast cancer risk.

Abstract LB_B07: Probability of negative impact on adherence caused by the most frequent side effects of adjuvant endocrine therapy for premenopausal breast cancer in SOFT and TEXT Trials

Abstract Background: Regardless of adjuvant chemotherapy, the addition of ovarian function suppression (OFS) to adjuvant endocrine therapy tamoxifen or exemestane in pre-menopausal women with estrogen receptor (ER)-positive breast cancer cause adverse events may affect adherence. Among the 22 targeted adverse events systematically reported in SOFT and TEXT trials, adverse events commonly experienced in exemestane–OFS group (32.3%) and tamoxifen–OFS group (31.0%), compared with tamoxifen alone group (24.6%). Side effects associated with endocrine therapy cause negative impact on adherence. Early discontinuation of endocrine therapy in 22.5%, 19.3%, and 23.7% of the tamoxifen, tamoxifen–OFS, and exemestane–OFS groups, respectively, in SOFT and TEXT trials. This report is intended to evaluate the possible contribution of the 8 most frequently studied side effects that have negative impact on adherence to hormone therapy in breast cancer. Methods: Calculating the probability of negative impact of most frequent endocrine therapy`s side effects (per SOFT-TEXT trials) on adherence per Leanne Fleming et al quantitative systematic review “The impact of medication side effects on adherence and persistence to hormone therapy in breast cancer survivors” Results: Musculoskeletal/joint pain had the most negative impact on the adherence in tamoxifen, tamoxifen–OFS, and exemestane–OFS groups (56%, 63% and 73%, respectively). Average of negative impact of tamoxifen, tamoxifen–OFS, and exemestane–OFS on adherence is 22%, 25% and 27%) Conclusions: The probability of adherence of using tamoxifen alone seems better than tamoxifen–OFS and exemestane–OFS. Citation Format: Tariq Hassan AL Qurayshah. Probability of negative impact on adherence caused by the most frequent side effects of adjuvant endocrine therapy for premenopausal breast cancer in SOFT and TEXT Trials [abstract]. In: Proceedings of the AACR-NCI-EORTC Virtual International Conference on Molecular Targets and Cancer Therapeutics; 2023 Oct 11-15; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2023;22(12 Suppl):Abstract nr LB_B07.

Lifetime dairy product consumption and breast cancer risk: a prospective cohort study by tumor subtypes

BackgroundPrevious literature on dairy products and risk of breast cancer is inconsistent, and the relationship may depend on the life-period of dietary assessment. ObjectiveWe examined dairy consumption from adolescence through later adulthood and incidence of breast cancer by menopausal status and tumor molecular subtypes in the Nurses’ Health Study (NHS), a prospective cohort study. MethodsWe analyzed data from 63,847 females in the NHS collected from 1980 to 2018. Average intake of dairy products during adulthood was assessed by validated semiquantitative food frequency questionnaires throughout follow-up. Participants recalled adolescent dietary intake in 1986. Multivariable Cox proportional hazards models were used to estimate hazard ratios (HRs) relating dairy product consumption to breast cancer risk overall, by menopausal status, and by subtypes. ResultsWe documented 5733 incident cases of invasive breast cancer during 32 y of follow-up (n = 5298 postmenopausal). Lifetime, adolescent, adulthood, and postmenopausal total dairy and milk intakes were not associated with overall breast cancer risk (nonsignificant HRs comparing highest with lowest quintile range = 0.97–1.08), although there was a suggestive positive association between adolescent milk intake and breast cancer risk (HR: 1.09; 95% CI: 1.00, 1.18). Higher lifetime and premenopausal cheese intakes were associated with modestly lower risks of breast cancer (comparing highest with lowest quintile, HR for lifetime cheese intake: 0.90; 95% CI: 0.82, 0.98; HR for premenopausal cheese intake: 0.89; 95% CI: 0.79, 1.00). Results varied by tumor subtype and some evidence for heterogeneity was observed for an association between premenopausal milk intake and breast cancer (HR for estrogen receptor [ER]-positive: 0.84; 95% CI: 0.72, 0.99; ER-negative: 1.36; 95% CI: 1.00, 1.84; P heterogeneity = 0.04). ConclusionsThese findings suggest that overall dairy consumption was not associated with risk of breast cancer. However, heterogeneity was observed for type of dairy food, period of life, and tumor subtypes.

Smoking history and breast cancer risk by pathological subtype: MCC-Spain study.

The role of cigarette smoking on breast cancer risk remains controversial, due to its dual carcinogenic-antiestrogenic action. In the population-based multi-case-control study (MCC-Spain), we collected epidemiological and clinical information for 1733 breast cancer cases and 1903 controls, including smoking exposure. The association with breast cancer, overall, by pathological subtype and menopausal status, was assessed using logistic and multinomial regression models. Smokers had higher risk of premenopausal breast cancer, particularly if they had smoked ≥30 years (AOR=1.75; 95% CI: 1.04-2.94), although most estimates did not achieve statistical significance. In contrast, among postmenopausal women, smoking was associated with lower risk of breast cancer, mainly in overweight and obese women. The strongest risk reductions were observed among postmenopausal women who had stopped smoking ≥10 years before cancer diagnosis, particularly for HER2+ tumors (AOR=0.28; 95% CI: 0.11-0.68); p for heterogeneity = 0.040). Also, those who had smoked <10 pack-years (AOR=0.68; 95% CI: 0.47-0.98) or 10-25 pack-years (AOR=0.62; 95% CI: 0.42-0.92) during their lifetime were at a reduced risk of all breast cancer subtypes (p for heterogeneity: 0.405 and 0.475, respectively); however, women who had smoked more than 25 pack-years showed no reduced risk. Menopausal status plays a key role in the relationship between tobacco and breast cancer for all cancer subtypes. While smoking seems to increase the risk in premenopausal woman, it might be associated to lower risk of breast cancer among postmenopausal women with excess weight.

Mutational and expressional association of the PIK3CA gene with the risk of breast cancer in the Pakistani population.

PI3K pathway is a very important pathway that is reported to be involved in breast cancer. Mutation ofPI3Kand p110 alpha-catalytic subunit of phosphatidylinositol 3-kinase (PIK3CA) is of high predictive and prognostic values in breast cancer. The purpose of the current study was to screen the hotspot mutations of thePIK3CAgene i.e. rs2677760, rs3806685, rs121913273 & rs121913279 along with expressional analysis ofPI3KandPIK3CAgenes in breast cancer female patients. For mutational analysis, TaqMan assay & Sanger sequencing were performed while for expressional analysis real-time PCR was carried out. Mutant allele C of rs2677760 was observed to be high in postmenopausal patients. The frequency of mutant allele G of rs3806685 was significantly high in breast cancer patients. All diseased and control samples were of wild type for the hotspot rs121913273 and rs121913279 with allele G for rs121913273 and A for rs121913279. Expression of the PI3K was high in breast cancer tissue samples as compared to the adjacent controls. While the expression ofthe thePIK3CAgene was significantly high in premenopausal breast cancer patients. It was concluded that the mutant allele C of rs2677760 might have some sort of association with the menopausal status and it could be used as a diagnostic marker in post-menopausal women if studied further. Mutant allele G of rs3806685 was also found to be associated with breast cancer. While multiallelic rs121913273 and rs121913279 showed a different trend for the studied population. For expressional analysis, PI3Kshowed over-expression in the cases while PIK3CAgene expression was observed to be significantly associated with pre-menopausal status.

Clinical guidelines for managing menopausal symptoms in women with (a history of) breast cancer.

One in eight women will be diagnosed with breast cancer. At the time of diagnosis, 75% of patients are postmenopausal. Many will receive anti-hormone therapy, which often induces menopausal symptoms. Premenopausal breast cancer patients frequently become postmenopausal as a result of the treatment and often experience menopausal symptoms. The increased incidence of breast cancer, combined with longer survival, has led to an increase in the number of women experiencing menopausal symptoms. Therefore, the management of menopausal symptoms in women with a history or current breast cancer is a relevant and common clinical problem. To provide a clinically useful overview of the steps in the management of menopausal symptoms in women with (a history of) breast cancer. A comprehensive literature review was conducted by authors JS and WT using the PubMed and Medline databases. Abstracts were critically appraised and, where appropriate, the full text was analysed. Not applicable. Depending on the condition, either meta-analyses, randomised controlled trials or retrospective cohorts were identified. No evidence was found for some proposed treatments. Menopausal symptoms in women with (a history of) breast cancer require a patient-tailored approach. Shared decision making is paramount and adequate up-to-date knowledge can help the breast cancer specialist to advise and guide patients accordingly. A comprehensive, clinically-based overview of evidence-based treatment options for menopausal symptoms in women with (a history of) breast cancer.

Prediagnostic selenium status, selenoprotein gene variants and association with breast cancer risk in a European cohort study

Selenium (Se) may help prevent breast cancer (BC) development. Owing to limited observational evidence, we investigated whether prediagnostic Se status and/or variants in the selenoprotein genes are associated with BC risk in a large European cohort. Se status was assessed by plasma measures of Se and its major circulating proteins, selenoprotein P (SELENOP) and glutathione peroxidase 3 (GPX3), in matched BC case-control pairs (2208 for SELENOP; 1785 for GPX3 and Se) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Single nucleotide polymorphisms (SNPs, n = 452) in 55 selenoprotein and Se metabolic pathway genes and an additional 18 variants previously associated with Se concentrations were extracted from existing genotyping data within EPIC for 1564 case-control pairs. Multivariable-adjusted logistic regression models were used to calculate the odds ratios (ORs) and 95 % confidence intervals (CIs) of the association between Se status markers, SNP variants and BC risk. Overall, there was no statistically significant association of Se status with BC risk. However, higher GPX3 activity was associated with lower risk of premenopausal BC (4th versus 1st quartile, OR = 0.54, 95 % CI: 0.30–0.98, Ptrend = 0.013). While none of the genetic variant associations (P ≤ 0.05) retained significance after multiple testing correction, rs1004243 in the SELENOM selenoprotein gene and two SNPs in the related antioxidant TXN2 gene (rs4821494 and rs5750261) were associated with respective lower and higher risks of BC at a significance threshold of P ≤ 0.01. Fourteen SNPs in twelve Se pathway genes (P ≤ 0.01) in interaction with Se status were also associated with BC risk. Higher Se status does not appear to be associated with BC risk, although activity of the selenoenzyme GPX3 may be inversely associated with premenopausal BC risk, and SNPs in the Se pathway alone or in combination with suboptimal Se status may influence BC risk.

Association of physical weight statuses defined by body mass index (BMI) with molecular subtypes of premenopausal breast cancer: a systematic review and meta-analysis.

The association between overweight/obesity and postmenopausal breast cancer has been proven. However, uncertainty exists regarding the association between physical weight statuses and premenopausal breast cancer subtypes. This study aimed to explore the association of body weight statuses with molecular subtypes of premenopausal breast cancer. A systematic search of Medline, PubMed, Embase, and Web of Science was performed. The Newcastle-Ottawa Scale (NOS) and the Joanna Briggs Institute (JBI) Critical Appraisal tools were used to evaluate the quality of the literature. STATA and R software were used to analyze the extracted data. The meta-analysis included 35 observational studies with a total of 41,049 premenopausal breast cancer patients. The study showed that the proportion of underweight patients was 4.8% (95% CI = 3.9-5.8%, P = 0.01), overweight was 29% (95%CI = 27.1-30.9%, P < 0.01), obesity was 17.8% (95% CI = 14.9-21.2%, P < 0.0001), and normal weight was 51.6% (95% CI = 46.7-56.5%, P < 0.0001). The pooled results showed that in comparison to the normal weight group, being physically underweight is related to a 1.44-fold risk (OR = 1.44, 95%CI = 1.28-1.63, P < 0.0001) of HER2 + breast cancer. Overweight is related to a 1.16-fold risk (OR = 1.16, 95%CI = 1.06-1.26, P = 0.002) of TNBC and a 16% lower risk (OR = 0.84, 95%CI = 0.75-0.93, P = 0.001) of ER + breast cancer. When compared to underweight/normal weight populations, both overweight (OR = 0.74, 95%CI = 0.56-0.97, P = 0.032) and obesity (OR = 0.70, 95%CI = 0.50-0.98, P = 0.037) can reduce the risk of ER + PR + breast cancer. In the premenopausal breast cancer population, the distribution of patients' numbers with different weight statuses was significantly distinct among the various breast cancer subtypes. Additionally, the associations between physical weight statuses and the risk of premenopausal breast cancer subtypes are divergent.

Use of the Gene Expression Test Prosigna® in Premenopausal Patients with HR+, HER2− Early Breast Cancer: Correlation of the Results with the Proliferation Marker Ki-67

Introduction: In hormone receptor-positive (ER+/PR+) and human epidermal growth factor receptor 2-negative (HER2−) early-stage breast cancer (EBC), gene expression tests such as the Prosigna are increasingly used since classic clinicopathological parameters and the proliferation factor Ki-67 often do not allow a definite therapy decision regarding an adjuvant chemotherapy. While the Prosigna test has been validated for postmenopausal patients, few data are available regarding its use in premenopausal patients. The present study compared the Prosigna test with the Ki-67 index in premenopausal patients. Materials and Methods: Premenopausal patients with HR+ HER2−, pN0-1, G1-2 EBC were retrospectively enrolled (n = 55). The Prosigna assay was performed in formalin-fixed paraffin-embedded tumor samples of surgical resection specimens. Ki-67 was reassessed in original diagnostic core needle biopsy specimens and defined as low, intermediate, or high with the threshold of <10%, 10–24%, ≥25%. Results: According to Ki-67, patients were in the low (LR)-, intermediate (IR)-, and high-risk (HR) groups in 40%, 36%, and 24% of the cases. The Prosigna gene signature assay assessed the risk of recurrence as LR for 45% of the patients, IR for 35%, and HR for 20%. The most frequent intrinsic subtypes were luminal A in 73% and luminal B in 24% of the patients. A moderate correlation was found between Prosigna and Ki-67 scores with a Pearson correlation coefficient of 0.51. In the overall cohort, 47% of the Ki-67-based therapy decision would correspond to those based on the Prosigna score. After exclusion of IR patients, matching of low/low or high/high results was observed in 57% of the cases. Conclusion: According to the present study, there is only limited concordance regarding the risk group stratification between Ki-67 and Prosigna-based risk assessment. The relevance and frequency of premenopausal breast cancer emphasizes the need for further evaluation of gene expression analyses in this setting and the correlation with classic clinicopathological parameters regarding therapy decision-making.

Exosomes isolated from metabolically unhealthy normal weight and overweight phenotypes deteriorate the ER/PR positive breast cancer behavior.

Obesity has been linked to a higher risk of postmenopausal breast cancer Yet, research indicates an opposite correlation between obesity and premenopausal breast cancer risk. Various obesity phenotypes based on metabolic health could play a significant part. This study aims to assess how plasma exosomes taken from women with varying obesity phenotypes impact MCF-7 cell migration, matrix metalloproteinase-2 activity, and apoptosis. The characterization of isolated exosomes and their internalization into MCF-7 cells was evaluated. The treatment of MCF-7 cells with exosomes isolated from different groups was done. Migration, the activity of MMP-2, mRNA expression of Bax and Bcl-2, protein expression of p-53 and Thr55 p-p53, and apoptosis were assessed. Isolated exosomes from unhealthy obese individuals increase MCF-7 cell migration. Regarding MMP activities, unhealthy normal weight and overweight and healthy obese groups isolated exosomes increase the MMP-2 activity than the treated group with exosomes isolated from counterpart groups. Furthermore, unhealthy normal weight and overweight and healthy obese obtained exosomes decrease apoptosis compared to counterpart groups. Altogether, plasma exosomes derived from both unhealthy individuals with normal weight and overweight status, as well as those with unhealthy obesity, negatively impacted the behavior of estrogen/progesterone receptor-positive breast cancer cells. The online version contains supplementary material available at 10.1007/s40200-023-01295-1.

Tamoxifen-predictive value of gene expression signatures in premenopausal breast cancer: data from the randomized SBII:2 trial

BackgroundGene expression (GEX) signatures in breast cancer provide prognostic information, but little is known about their predictive value for tamoxifen treatment. We examined the tamoxifen-predictive value and prognostic effects of different GEX signatures in premenopausal women with early breast cancer.MethodsRNA from formalin-fixed paraffin-embedded tumor tissue from premenopausal women randomized between two years of tamoxifen treatment and no systemic treatment was extracted and successfully subjected to GEX profiling (n = 437, NanoString Breast Cancer 360™ panel). The median follow-up periods for a recurrence-free interval (RFi) and overall survival (OS) were 28 and 33 years, respectively. Associations between GEX signatures and tamoxifen effect were assessed in patients with estrogen receptor-positive/human epidermal growth factor receptor 2-negative (ER+ /HER2−) tumors using Kaplan–Meier estimates and Cox regression. The prognostic effects of GEX signatures were studied in the entire cohort. False discovery rate adjustments (q-values) were applied to account for multiple hypothesis testing.ResultsIn patients with ER+/HER2− tumors, FOXA1 expression below the median was associated with an improved effect of tamoxifen after 10 years with regard to RFi (hazard ratio [HR]FOXA1(high) = 1.04, 95% CI = 0.61–1.76, HRFOXA1(low) = 0.30, 95% CI = 0.14–0.67, qinteraction = 0.0013), and a resembling trend was observed for AR (HRAR(high) = 1.15, 95% CI = 0.60–2.20, HRAR(low) = 0.42, 95% CI = 0.24–0.75, qinteraction = 0.87). Similar patterns were observed for OS. Tamoxifen was in the same subgroup most beneficial for RFi in patients with low ESR1 expression (HRRFi ESR1(high) = 0.76, 95% CI = 0.43–1.35, HRRFi, ESR1(low) = 0.56, 95% CI = 0.29–1.06, qinteraction = 0.37). Irrespective of molecular subtype, higher levels of ESR1, Mast cells, and PGR on a continuous scale were correlated with improved 10 years RFi (HRESR1 = 0.80, 95% CI = 0.69–0.92, q = 0.005; HRMast cells = 0.74, 95% CI = 0.65–0.85, q < 0.0001; and HRPGR = 0.78, 95% CI = 0.68–0.89, q = 0.002). For BC proliferation and Hypoxia, higher scores associated with worse outcomes (HRBCproliferation = 1.54, 95% CI = 1.33–1.79, q < 0.0001; HRHypoxia = 1.38, 95% CI = 1.20–1.58, q < 0.0001). The results were similar for OS.ConclusionsExpression of FOXA1 is a promising predictive biomarker for tamoxifen effect in ER+/HER2− premenopausal breast cancer. In addition, each of the signatures BC proliferation, Hypoxia, Mast cells, and the GEX of AR, ESR1, and PGR had prognostic value, also after adjusting for established prognostic factors.Trial registration This trial was retrospectively registered in the ISRCTN database the 6th of December 2019, trial ID: https://clinicaltrials.gov/ct2/show/ISRCTN12474687.

Association between vaginal bleeding in pregnancy that resulted in delivery and risk of cancer: A Danish registry-based cohort study.

Vaginal bleeding (VB) before 20 gestational weeks of a viable pregnancy is a manifestation of a threatened miscarriage. VB is associated with increased levels of pro-inflammatory cytokines such as interferon-gamma, tumour necrosis factor-alpha and interleukin-6. Increased levels of these cytokines and oxidative stress are risk factors for cancer. The risk of cancer following a VB-affected pregnancy that ended in childbirth is unknown. To investigate the associations between VB in pregnancy that resulted in delivery and risk of incident cancer. We conducted a cohort study (1995-2018) in Denmark using administrative and healthcare registries. We included 37,082 VB-affected deliveries, 1,363,614 VB-unaffected deliveries, 324,328 pregnancies ending in terminations, and 137,104 miscarriages. We computed the absolute risk of cancer and hazard ratios (HR) with 95% confidence intervals (CI) adjusted for age, calendar year, morbidities, and socio-economic factors using Cox proportional hazards regression. Multiple pregnancies to the same woman were accounted for in the analysis. The median (25th-75th percentile) follow-up in the study was 12.6 (6.9, 18.2) years. The prevalence of VB in the present study was 3%. At the end of the follow-up, there were 1320 cancer cases among the VB-affected delivery cohort, 40,420 among the VB-unaffected delivery cohort, 10,300 among the termination cohort and 4790 among the miscarriage cohort. HRs for any cancer among VB-affected deliveries were 1.03 (95% CI 0.97, 1.08) compared with VB-unaffected deliveries, 1.03 (95% CI 0.97, 1.09) compared with terminations and 0.90 (95% CI 0.84, 0.95) compared with miscarriages. There were no increased risks of premenopausal breast cancer, cervical cancer, ovary and fallopian tube cancer or uterine cancer following VB-affected deliveries vs. comparison cohorts. We found no evidence of an association between vaginal bleeding in pregnancy and an increased risk of cancer.

Dose response relationship between breast cancer and somatotypes during childhood: a systematic review and meta-analysis.

This study aims to evaluate the relationship between breast cancer and somatotypes during early life by meta-analysis and give the corresponding advice. Observational studies till April 5, 2021, which explore women with/without breast cancer who used the Stunkard Figure Rating Scale/Sørensen Somatotypes to evaluate their somatotype before 18 years of age and distant breast cancer risk were included. Using random/fixed-effect models, the pooled relative risks (RRs) and 95% confidence intervals (CIs) were estimated. Then a nonlinear dose-response meta-analysis was conducted using restricted cubic spline analysis. Six articles involving 15,211 breast cancer patients from 341,905 individuals were included for performing a meta-analysis of early somatotype and breast cancer risk. The pooled results showed that the protection became stronger with the increase of somatotype until it reached 6. The restricted cubic spline model indicated a linear relationship between somatotypes and breast cancer (P-nonlinearity = 0.533). Subgroup analysis of menopausal status showed that increasing somatotype during childhood was increasingly protective against postmenopausal breast cancer from somatotype 3 to somatotype 6, with a 0.887-fold (RR = 0.887, 95% CI: 0.842, 0.934) to 0.759-fold (RR = 0.759, 95% CI: 0.631, 0.913) decreased risk of breast cancer (P-nonlinearity = 0.880), but this association was not found in the population with premenopausal breast cancer (P-nonlinearity = 0.757). When stratified by age, among people younger than 10 years of age, an increase in somatotype was associated with a statistically significant reduction in breast cancer risk. From somatotype 3 to somatotype 6, the risk of breast cancer was reduced by 9.7-27.7% (P-nonlinearity = 0.175). With early-life adiposity, our data support an inverse association with breast cancer risk, especially age less than 10 years and in postmenopausal women. Since girls with overweight likely remain overweight or even develop obesity in adulthood. While adults with overweight and obese are at increased risk of breast cancer and other types of cancer and various chronic diseases. Hence, we recommend that children should maintain a normal or slightly fat somatotype throughout all periods of life.

Single nucleotide polymorphisms associated with female breast cancer susceptibility in Chinese population

Breast cancer is a complex disease influenced by both external and internal factors, among which genetic factors play a critical role. Single-nucleotide polymorphisms (SNPs) are major contributors to the heritability of breast cancer, and their frequencies vary across ethnic groups. In this study, we aimed to investigate the association between 34 SNPs identified in previous genome-wide association studies (GWAS) and overall breast cancer risk, as well as breast cancer subtypes, in the Chinese female population. To accomplish this, we conducted an extensive association analysis using the high-throughput Sequenom MassARRAY® platform in a case-control study comprising 1848 breast cancer patients and 709 healthy controls. Our analysis, which utilized the SNPassoc package in R based on chi-squared (χ2) test and genetic model analysis, identified significant associations between breast cancer risk and SNP rs12493607 (TGFBR2, risk allele C, OR = 1.28 [1.11–1.47], P = 0.0005), as well as a less conservatively significant association with rs4784227 (CASC16, risk allele T, OR = 1.24 [1.08–1.42], P = 0.0017) and rs2046210 (ESR1, risk allele A, OR = 1.50 [1.16–1.95], P = 0.0016). Furthermore, our stratified analyses revealed that rs12493607 was significantly associated with invasive carcinoma, estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, HER2-negative, and young (aged younger than 45) breast cancer. SNP rs4784227 and rs3803662 (CASC16) were associated with invasive carcinoma and ER-positive breast cancer, while rs2046210 was linked to ductal carcinoma in situ, ER-negative, PR-negative, HER2-positive, and elder (aged more than 45) breast cancers. SNPs rs10484919 (ESR1) and rs1038304 (CCDC170) showed links to HER2-positive breast cancer, and rs616488 (PEX14) with premenopausal breast cancer. In summary, our study shed light on the relationship between SNPs and breast cancer susceptibility within a vast Chinese cohort, supporting the development of polygenetic risk scores for the Chinese population. These findings provide valuable insights into the genetic basis of breast cancer and have important implications for risk prediction, early detection, and personalized treatment of this disease.

Differential distribution of actual and surrogate oncotype DX recurrence scores in breast cancer patients by age, menopausal status, race, and body mass index.

The Oncotype DX Recurrence Score (RS) is a widely used prognostic tool for estrogen receptor-positive breast cancer patients. Multiple surrogate models can predict RS with good accuracy. In this study we aimed to determine whether the RS and two surrogate indices were differentially distributed by age, menopausal status, race, and body mass index (BMI). 516 breast cancer cases treated at a single institution were analyzed. Epidemiologic data, RS, tumor size, grade, and biomarker data were abstracted. Breast Cancer Prognostic Score (BCPS) and modified Magee equation2 were used to calculate surrogate RS. Patients were stratified into different groups based on age, menopausal status, race, BMI, or a combination of strata. Mean and standard deviation were calculated for each group/subgroup. Age below median (< 63) was associated with higher RS, especially in obese and Black patients. RS was also higher in obese and Black patients in the premenopausal subgroup. Black patients had a higher RS compared to White women in the premenopausal and non-obese subgroups. BMI < 30 was associated with higher RS, especially in older, postmenopausal, and Black patients. Some of these observations were replicated by the two surrogate models. The surrogate recurrence scores were higher in the younger age group, in non-obese older/postmenopausal women, and in younger/premenopausal obese individuals. Higher RS was observed in younger and premenopausal breast cancer patients, especially among the Black and obese subgroups, and in non-obese patients, especially among Black and older/postmenopausal women, suggesting more aggressive disease in these subgroups. Some statistical differences could be replicated by both surrogate models, suggesting that they may have utility in breast cancer epidemiology studies that do not have access to Oncotype DX RS or patient outcome data.

Adjuvant Endocrine Therapy in Premenopausal Women With Hormone Receptor-Positive Early-Stage Breast Cancer: Risk Stratification in a Real-World Setting

BackgroundOvarian function suppression (OFS) and hormone therapy (HT) represent an adjuvant option in premenopausal hormone receptor-positive early breast cancer (HR+EBC). The SOFT-TEXT trials showed improved outcomes upon receiving aromatase inhibitors (AIs)/OFS. MethodsIn order to estimate the magnitude of absolute improvements, we conducted a retrospective study applying composite risk (CR) to 237 premenopausal HR+EBC patients. ResultsOverall, 119 of these received tamoxifen (T)/OFS and 118 received AIs/OFS. The median age was 45 years (ys). After a median follow up of 65 months, recurrence was 6.7% in T patients and 10.2% in AI ones. CR (cutoff: 2.67) and ET duration (five-year cutoff) was found to have a significant impact on DFS. Invasive disease-free survival (IDFS) at 5 ys amounted to 82.9% for a CR>2.67 and 95% with CR</=2.67 (p 0.0046). Five-year IDFS was 98.3% in patients who had completed 5-year HT compared to 54.6% of those who had stopped before 5 years (P < .0001). Excluding patients who had discontinued therapy due to disease relapse, IDFS difference at 5 years remained statistically significant (p=0.03) between the two groups, with an iDFS rate of 86.5% at 5 years in the second group. Adverse events of different grades were reported in 116 and 112 patients in the T/OFS group and the AIs/OFS, respectively. Early discontinuation due to toxicity was 3.8%. Seven patients (19.4%) discontinued therapy due to pregnancy desire (6 in the T group, 1 in the AI one); of these, one patient relapsed. ConclusionIn a real-world setting, treatment options for premenopausal patients who are candidates for HT and OFS should take risk status into account. Therefore, every effort should be made to maintain patient adherence to treatment in order to manage toxicities and improve outcomes.

The roles of anti-Müllerian hormone in breast cancer.

Anti-Müllerian hormone (AMH) is produced and secreted by granulosa cells of growing follicles, and its main role is to inhibit the recruitment of primordial follicles, reduce the sensitivity of follicles to follicle-stimulating hormone (FSH), and regulate FSH-dependent preantral follicle growth. It has become an effective indicator of ovarian reserve in clinical practice. Research on AMH and its receptors in recent years has led to a better understanding of its role in breast cancer. AMH specifically binds to anti-Müllerian hormone receptor II (AMHRII) to activate downstream pathways and regulate gene transcription. Since AMHRII is expressed in breast cancer cells and triggers apoptosis, AMH/AMHRII may play an important role in the occurrence, treatment, and prognosis of breast cancer, which needs further research. The AMH level is a potent predictor of ovarian function after chemotherapy in premenopausal breast cancer patients older than 35 years, either for ovarian function injury or ovarian function recovery. Moreover, AMHRII has the potential to be a new marker for the molecular typing of breast cancer and a new target for breast cancer treatment, which may be a link in the downstream pathway after TP53 mutation.