Available online at www.sciencedirect.
com Current Opinion in
ScienceDirect
Review
The menstrual cycle is an under-appreciated factor in
premenopausal breast cancer diagnosis and treatment
Sarah M. Bernhardt1,2, Pallave Dasari1,2, David Walsh1,
Wendy Raymond3, M Louise Hull2, Amanda R. Townsend4,
Timothy J. Price4 and Wendy V. Ingman1,2
Abstract
Premenopausal breast cancer is a complex disease with
poorer outcomes compared to postmenopausal breast cancer.
Despite the well-known impact of estrogen and progesterone
on the biology of hormone responsive breast cancers, the
effect of menstrual cycle phase on diagnosis, treatment, and
survival outcomes has been under-studied. Evidence is now
emerging that menstrual cycle-associated hormonal fluctua-
tions affect expression of clinically-employed biomarkers and
impact upon surgical and adjuvant treatment outcomes. As we
engage in a new era of precision medicine, there is an ongoing
effort to improve prediction of treatment response. For pre-
menopausal breast cancer, this must include incorporation of
menstrual cycle data into treatment recommendations. We
advocate that menstrual cycle phase at the time of diagnosis
and treatment be routinely recorded. This will enable estab-
lishment of robust datasets to support research on how best to
incorporate menstrual cycle-associated changes in breast
cancer biology into breast cancer care.
Addresses
1
Discipline of Surgery, Adelaide Medical School, The Queen Elizabeth
Hospital, University of Adelaide, Woodville, SA, 5011, Australia
2
The Robinson Research Institute, University of Adelaide, Adelaide,
SA, 5005, Australia
3
Flinders Medical Centre, Flinders University of South Australia and
Clinpath Laboratories, Adelaide, Australia
4
Department of Medical Oncology, The Queen Elizabeth Hospital,
Woodville, SA, 5011, Australia
Corresponding author: Ingman, Wendy V (wendy.ingman@adelaide.
edu.au)
Current Opinion in Endocrine and Metabolic Research 2020,
15:37–42
This review comes from a themed issue on Breast Cancer
Edited by Evan Simpson and Theresa Hickey
For a complete overview see the Issue and the Editorial
Available online 7 November 2020
https://doi.org/10.1016/j.coemr.2020.11.001
2451-9650/© 2020 Elsevier Ltd. All rights reserved.
Keywords
Breast cancer, Menstrual cycle, Tumour biology, Estrogen,
Progesterone.
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Endocrine and Metabolic Research
Introduction
Breast cancer is one of the most commonly diagnosed
cancers in women worldwide and approximately 25% of
cases occur in premenopausal women [1]. Premeno-
pausal breast cancers exhibit a distinct tumour biology
and present unique clinical features compared to breast
cancer in postmenopausal women. Young women are
more likely to present with aggressive breast cancer
subtypes and advanced disease, and often exhibit worse
clinical outcomes compared to older women. Interest-
ingly however, while young women with estrogen
receptor-positive breast cancer experience higher rates
of disease recurrence and reduced overall survival [2,3],
survival outcomes are similar between premenopausal
and postmenopausal women with estrogen receptor-
negative disease [3,4].
The poorer outcomes for young women may be due to
the unique biology of estrogen receptor-positive pre-
menopausal breast cancer and the effects of menstrual
cycling on biomarker expression, treatment decision-
making, and metastatic potential. Estrogen receptor-
positive tumours in premenopausal women exhibit
distinct gene profiles and signalling signatures compared
to postmenopausal breast cancers [5,6]. Furthermore,
fluctuating concentrations of circulating estrogen and
progesterone across the course of the menstrual cycle
affect gene [7e9] and protein [10,11] biomarker
expression. Changes in biomarker expression during the
menstrual cycle may lead to suboptimal treatment
decision-making, which could explain why survival
outcomes are worse for younger women with estrogen
receptor-positive disease. Recent reports suggest that
results generated by gene expression-based assays
should be interpreted with caution [12], and that results
may be critically affected by the menstrual cycle phase
at the time of tissue collection (Bernhardt et al. Abstract
P1-10-12, San Antonio Breast Cancer Symposium,
December 2019) [13]. Menstrual cycling can also affect
the sensitivity and detection of breast tumours during
mammography [14], and may influence both surgical
[15] and chemotherapy [16] treatment outcomes. The
potential impact of menstrual cycle phase on the diag-
nosis and treatment of premenopausal breast cancer is
summarised in Table 1.
Current Opinion in Endocrine and Metabolic Research 2020, 15:37–42
38 Breast Cancer

Table 1

The potential effects of menstrual cycle phase on breast cancer biomarker expression and treatment outcomes. Emerging research
suggests that expression of breast cancer mRNA and protein biomarkers, as well as recurrence scores generated by genomic assays,
are different depending on the menstrual cycle phase at the time of tissue collection. Reports of menstrual cycle phase affecting
treatment outcomes are conflicting, some studies suggest improved survival if surgery or chemotherapy is commenced during the
follicular phase, other studies suggest surgery during the ovulatory or luteal phase is optimal. Abbreviations, protein biomarkers
ER [ estrogen receptor; PR [ progesterone receptor; HER2 [ human epidermal growth factor receptor-2, KI67 [ marker of prolifer-
ation; and gene biomarkers PGR [ progesterone receptor gene; MKI67 marker of proliferation KI67 gene.

Cycle Stage Biomarkers Treatment

Follicular Protein biomarkers: Surgical outcomes:

[ER [10,11] [ Disease-free and
[HER2 [55] overall survival [39,40]
Gene biomarkers: Chemotherapy outcomes:
[PGR [56] [ Incidence of
chemotherapy-
induced amenorrhea
[16]
Ovulatory Protein biomarkers: Surgical outcomes:
[PR [11] [Disease-free and
overall survival [57]
Luteal Protein biomarkers: Surgical outcomes:
[KI67 [18] [Disease-free and
[HER2 [19] overall survival
[30–38]
Gene biomarkers:
YMKI67 [58]
[21-gene recurrence
scores [13] (Bernhardt
et al. Abstract P1-10-
12, San Antonio
Breast Cancer
Symposium,
December 2019)

Despite evidence that menstrual cycling can affect
diagnosis and treatment of premenopausal breast cancer,
this is not considered during routine management.
Premenopausal women are an under-represented sub-
population in clinical research and our ability to better
understand the impact of the menstrual cycle is
impeded by the lack of large datasets that include in-
formation on menstrual cycle history. Therefore, many
treatment strategies for premenopausal breast cancer
patients are based on data obtained from studies
performed in postmenopausal women [17], with the
assumption that such approaches are as effective for
premenopausal women. This is exemplified by the
Fourth International Consensus Guidelines for Breast
Cancer in Young Women which states that surgical
treatment and therapeutic recommendations for young
breast cancer patients should not differ in general from
that of older patients, except for the addition of ovarian
suppression for premenopausal women [12].
In this review, we discuss how menstrual cycling can
affect the expression of clinically-employed breast
cancer biomarkers and highlight the potential for the
menstrual cycle to impact on surgical and adjuvant
treatments. We recommend clinicians record menstrual
cycle phase, duration and regularity at the time of
diagnosis, surgery and adjuvant treatment, and confirm
with serum hormone levels at the time of surgery.
The effect of menstrual cycling on protein
and gene predictive biomarker expression
Protein biomarkers are used in the clinic to guide
treatment decisions for breast cancer patients as they
provide useful information on patient prognosis and can
indicate a tumour’s likely response to a given therapy.
Expression of the estrogen receptor (ER), progesterone
receptor (PR) and human epidermal growth factor
receptor-2 (HER2) are routinely assessed during breast
cancer diagnosis, and their expression levels are the
current gold standard for guiding treatment decisions.
However, in premenopausal women, protein biomarker
expression fluctuates across the course of the menstrual
cycle in hormone receptor-positive tumours. Breast
cancer tissue samples are more likely to be ER positive
and exhibit a higher level of ER positivity when taken
during the follicular phase of the menstrual cycle,
compared to the luteal phase [10,11]. Furthermore,
breast cancer samples exhibit greater PR positivity
during the ovulatory phase, compared to either follicular
or luteal phases [11]. Tumour proliferation as assessed

Current Opinion in Endocrine and Metabolic Research 2020, 15:37–42 www.sciencedirect.com

 Menstrual cycle in premenopausal breast cancer Bernhardt et al.
through Ki67 [18], as well as HER2 protein expression
[19], also vary across the course of the menstrual cycle.
Despite this, there is little research into the extent to
which the menstrual phase at the time of biomarker
testing affects treatment decision-making based on
protein biomarkers.
In the last 2 decades, there has been an abundance of
research into identifying new gene biomarkers and
genomic signatures that predict therapy response and
patient prognosis. These emerging genomic signatures
have the potential to predict treatment response better
than the traditional protein-based methods. Assays that
use gene expression profiling to help guide treatment
decisions for breast cancer patients are now being in-
tegrated into clinical practice, leading the way in a new
era of genomic-based precision medicine. These assays,
such as Oncotype DX, Prosigna, Mammaprint, Endo-
Predict, and the Breast Cancer Index, assess a panel of
gene biomarkers and through an algorithm predict the
risk of disease recurrence and likely benefit from adju-
vant therapy [20e24]. These tests are recommended in
guidelines for assisting treatment decisions for both
premenopausal and postmenopausal women [25,26] and
their use has a significant impact on treatment decision-
making in the clinic [27].
Despite their use in premenopausal women, the devel-
opment and validation of gene expression-based assays
was largely conducted using breast cancer samples from
postmenopausal women [28]. It is possible that men-
strual cycling may affect the recurrence score generated
by the assay algorithm. Indeed, a recent study suggests
that results generated by the clinically-employed
Oncotype DX 21-gene algorithm are critically affected
by patient age at the time of tissue collection, and that
this age-related difference is likely due to menstrual
cycling [13]. This study used paired diagnostic and
surgical breast cancer samples to demonstrate that dis-
cordances in 21-gene recurrence scores between paired
samples were greater in younger women compared to
older women. As samples were collected from the same
tumour approximately 18 days apart, it was proposed that
discordances in 21-gene scores were likely a result of
menstrual phase. Due to the retrospective nature of this
study, investigation of a direct link between menstrual
cycle phase and discordance in 21-gene scores could not
be performed [13]. However, a study in naturally cycling
mice suggests that the 21-gene recurrence score is
indeed affected by the cycle (Bernhardt et al. Abstract
P1-10-12, San Antonio Breast Cancer Symposium,
December 2019). Increased recurrence scores were
observed in mammary tumours dissected during the
diestrus phase of the ovarian cycle, which is equivalent to
the luteal phase of the menstrual cycle in women.
Results from a large-scale prospective analysis further
support the possibility that Oncotype DX Recurrence
www.sciencedirect.com
39
Scores may be affected by patient age. Results from the
TAILORx study demonstrated that there were age-
related differences in chemotherapy benefit. While
women over the age of 50 years with Oncotype DX
Recurrence Scores between 16 and 26 do not receive
additional benefit from adjuvant chemotherapy,
compared to endocrine therapy alone, women under the
age of 50 still derived some benefit [21]. The prediction
of which young patients would benefit from chemo-
therapy was not improved when clinical information was
integrated with Oncotype DX Recurrence Scores [29].
The authors suggested that chemotherapy-induced
amenorrhea might contribute to differences in chemo-
therapy benefit between younger and older women,
however further studies are required to address this
possibility.
While these findings suggest the need for consideration
of patient age and menstrual cycle phase when using
gene expression-based algorithms, studies have not yet
defined an optimal time of the month to perform gene
biomarker testing or how this could be incorporated into
treatment decision-making. It is also unknown whether
oral contraceptive use or irregular menstrual cycling af-
fects the interpretation of predictive biomarkers.
Currently, there is insufficient evidence to make spe-
cific recommendations on how to incorporate the men-
strual cycle into clinical decision-making.
The effect of menstrual cycling on treatment
outcomes for young breast cancer patients
Another under-studied area in premenopausal breast
cancer is the impact of menstrual cycling on breast
cancer treatment outcomes. There is some evidence
that the menstrual cycle stage at the time of breast
cancer surgery might affect survival outcomes. Changes
in the characteristics of the tumour and tumour micro-
environment with menstrual cycle stage have been
suggested to influence the metastatic potential of
tumour cells [15]. However, there is significant con-
troversy in the literature. While a majority of studies
suggest that surgery performed during the luteal phase
is associated with favourable outcomes [30e38], other
studies instead report the follicular phase is more
favourable [39,40], or that there is no association [41e
48]. Currently, whether there is an optimal time of the
month to perform breast cancer surgery remains
controversial.
Similarly, whether menstrual cycling can influence
tumour response to endocrine and/or chemotherapy has
been little studied. In hormone receptor positive tu-
mours, the percentage of ER and PR positive cells in a
tumour is a predictor of response to therapy, where
increasing expression is associated with an increased
benefit of endocrine therapy [49]. Conversely, increased
hormone receptor expression is reflective of poorer
response to chemotherapy [49]. The expression of Ki67
Current Opinion in Endocrine and Metabolic Research 2020, 15:37–42
40 Breast Cancer
has also been suggested to be a prognostic factor; how-
ever, its value in predicting chemotherapy treatment
response is less clear [50]. Critically, changes in the
expression of ER, PR, or Ki67 with menstrual cycle
phase might influence the extent to which a tumour
responds to treatment. Despite the absence of studies
to address how menstrual cycle stage affects chemo-
therapy treatment response, there is some evidence that
the timing of therapy commencement may impact
outcome. In 2004, a retrospective analysis by Di Cosimo
et al. [16] reported that for women with breast cancer,
the timing of chemotherapy commencement in accor-
dance with a specific menstrual cycle stage significantly
influences the onset of chemotherapy induced amen-
orrhea. However, no significant progress towards un-
derstanding if this affects treatment outcome has been
made.
Whether menstrual cycling affects surgical and adjuvant
therapy outcomes remains poorly understood. If the
hormone milieu at a specific phase of the menstrual
cycle results in a more favourable treatment outcome,
then the timing of breast cancer surgery or chemo-
therapy commencement in relation to this phase might
be a possible means of improving the outcomes for
young breast cancer patients.
Recommendations for improving clinical
outcomes for young breast cancer patients
Currently, most of our understanding on the utility of
predictive biomarkers is based upon studies performed
in postmenopausal women, with the results of such trials
generalised to premenopausal women without sufficient
evidence of their applicability for these women. As we
engage in a new era of precision medicine, it is vital to
personalise prediction of treatment response, and for
premenopausal breast cancer, this must include how
best to incorporate menstrual cycle data into treatment
recommendations. There is a pressing need for dedi-
cated studies in premenopausal women to validate
emerging biomarker use for these younger women, with
information on the patient’s age and menstrual cycle
stage at the time of tissue collection taken into
consideration during the design and conduct of such
clinical trials.
In addition to prospective trials, retrospective studies
can provide valuable preliminary clinical evidence of the
impact of menstrual cycling on treatment outcomes that
guides development of appropriate clinical trials. How-
ever, the ability to study menstrual cycling retrospec-
tively is severely impaired by the lack of and/or
inconsistencies in recorded information on menopausal
status and menstrual cycle phase. As the majority of
breast cancers are diagnosed in postmenopausal women,
currently available retrospective datasets are largely
comprised of data collected from postmenopausal
Current Opinion in Endocrine and Metabolic Research 2020, 15:37–42
women. Furthermore, these datasets are frequently
limited by a lack of information on the patient’s meno-
pausal status, and utilise an arbitrary age-based cut-off
of 50 years to separate premenopausal and post-
menopausal women. This aged-based classification of
menopausal status is likely inaccurate as it does not
consider the perimenopausal period, which can occur
over a ten-year timeframe [51]. Of the datasets where
menopausal status is known, they are frequently limited
by missing, inaccurate, or poorly recorded information
on patient menstrual history; an issue that stems from
the fact that menstrual cycle stage and oral contracep-
tive use are not routinely recorded at the time of breast
cancer diagnosis.
In order to develop more robust retrospective datasets,
patient’s menstrual cycle phase should be recorded at
the time of breast cancer diagnosis and at surgical and
adjuvant treatments. Women can become anovulatory in
response to anxiety, low mood, weight fluctuations and
medical conditions [52] and menstrual cycles can
become irregular during the process of cancer diagnosis
and treatment. Documentation of the date of last
menstrual period, menstrual cyclicity (the average
number of days between 2 consecutive first days of a
period), the use of hormonal contraceptives, and any
recent menstrual changes will thus provide historical
evidence of menstrual cycle phase. However, we
recommend this information be accompanied by serum
concentrations of estrogen, progesterone, and luteiniz-
ing hormone in a blood sample taken at the time of
surgery. These measurements definitively determine
estrogen and progesterone exposure and more objec-
tively estimate menstrual cycle phase [53,54]. The
incorporation of this information in health records would
enable the generation of large datasets to ultimately
improve treatment outcomes in premenopausal women.
Conclusions
The menstrual cycle is often under-appreciated in
breast cancer research. Many treatment approaches for
premenopausal breast cancer patients are based on
studies performed predominantly in postmenopausal
women with the assumption that findings can be
extrapolated to premenopausal women. However,
recent research suggests that menstrual cycling affects
predictive biomarker expression and treatment out-
comes. There is a pressing need to record information on
the patient’s menstrual cycle at the time of breast
cancer diagnosis and treatment so that large-scale
datasets can be developed to optimise breast cancer
care for premenopausal women.
Funding
This research was supported by The Hospital Research
Foundation and The Queen Elizabeth Hospital Haem/
Onc Scheme A.
www.sciencedirect.com
 Menstrual cycle in premenopausal breast cancer Bernhardt et al.
Conflict of interest statement
Nothing declared.
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