Impact of the menstrual cycle on commercial prognostic gene signatures in oestrogen receptor-positive primary breast cancer.

PURPOSE: Changes occur in the expression of oestrogen-regulated and proliferation-associated genes in oestrogen receptor (ER)-positive breast tumours during the menstrual cycle. We investigated if Oncotype® DX recurrence score (RS), Prosigna® (ROR) and EndoPredict® (EP/EPclin) prognostic tests, which include some of these genes, vary according to the time in the menstrual cycle when they are measured. METHODS: Pairs of test scores were derived from 30 ER-positive/human epidermal growth factor receptor-2-negative tumours sampled at two different points of the menstrual cycle. Menstrual cycle windows were prospectively defined as either W1 (days 1-6 and 27-35; low oestrogen and low progesterone) or W2 (days 7-26; high oestrogen and high or low progesterone). RESULTS: The invasion module score of RS was lower (- 10.9%; p = 0.098), whereas the ER (+ 16.6%; p = 0.046) and proliferation (+ 7.3%; p = 0.13) module scores were higher in W2. PGR expression was significantly increased in W2 (+ 81.4%; p = 0.0029). Despite this, mean scores were not significantly different between W1 and W2 for any of the tests and the two measurements showed high correlation (r = 0.72-0.93). However, variability between the two measurements led to tumours being assigned to different risk categories in the following proportion of cases: RS 22.7%, ROR 27.3%, EP 13.6% and EPclin 13.6%. CONCLUSION: There are significant changes during the menstrual cycle in the expression of some of the genes and gene module scores comprising the RS, ROR and EP/EPclin scores. These did not affect any of the prognostic scores in a systematic fashion, but there was substantial variability in paired measurements.

A Novel BRCA1 Gene Mutation Detected With Breast Cancer in a Vietnamese Family by Targeted Next-Generation Sequencing: A Case Report.

Hereditary breast cancer is an inherited genetic condition, mainly caused by BRCA1 and BRCA2 gene mutations. These genetic changes can increase the risks of breast and ovarian cancers in women, while prostate and breast cancers in men. Especially, mutations in either BRCA1 or BRCA2 genes take important roles in early-onset breast cancer. The present study focused on a 47-year-old Vietnamese woman with breast cancer by applying targeted next-generation sequencing technique. A novel BRCA1 gene mutation, namely NM_007294.3 (BRCA1): c.4998insA (p. Tyr1666Terfs), was identified both in this patient and in some of the members in her family proved the fact that the mutated genes passed down through generations. This change may exponentially initiate breast cancer risks and become a valuable marker for exact clinical prognosis and treatment.

Menstrual cycle associated changes in hormone-related gene expression in oestrogen receptor positive breast cancer.

The major changes in hormone levels that occur through the menstrual cycle have been postulated to affect the expression of hormone-regulated and proliferation-associated genes (PAGs) in premenopausal ER+ breast cancer. Whilst previous studies have demonstrated differences in gene expression, here, we investigated if there are within patient changes in the expression of oestrogen- and progesterone-regulated genes (ERGs and PRGs) and PAGs in ER+ breast cancer during the menstrual cycle. Samples from 96 patients in two independent prospective studies of the effect of menstrual cycle on ER+ breast cancer were used. Plasma hormone measurements were used to assign tumours to one of three pre-defined menstrual cycle windows: W1 (days 27-35 and 1-6; low oestradiol and low progesterone), W2 (days 7-16; high oestradiol and low progesterone) and W3 (days 17-26; intermediate oestradiol and high progesterone). RNA expression of 50 genes, including 27 ERGs, 11 putative PRGs and seven PAGs was measured. The AvERG (geomean of PGR, GREB1, TFF1 and PDZK1) was used as a composite measure of ERG expression and showed significant changes between the three windows of the menstrual cycle increasing over 2.2-fold between W1 and W2 and decreasing between W2 and W3 and between W3 and W1. Proliferation gene expression also varied significantly, following the same pattern of changes as ERG expression, but the changes were of lower magnitude (1.4-fold increase between W1 and W2). Significant changes in the expression of eight individual ERGs, including GREB1, PGR and TFF1, and two PAGs were observed between W1 and either W2 or W3 with all genes showing higher levels in W2 or W3 (1.3-2.4-fold; FDR 0.016-0.05). The AvProg, a composite measure of PRG expression, increased significantly (1.5-fold) in W3 compared to W1 or W2 but no significant changes were observed for individual PRGs. In conclusion, we observed significant changes in ERG, PRG and PAG expression in ER+ breast tumours during the menstrual cycle that may affect the assessment and interpretation of prominent biomarkers (e.g. PgR) and commonly used multigene prognostic signatures in premenopausal ER+ breast cancer.

Molecular changes in premenopausal oestrogen receptor-positive primary breast cancer in Vietnamese women after oophorectomy.

For premenopausal women with primary ER + breast cancer, oophorectomy (OvX) is an evidence-based cost-effective option and is standard treatment in many countries. However, there is virtually no data describing the effects of OvX on breast tumour biology. We therefore, characterised the endocrine and genome-wide transcriptional impact of OvX in 56 premenopausal women with ER + breast cancer for 2 weeks prior to mastectomy. Plasma estradiol concentrations decreased from 406 ± 41 to 20.7 ± 2.6 pmol/l (mean ± sem) 24 h after OvX, and to 8.1 ± 0.8 pmol/l 2 weeks later at mastectomy. Ki67 decreased in 33/36 (91.7%) tumours. The expression of 655 genes changed significantly (FDR < 1%) with an absolute mean fold-change (FC) ≥ 1.25 (257 up, 398 down). Archetypal oestrogen-regulated genes (TFF1, GREB1, PGR and PDZK1) showed large decreases in expression (FC = 0.20-0.69; p < 1e-6-1e-7). Proliferation-associated genes (e.g. TOP2A, AURKA and UBE2C) were also strongly downregulated (FC = 0.38-0.56; p < 1e-7) along with putative progesterone-regulated genes (e.g. FKBP4, MYB; FC = 0.64-0.68; p < 1e-4-1e-7). The gene expression changes did not differ according to HER2 status and correlated strongly with the changes reported previously after aromatase inhibitor (AI) treatment in postmenopausal women (rho = 0.55, p < 1e-04). However, after OvX the mean FC was significantly higher compared to AI (p < 1e-04). In conclusion, changes in tumoural gene expression after OvX were largely similar, but of a greater magnitude to those observed after AI in postmenopausal patients; however, OvX appeared to have a greater effect on progesterone-regulated genes than AI.