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

Abstract

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.

Correlation between the RNA Expression and the DNA Methylation of Estrogen Receptor Genes in Normal and Malignant Human Tissues

“…Previous studies have established a correlation between the presence of estrogen receptors and estrogen signaling and the development of cancers, particularly breast carcinoma [23][24][25]. We conducted a more in-depth analysis of the expression pattern of estrogen receptors in various cancerous tissues.…”

Oncotype DX Recurrence Score in premenopausal women

“…While our review of current literature found inconclusive evidence for statistically significant variability of RS associated with menstrual cycling, Haynes et al data suggest that variations in RS can be clinically significant, leading to reassignment of risk categories and possible subsequent changes in treatment recommendations. 53 Addressing this question would not require a large randomized trial. Instead, a relatively small study could be conducted in which serum hormone levels, tumor RS testing and menstrual history are obtained twice (at the time of breast biopsy and breast surgery) from premenopausal patients diagnosed with HR-positive HER2-negative breast.…”

“…Perhaps the best study evaluating the possible effect of the menstrual cycle on RS is the 2021 study by Haynes et al . 53 The authors evaluated paired tumor samples of ER-positive breast cancer taken at breast biopsy and again at 1 to 4 weeks later along with corresponding serum hormone concentrations and menstrual cycle history. The authors predefined two different menstrual cycle windows: W1, corresponding to low estrogen and low progesterone, occurring very early or late in the menstrual cycle at days 1–6 or 27–35; and W2, corresponding to high levels of estrogen and low or high levels of progesterone, occurring at mid to late cycle on days 7–26.…”

“…However, interestingly, when the same group evaluated Oncotype DX RS in a HR-positive mammary tumor mouse model, Bernhardt et al found increased expression in these same group genes (proliferation and HER2), which were responsible for increased RS in the mice diestrus phase, corresponding to the human luteal phase. 56 Perhaps the best study evaluating the possible effect of the menstrual cycle on RS is the 2021 study by Haynes et al 53 The authors evaluated paired tumor samples of ER-positive breast cancer taken at breast biopsy and again at 1 to 4 weeks later along with corresponding serum hormone concentrations and menstrual cycle history. The authors predefined two different menstrual cycle windows: W1, corresponding to low estrogen and low progesterone, occurring very early or late in the menstrual cycle at days 1-6 or 27-35; and W2, corresponding to high levels of estrogen and low or high levels of progesterone, occurring at mid to late cycle on days 7-26.…”