CAUSES OF BREAST CANCER IN YOUNG WOMEN UNDER 40 2BREAST C.docx

CAUSES OF BREAST CANCER IN YOUNG WOMEN UNDER
40 2
BREAST CANCER IN YOUNG WOMEN UNDER 40 2
DSL 301 Paper Outline
TEMPLATE
Name: Maria Guerrero
Title: Causes of Breast Cancer in Young Women Under 40
Introduction
I. Introduction of scientific subject: Breast cancer is becoming a
common disease among young women and girls.
II. Relationship of scientific subject to your life: Breast Cancer
has taken the life of two of my aunts. One of them was 38 years
old when she died.
III. Thesis or goal of paper: This paper seeks to analyze how
cancer is affecting young women under the age of 40 years.
Transition into body
Body
I. (Main point 1/study 1): The risk factors of breast cancer.
a. Introduction of scientific study One out of eight women has
been diagnosing with breast cancer.
b. Observations that led to the study: Women who have been
diagnosed with breast cancer do not present the same risk
factor, therefore there is not an exact cause of the diseases.

c. Conclusions of study: Women can develop breast cancer for
genetic and environmental factors.
d. Relationship to your thesis/goal: Types of risks are related to
breast cancer.
Transition into main point 2
II. (Main point 2/study 2): Genetic Factors
a. Introduction of scientific study: Most of the women
diagnosed with breast cancer, are above 40 years; however,
women below 40 years are likely to been diagnosed with breast
cancer as much as them.
b. Observations that led to the study: Family history since we
share the same genes with our family members.
c. Conclusions of study: If one is diagnosed with one breast
cancer, one has a higher risk of being diagnosed with the other
breast cancer later on.
d. Relationship to your thesis/goal: Personal health history can
lead to a high percentage to develop breast cancer.
III. (Main point 3/study 3): Lifestyle and environmental risk
factors.
a. Introduction of scientific study: Frequent alcohol
consumption or overweight increase risks of breast cancer.
b. Observations that led to the study: Women living a sedentary
life can increase their breast cancer risk.
c. Conclusions of study: The way of living put young women at
high risk of increased breast cancer.
d. Relationship to your thesis/goal: Females under 40 should
take charge of their lifestyle by avoiding breast cancer risk
factors.

IV. (Main point 4/study 4): Breast cancer diagnosis and staging
a. Introduction of scientific study: Breast cancer is a complex
disease under the age of 40 years due to the fertility-related
factors to be included.
b. Observations that led to the study: Women with a family
history should be encouraged to practice mammography as well
as screening techniques.
c. Conclusions of study: More studies should be encouraged on
women under 40 that can carry the first degree of BRCA 1 or
BRCA 2.
d. Relationship to your thesis/goal: Young women with a family
history or breast cancer genetic should have breast cancer
professionals evaluated the risk.
V. (Main point 5/study 5): The four mains intrinsic of breast
cancer about clinical implications.
a. Introduction of scientific study: They include luminal A, B,
HER- two overexposed and basal-like breast cancer.
b. Observations that led to the study: Young age is an essential
risk factor for tumors to develop without any symptoms.
c. Conclusions of study: Cancer can be detected at the last stage
where treatment cannot be offered.
d. Relationship to your thesis/goal: It is hard to detect breast
cancer in women under 40. Mammography is not appropriate for
their age.
Transition into conclusion
Conclusion
I. Sum up the research findings of your various studies: There is
not a particular cause of breast cancer in women of young age.
II. What new questions arise? Should we have a better breast
cancer prevention that it is not based on age? /Does

mammography detect breast cancer in women under 40?
III. Summarize how these studies relate to your life/topic: As a
woman under 40, any age is a vital factor to consider early
breast cancer prevention, and other factors should be included
in the treatment of breast cancer.
IV. Close the paper: A special attention should be paid to
women under 40 toward age-related breast cancer side effects
for systemic treatment such as fertility issues and social
impacts. Research should be carried out to manage early breast
cancer prevention and advanced breast cancer where there is
limit amount of information available.
References
Appleton, D., Hackney, L., & Narayanan, S. (2014).
Ultrasonography alone for diagnosis of breast cancer in women
under 40. Annals of the Royal College of Surgeons of England,
96(3), 202-206.
https://lynn-
lang.student.lynn.edu:2262/pmc/articles/PMC4474049/

Dobi, Á., Kelemen, G., Kaizer, L., Weiczner, R., Thurzó, L., &
Kahán, Z. (2011). Breast cancer under 40 years of age:
Increasing number and worse prognosis. Pathology Oncology
Research : POR, 17(2), 425-8. doi:http://lynn-
lang.student.lynn.edu:2083/10.1007/s12253-010-9305-3
Houssami, N., Bernardi, D., Pellegrini, M., Valentini, M.,
Fantò, C., Ostillio, L., . . . Macaskill, P. (2017). Breast cancer
detection using single-reading of breast tomosynthesis (3D-
mammography) compared to double-reading of 2D-
mammography: Evidence from a population-based trial. Cancer
Epidemiology, 47, 94-99. doi:http://lynn-
lang.student.lynn.edu:2083/10.1016/j.canep.2017.01.008
Kehl, K. L., Shen, C., Litton, J. K., Arun, B., & Giordano, S. H.
(2016). Rates of BRCA1/2 mutation testing among young
survivors of breast cancer. Breast Cancer Research and
Treatment, 155(1), 165-173. doi:http://lynn-
lang.student.lynn.edu:2083/10.1007/s10549-015-3658-y
Ribnikar, D., Ribeiro, J., Pinto, D., Sousa, B., Pinto, A., Gomes,
E., . . . Cardoso, F. (2015). Breast cancer under age 40: A
different approach. Current Treatment Options in Oncology,
16(4), 16-16. doi:10.1007/s11864-015-0334-8
Parenthetical citations (convert the same references into
parenthetical style citations)
(Houssami, 2017)
(Kehl, 2016)
(Kuchenbaecker, 2017)
(Ribnikar, 2015).
Guerrero 2

Maria Guerrero
DSL – 301
Professor: Dr. Erika Doctor
Friday 03/22/2019
· Topic Choice: CAUSES OF BREAST CANCER IN
YOUNG WOMEN UNDER 40
· Description: My research will be about how cancer is
affecting young women since we think that because we are
young, we won’t have the risk of having this horrible disease. It
has caught my attention that breast cancer is getting common in
ladies under 40. My research will be focused on the risk factors,
how to prevent it, and treatment depending on the stage. I
personally interesting about this topic because I have breast
cancer history on my family, I am less than 40, and I have three
beautiful daughters to take care.
DSL 301 Paper Rubric
Outcomes Excellent (90-100%)
Above
average
(70-80%)
Sufficient
(50-60%)
Emerging
(30-40%)

Unsatisfactory
(0-20%)
Writing Strategy (10 points)
o Topic is related to natural science research
o Current experimental research is discussed
o Paper meets length requirement (10-12 pages)
9-10 7-8 5-6 3-4 0-2
Position/thesis (5 points)
o Purpose of paper is clearly stated
o Purpose is supported by body of paper
4.5-5 3.5-4 2.5-3 1.5-2 0-1
Introduction (5 points)
o Clearly introduce scientific subject
o Definitions provided for scientific jargon
o Sufficient background is provided to justify hypotheses
o Scope of introduction is neither too narrow nor too wide
4.5-5 3.5-4 2.5-3 1.5-2 0-1
Organization of main points (5 points)
o Each point is clearly delineated
o Points are well-supported
4.5-5 3.5-4 2.5-3 1.5-2 0-1
Content area for each main point (40 points)
o Hypothesis
o Test or Experiment
o Results
o Conclusion
o Research is properly interpreted

36-40 28-32 20-24 12-16 0-8
Transitions (5 points)
o Moves from one idea to the next
o Transitions provide clarity
o Variety of mechanisms are used
4.5-5 3.5-4 2.5-3 1.5-2 0-1
Evaluating and applying evidence and/or supporting ideas (10
points)
o Sources are academically valid
o Sources meet the requirements for this assignment
o Sources support arguments/assertions
9-10 7-8 5-6 3-4 0-2
Conclusion (10 points)
o Signaled end of paper
o Suggests direction for future research
o Provides closure to paper
9-10 7-8 5-6 3-4 0-2
Presentation, style, and grammar (5 points)
o Proper usage of format, style, and grammar 4.5-5 3.5-4 2.5-3
1.5-2 0-1
Documentation (5 points)
o Proper style format (APA) and citations
o Used at least five sources
4.5-5 3.5-4 2.5-3 1.5-2 0-1

EPIDEMIOLOGY
Rates of BRCA1/2 mutation testing among young survivors
of breast cancer
Kenneth L. Kehl1 • Chan Shen2 • Jennifer K. Litton3 •
Banu Arun3 • Sharon H. Giordano2
Received: 1 December 2015 / Accepted: 8 December 2015 /
Published online: 26 December 2015
� Springer Science+Business Media New York 2015
Abstract Guidelines in the United States recommend
consideration of testing for mutations in the BRCA1 and
BRCA2 genes for women diagnosed with breast cancer
under age 45. Identification of mutations among survivors
has implications for secondary prevention and familial risk
reduction. Although only 10 % of breast cancers are
diagnosed under age 45, there are approximately 2.8 mil-
lion breast cancer survivors in the United States, such that
the young survivor population likely numbers in the hun-
dreds of thousands. However, little is known about genetic

testing rates in this population. We assessed trends in
BRCA1/2 testing among breast cancer survivors who were
under age 45 at diagnosis and were treated from 2005 to
2012. Using insurance claims from a national database
(MarketScan), we identified incident breast cancer cases
among (1) women aged B40 and (2) women aged 41–45.
We measured BRCA1/2 testing using Kaplan–Meier
analysis and Cox proportional hazards models. Among
26,985 patients analyzed, BRCA1/2 testing rates increased
with each year of diagnosis from 2005 to 2012
(P 0.001). However, among women treated in earlier
years, testing rates did not approach those of patients
treated later, even after extended follow-up (median time
from surgery to testing among patients treated in 2005, not
reached; median time to testing among patients treated in
2012, 0.2 months for women aged B40 and 1.0 month for
women aged 41–45). Women aged 41–45 had lower rates
than women aged B40 throughout the analysis period

(P 0.001 for each year). BRCA1/2 testing rates among
young women with incident breast cancer increased sub-
stantially in the last decade. However, most survivors
treated in earlier years have never been tested. Our results
demonstrate a need to better incorporate genetic counseling
into survivorship and primary care for this population.
Keywords BRCA1 � BRCA2 � Breast cancer genetics �
Health services research
Introduction
Mutations in the BRCA1 and BRCA2 genes are associated
with under 10 % of breast cancer cases [1, 2]. However,
germline mutations in BRCA1 or BRCA2 confer a sub-
stantially increased risk of breast cancer, with a cumulative
incidence by age 70 of 44–78 % among BRCA1 mutation
carriers and 31–56 % among BRCA2 mutation carriers
[1, 3].
In 2001, the National Comprehensive Cancer Network
(NCCN) recommended consideration of genetic testing for
patients with a history of breast cancer diagnosed at age

B40 and for patients with clinical or family histories
otherwise suggestive of the hereditary breast and ovarian
cancer syndrome [4]. By 2005, consideration of testing was
additionally recommended for patients between ages 40
and 50, if deemed clinically appropriate [5]. The 2009
Electronic supplementary material The online version of this
article (doi:10.1007/s10549-015-3658-y) contains
supplementary
material, which is available to authorized users.
& Kenneth L. Kehl
[email protected]
1
Division of Cancer Medicine, University of Texas MD
Anderson Cancer Center, 1515 Holcombe Blvd, Unit 463,
Houston, TX 77030, USA
2
Department of Health Services Research, University of Texas
MD Anderson Cancer Center, Houston, TX, USA
3
Department of Breast Medical Oncology, University of Texas
MD Anderson Cancer Center, Houston, TX, USA
123

Breast Cancer Res Treat (2016) 155:165–173
DOI 10.1007/s10549-015-3658-y
http://dx.doi.org/10.1007/s10549-015-3658-y
http://crossmark.crossref.org/dialog/?doi=10.1007/s10549-015-
3658-y&domain=pdf
http://crossmark.crossref.org/dialog/?doi=10.1007/s10549-015-
3658-y&domain=pdf
guidelines increased the upper limit for age at diagnosis for
which testing should be generally considered from 40 to
45 years [6]. Other testing criteria for women include triple
negative breast cancer diagnosed at age B60, any epithelial
ovarian cancer, and pancreatic cancer in the setting of a
concerning family history [7]. In one study of patients with
incident breast cancer diagnosed from 2004 to 2007, 30 %
of women aged B40 had BRCA1/2 testing, and black and
Hispanic women were less likely to have testing than white
women [8]. However, testing rates began to increase sub-
stantially for women diagnosed at the end of that study
period, and it is not known to what degree that trend has

impacted survivors with more remote diagnoses.
There are currently 2.8 million survivors of breast can-
cer living in the United States [9], so although just 10 % of
cases of breast cancer are diagnosed at age B45 [10], the
number of survivors from that age group is likely in the
hundreds of thousands. Within the oncology community,
there is increasing interest in genetic testing and especially
in novel gene panel testing in breast cancer [11–14], but
long-term survivors of breast cancer have fewer visits to an
oncologist with each passing year [15]. Consideration of
even basic, standard-of-care genetic testing may therefore
not be routinely incorporated into the care of young sur-
vivors who were not tested at the time of diagnosis. Nev-
ertheless, identification of BRCA1 and BRCA2 mutations
within the survivor population has implications for pre-
vention of ovarian cancer and a second primary breast
cancer [16], as well as for genetic testing and risk reduction
within families.

In this study, we used insurance claims data to assess
rates of BRCA1/2 testing within a cohort of privately
insured young women with incident breast cancer treated in
the United States from 2005 to 2012. Since the 2009
NCCN guidelines were the first to explicitly recommend
consideration of testing for all women diagnosed under age
45, we separately analyzed women diagnosed at age B40
and women diagnosed at age 41 to 45. Our specific aim was
to assess for differences in genetic testing rates among
survivors according to year of diagnosis.
Methods
We identified patients with incident breast cancer diag-
nosed from 2005 to 2012 using the MarketScan database
[17]. We specifically analyzed rates of BRCA1/2 testing
among (1) women aged B40 at diagnosis and (2) women
aged 41–45 at diagnosis.
MarketScan [17] is a proprietary database consisting of
a convenience sample of paid medical claims for patients

with employment-based health insurance. This dataset
contains health insurance claims data for individuals in the
United States with primary or Medicare supplemental
coverage. The data are de-identified and meet Health
Insurance Portability and Accountability (HIPAA) confi-
dentiality requirements [17, 18]. For this analysis, we used
data from the Commercial Claims and Encounters and the
Medicare Supplemental and Coordination of Benefits
databases. We applied a modified version of the Nattinger
algorithm [19–21] to identify incident breast cancer cases.
Briefly, potential cases were identified based upon a breast
cancer ICD-9 code (174.x, malignant neoplasm of the
female breast). The algorithm further identified patients
who additionally had a procedure code for mastectomy,
lumpectomy, or axillary lymph node dissection. Patients
who met these criteria were included if they had at least
two outpatient claims on different dates with a primary
diagnosis of breast cancer, as well as either (1) a mastec-

tomy claim or (2) a lumpectomy or partial mastectomy
claim followed by at least one radiation therapy claim.
They could also be included if they had a surgical claim
plus at least two claims with a primary breast cancer
diagnosis but did not have both a claim for another type of
cancer and a claim for secondary cancer of the breast (ICD-
9 codes 198.81 or 198.2). Patients with a claim under a
breast cancer diagnosis or for a breast cancer procedure
within the preceding 3 years, indicating prevalent rather
than incident cases, were excluded. To capture claims for
BRCA1/2 testing that occurred close in time to the diag-
nosis of the index cancer, we included patients diagnosed
from 2005 to 2012 who had continuous coverage through
6 months prior to the month of their index cancer-directed
procedure and during the month of that procedure. We did
not otherwise require a continuous coverage period after
the index cancer-directed procedure, but rather censored
patients in our analyses on the date they no longer had

continuous documented coverage. Patients with docu-
mented BRCA testing claims prior to 6 months before
diagnosis were excluded. The year of diagnosis was
defined as the year in which there was a claim for the index
breast cancer surgery.
We identified BRCA1/2 testing claims using mutation-
specific HCPCS procedure codes S1818–S1823, as previ-
ously described [8]. These codes were discontinued in
2012, and Medicare then introduced new specific HCPCS
codes 81211–81217 for BRCA testing [22, 23]; we also
included claims filed under the new codes. A primary aim
of our analysis was to identify potential underuse of testing,
so we sought to capture as many potential BRCA mutation
testing claims as possible. In our primary analysis, we
therefore also included claims filed under stackable CPT
codes 83890–83909, 83912, 83914, or 88271, which until
2012 could be used to bill for molecular biological tech-
niques that might have been used for BRCA1/2 testing.

Since these codes were not specific for BRCA testing, we
166 Breast Cancer Res Treat (2016) 155:165–173
123
included them only when filed under an ICD-9 code for a
personal history of breast cancer (174.x–175.x, 233.0,
V10.03), genetic counseling and testing (V26.3x), or other
genetic screening (V82.79). We also conducted a sensi-
tivity analysis that included only the BRCA1/2 mutation-
specific procedure codes. Since HCPCS procedure codes
S1818–S1823 would not have been covered by Medicare,
and Medicare patients may therefore not have had such
claims submitted, we performed a second sensitivity
analysis excluding patients with Medicare supplemental
coverage.
We assessed rates of BRCA1/2 mutation testing, and
timing of testing, using Kaplan–Meier analyses. To capture
BRCA1/2 testing claims that followed identification of

cancer but predated cancer surgery, we defined the index
date for these analyses as 6 months (180 days) prior to
surgery. Patients were censored on the date they were no
longer included in the database due to changes in insurance
coverage or at the end of the follow-up period (December
31, 2013). Time to testing was compared among years of
diagnosis within patient cohorts via the log-rank test.
Confidence bands in our figures were generated via the
Hall–Wellner method [24]. We conducted multivariable
analyses using Cox proportional hazards models. Two-
sided P values less than 0.05 were considered statistically
significant. Analyses were performed using SAS software,
version 9.4 (SAS Institute, Cary, NC).
Results
We identified 35,388 patients with incident breast cancer
(15,149 women aged B40 and 20,239 women aged 41–45)
who had surgery from 2005 to 2012. Of those patients, we
excluded 3584 women aged B40 and 4223 women aged

41–45 who did not have continuous documented insurance
coverage for the month of their index breast cancer surgery
and the 180 days prior to surgery. We also excluded 365
women aged B40 and 231 women aged 41–45 who had
documentation of BRCA1/2 testing prior to a 180 day
period before surgery. Our analysis cohort therefore
included 26,985 patients (Table 1). Continuous insurance
coverage data for patients treated in each year are listed in
Supplemental Table 1.
Patients treated in later years were more likely to have
genetic testing; nevertheless, despite these increases,
patients treated in earlier years had lower plateaus in their
testing rates with time (Table 2; Fig. 1; log-rank P 0.001
for women aged B40 at diagnosis and for women aged
41–45 at diagnosis). Among women aged B40 treated in
2012, 72.9 % (95 % CI 70.7–75.1 %) had genetic testing
within 1 year after breast cancer surgery, and the median
time from surgery to testing was 0.2 months. Similarly,
among women aged 41–45 treated in 2012, 65.3 % (95 %

CI 63.3–67.3 %) had genetic testing by 1 year after sur-
gery, and the median time from surgery to testing was
1.0 month. However, among women treated in 2005 and
followed over time, less than half had testing as of
December 31, 2013 (median not reached for women aged
B40 at diagnosis or women aged 41–45 at diagnosis;
Table 2). Among women aged B40 treated in 2005, 4.9 %
(95 % CI 3.7–6.5 %) had a claim for genetic testing by the
date of surgery, but among women aged B40 treated in
2012, 47.5 % (95 % CI 45.1–49.9 %) had a testing claim
by their surgery date.
In a multivariable Cox proportional hazards model,
women aged B40 consistently had a higher likelihood of
testing than women aged 41–45 (P 0.001 for the contrast
between the cohorts in each year from 2005 to 2012).
There was slight variation in testing rates according to
geographic region and insurance plan type (Table 3).
In a sensitivity analysis restricted to claims specific to

BRCA 1/2 mutation testing (excluding non-specific genetic
testing claims for molecular techniques), estimated testing
rates were lower, but the patterns of change over time were
similar (Supplemental Table 2; Supplemental Fig. 1). We
also conducted a second sensitivity analysis excluding
patients with Medicare supplemental coverage, since
Medicare would not have reimbursed HCPCS ‘S’ codes
under which most of the BRCA1/2 mutation testing claims
were billed. The patterns of change remained similar
(Supplemental Table 3; Supplemental Fig. 2).
Discussion
In a cohort of young women with employer-based or
Medicare supplemental insurance and breast cancer treated
from 2005 to 2012, we found that a large proportion of
young breast cancer survivors have not undergone testing
for mutations in the BRCA1 and BRCA2 genes. Rates of
testing increased substantially for patients treated in later
years, but testing rates for patients treated in earlier years

never approached those of patients treated later, even after
extended follow-up. In the United States, approximately
7 % of cases of breast cancer occur before the age 40 [25],
and approximately 10 % of cases occur before the age 45
[10]. During our study period alone, there were therefore
approximately 192,000 cases of breast cancer in this age
group. We found that less than half of patients diagnosed in
2005 had genetic testing by the end of 2013. At a time
when there is increasing interest in issues around expanded
panel genetic testing for newly diagnosed patients with
breast cancer [11–14], our results indicate that there is a
substantial population of survivors who have never
undergone established, standard-of-care genetic testing.
Breast Cancer Res Treat (2016) 155:165–173 167
123
We found an increase in testing rates with each suc-
cessive year at diagnosis, during a period when genetic

testing was becoming more readily available, likely indi-
cating that most young patients with breast cancer who are
offered genetic testing are interested in pursuing it. The
lower plateau in testing rates among young women diag-
nosed in earlier years, even after extended follow-up, is
therefore especially notable. Although some studies indi-
cate that patients with BRCA1/2-associated breast cancers
have a worse prognosis than those with sporadic disease
[26, 27], others have demonstrated that the two groups
have similar outcomes [28–32]. Furthermore, the large
majority of patients diagnosed with breast cancer will be
long-term survivors [33]. Some of these survivors, such as
the cohort of women in our analysis who were aged 41–45
at diagnosis, would meet current criteria for genetic testing
but may not have met criteria when they were diagnosed.
Other survivors may have been diagnosed when genetic
counseling and testing were less widely available or prior
to the protections extended by the Genetic Information

Nondiscrimination Act of 2008, which prohibited dis-
crimination in the workplace or health insurance market-
place on the basis of a genetic predisposition to disease.
Our results indicate that providers should consider offering
genetic testing to this population, given the possibility that
doing so may further mitigate cancer risks, both for
Table 1 Patient characteristics
Women aged B40 N (%) Women aged 41–45 N (%)
Total 11,200 (100) 15,785 (100)
Age at diagnosis
B25 210 (2)
26–30 831 (7)
31–35 2776 (25)
36–40 7383 (66)
41–45 15,785 (100)
Index surgery claim
Lumpectomy 5967 (53) 10,177 (64)
Mastectomy 4461 (40) 4878 (31)
Other* 772 (7) 730 (5)

Insurance plan type
�
PPO 6887 (61) 9673 (61)
CDHP 411 (4) 600 (4)
Comprehensive 145 (1) 282 (2)
EPO 178 (2) 250 (2)
HDHP 213 (2) 274 (2)
HMO 1828 (16) 2507 (16)
POS 943 (8) 1300 (8)
POS with capitation 104 (0.9) 142 (0.9)
Missing/unknown 491 (4) 757 (5)
Region
Northeast 1729 (15) 2673 (17)
South central 2579 (23) 3677 (23)
South 4774 (43) 6455 (41)
West 1868 (17) 2642 (17)
Missing/unknown 250 (2) 338 (2)
* Other surgery type includes patients whose index surgery
claim was for regional node dissection only or

whose index claim contained both a mastectomy and a
lumpectomy procedure code
�
Insurance plan type: PPO preferred provider organization;
CDHP consumer-driven health plan (PPO
combined with a health reimbursement arrangement);
comprehensive (coverage handled by one policy with
deductible and coinsurance, no incentive for use of particular
providers); EPO exclusive provider orga-
nization (all care managed by a primary care physician with
referrals required, payment non-capitated);
HDHP high deductible health plan combined with health savings
account; HMO health maintenance
organization; POS point-of-service (primary care physician
manages care; patients incentivized to use
particular providers)
123
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–
3
9
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)
W
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4
1
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4
5
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7
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6
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2
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N
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t
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(1
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)
1
3
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(1
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)
2
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W
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4
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)
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(2
9
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)
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)
W
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(6
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)
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6
1
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(5
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W
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n
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4
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4
5
2
1
6
7
4
2
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4
2
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6
7
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1
1
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(1
0
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2
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)
3
5
.4
(3
3
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–
3
7
.5
)
4
8
.4
(4
5
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–
5
1
.0
)

2
0
0
9
W
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6
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5
7
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(5
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9
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N

/A
W
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2
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(1
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)
4
3
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(4
1
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N
/A
2
0
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W
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N
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123
patients and their families [16]. Information regarding
hereditary risk factors and genetic testing results is a rec-
ommended component of survivorship care planning for
current patients [34]. However, patients with remote
diagnoses may be unaware of advances in genetic testing.
Optimizing this process will require engagement of
Fig. 1 Cumulative rates of
BRCA1/2 testing claims. Each
graph contains Kaplan–Meier
failure curves, where events
were defined as BRCA1/2
testing claims. The year of

diagnosis was defined as the
year in which breast cancer
surgery occurred; the
observation period began
180 days before the date of
breast cancer surgery. Patients
were censored on the date they
no longer had continuous
insurance coverage recorded
within the MarketScan database.
The shaded areas represent
95 % Hall–Wellner confidence
bands for each curve
123
primary care providers, since with more time since diag-
nosis, long-term survivors of breast cancer have more visits

with their primary care physicians and fewer visits with
their oncologists [15].
Strengths of our analysis included its basis in a large
database of privately insured patients, which provided a
nationwide sample [17] with which to assess rates of genetic
testing in young women with breast cancer. Nevertheless,
there are limitations. We studied subgroups of breast cancer
patients with indications for genetic testing based on age
alone, who could therefore be identified from insurance
claims data using a previously validated algorithm [19–21].
This is not a complete list of indications for BRCA1/2
testing; for example, individuals are also eligible if they
have consistent family history patterns, ovarian cancer, or
triple negative breast cancer diagnosed at age B60, or if they
are male [7]. We also studied a privately insured population,
which may limit the generalizability of our results. Still,
rates of genetic testing were likely higher in the population
we studied than in patients who were uninsured or covered

by Medicaid or Medicare without supplemental coverage, or
who had less obvious or more recently identified indications
for testing. In that case, the rates of genetic testing we
ascertained may, in fact, represent an upper limit relative to
those in the general population. This would further reinforce
the need to consider genetic testing for survivors to whom it
has not previously been offered.
In addition, follow-up in our analysis was based on
continuous insurance coverage within a plan included in
the MarketScan database. Given a median length of follow-
up of three to 4 years, many patients diagnosed in earlier
years were censored. However, the upper quartile of length
of follow-up extended to 7–8 years for patients diagnosed
in 2005–2006, which still allowed us to assess rates of
genetic testing over an extended period of time for patients
with long-term data. Although our data cannot inform this
question directly, there is no obvious reason to suspect that
censoring would lead to a systematic underestimation of

BRCA1/2 testing rates. Indeed, patients who were censored
may actually have been less likely to have BRCA1/2
testing due to competing health risks. In that case, our low
measured testing rates for patients diagnosed in earlier
years might again represent an upper limit estimate of
actual population rates among cancer survivors.
This analysis was based on paid insurance claims, and
we therefore could not assess how often providers dis-
cussed the possibility of genetic testing with these patients
or how often patients were referred for genetic counseling.
We also could not assess how often patients considered
genetic testing but decided not to have it done, chose to pay
privately for testing rather than submit an insurance claim,
or had a claim for genetic testing denied without subse-
quently submitting a claim that was paid.
Table 3 Multivariable Cox proportional hazards model for
BRCA1/2
testing
HR (95 % CI) P

Diagnosis year/cohort 0.001
2005
Women aged B40 Reference
Women aged 41–45 0.71 (0.60–0.84)
2006
Women aged B40 1.70 (1.44–2.00)
Women aged 41–45 0.97 (0.82–1.14)
2007
Women aged B40 2.11 (1.81–2.46)
Women aged 41–45 1.39 (1.19–1.62)
2008
Women aged B40 2.71 (2.34–3.13)
Women aged 41–45 1.83 (1.59–2.12)
2009
Women aged B40 3.42 (2.97–3.94)
Women aged 41–45 2.23 (1.94–2.57)
2010
Women aged B40 4.03 (3.50–4.65)

Women aged 41–45 2.75 (2.39–3.17)
2011
Women aged B40 4.77 (4.14–5.50)
Women aged 41–45 3.48 (3.03–4.00)
2012
Women aged B40 6.05 (5.26–6.97)
Women aged 41–45 4.63 (4.03–5.33)
Insurance plan type
� 0.001
PPO Reference
CDHP 1.14 (1.05–1.24)
Comprehensive 1.01 (0.87–1.17)
EPO 1.05 (0.93–1.19)
HDHP 1.26 (1.13–1.40)
HMO 0.86 (0.82–0.91)
POS 1.03 (0.97–1.10)
POS with capitation 1.17 (0.98–1.41)
Missing/unknown 0.90 (0.83–0.98)
Region 0.001

South Reference
Northeast 1.15 (1.09–1.21)
South central 1.18 (1.13–1.23)
West 1.06 (1.00–1.11)
Missing/unknown 1.18 (1.06–1.32)
The outcome was the first BRCA1/2 testing claim recorded,
using a
Cox proportional hazards model that included the three
independent
variables listed in this table
�
Insurance plan type: PPO preferred provider organization;
CDHP
consumer-driven health plan (PPO combined with a health reim-
bursement arrangement); EPO exclusive provider organization
(all
care managed by a primary care physician with referrals
required,
payment non-capitated); HDHP high deductible health plan
combined
with health savings account; HMO health maintenance
organization;
POS point-of-service (primary care physician manages care;

patients
incentivized to use particular providers)
123
Finally, our case-finding algorithm may not have cap-
tured all breast cancer patients who had metastatic disease
at diagnosis, and therefore did not undergo surgery [20].
However, only approximately 4 % of female patients with
breast cancer have distant metastatic disease at diagnosis
[35]. Furthermore, approximately half of patients diag-
nosed with stage IV disease undergo surgery for their
primary tumor [36] and may therefore have been captured
by our algorithm, so the proportion of patients excluded for
this reason was likely small.
In conclusion, within a cohort of young women treated
for breast cancer from 2005 to 2012, for whom current
guidelines recommend consideration of BRCA1/2 testing,

rates of testing increased with later years of diagnosis. Still,
survivors treated in earlier years and followed over time
never approached the testing rates of those diagnosed in
later years. There are approximately 2.8 million survivors
of breast cancer in the United States [9], and approximately
10 % of new cases are diagnosed at age B45 [10], such that
there are likely hundreds of thousands of current survivors
from this population. Our results point to a need to opti-
mize access to genetic counseling among eligible survivors
and to incorporate it into survivorship and primary care for
patients with a history of successful treatment for early-
stage disease. Further research should be conducted into
strategies for increasing awareness of advances in genetic
testing among cancer survivors and their physicians, and
into assessment of the clinical impact and cost of such
efforts.
Funding This work was supported by the Duncan Family
Institute,
the Baker Institute for Health and Biosciences, and the Cancer

Prevention Research Institute of Texas (Grant RP140020).
Compliance with ethical standards
Conflict of Interest Kenneth L. Kehl declares that he has no
con-
flict of interest. Chan Shen declares that she has no conflict of
interest.
Jennifer K. Litton declares that she has no conflict of interest.
Banu
Arun declares that she has no conflict of interest. Sharon H.
Giordano
declares that she has no conflict of interest.
Ethical approval This article does not contain any studies with
human participants or animals performed by any of the authors.
The
MarketScan insurance claims data were fully de-identified prior
to
analysis, and the Institutional Review Board at the University of
Texas MD Anderson Cancer Center exempted this study from
review.
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c.10549_2015_Article_3658.pdfRates of BRCA1/2 mutation
testing among young survivors of breast
cancerAbstractIntroductionMethodsResultsDiscussionFundingR
eferences

Curr. Treat. Options in Oncol. (2015) 16: 16
DOI 10.1007/s11864-015-0334-8
Breast Cancer (P Neven, Section Editor)
Breast Cancer Under Age 40:
a Different Approach
D. Ribnikar, MD1
J. M. Ribeiro, MD2
D. Pinto, MD2
B. Sousa, MD
2
A. C. Pinto, MD2
E. Gomes, MD2
E. C. Moser, MD, PhD2
M. J. Cardoso, MD2
F. Cardoso, MD, PhD2,*
Address
1Medical Oncology Department, Institute of Oncology
Ljubljana, Ljubljana,
Slovenia
*,2Breast Unit, Champalimaud Clinical Center, Av. De Brasília,
s/n, 1400-038,
Lisbon, Portugal
Email: [email protected]
Published online: 22 March 2015
* Springer Science+Business Media New York 2015

This article is part of the Topical Collection on Breast Cancer
Keywords Breast cancer I Young women I Age I Treatment I
Guidelines I Imaging I BRCA
Opinion statement
Breast cancer (BC) under age 40 is a complex disease to manage
due to the additionally
fertility-related factors to be taken in consideration. More than
90 % of young patients
with BC are symptomatic. Women G40 years are more likely to
develop BC with worse
clinicopathological features and more aggressive subtype. This
has been frequently
associated with inferior outcomes. Recently, the prognostic
significance of age G40 has
been shown to differ according to the BC subtype, being
associated with worst recurrence-
free survival (RFS) and overall survival (OS) for luminal BC.
The biology of BC G40 has also
been explored through analysis of large genomic data set, and
specific pathways
overexpressed in these tumors have been identified which can
lead to the development
of targeted therapy in the future. A multidisciplinary tumor
board should determine the
optimal locoregional and systemic management strategies for
every individual patient
with BC before the start of any therapy including surgery. This
applies to both early (early
breast cancer (EBC)) and advanced (advanced breast cancer

(ABC)) disease, before the
start of any therapy. Mastectomy even in young patients confers
no overall survival
advantage when compared to breast-conserving treatment
(BCT), followed by radiother-
apy. Regarding axillary approach, indications are identical to
other age groups. Young age
is one of the most important risk factors for local recurrence
after both breast-conserving
surgery (BCS) and mastectomy, associated with a higher risk of
distant metastasis and
death. Radiation after BCS reduces local recurrence from 19.5
to 10.2 % in BC patients
40 years and younger. The indications for and the choice of
systemic treatment for
invasive BC (both early and advanced disease) should not be
based on age alone but
driven by the biological characteristics of the individual tumor
(including hormone
receptor status, human epidermal growth factor receptor 2
(HER-2) status, grade, and
proliferative activity), disease stage, and patient’s
comorbidities. Recommendations
regarding the use of genomic profiles such as MammaPrint,
Oncotype Dx, and Genomic
grade index in young women are similar to the general BC
population. Especially in the
metastatic setting, patient preferences should always be taken
into account, as the
disease is incurable. The best strategy for these patients is the
inclusion into well-
designed, independent, prospective randomized clinical trials.
Metastatic disease should
always be biopsied whenever feasible for histological
confirmation and reassessment of
biology. Endocrine therapy is the preferred option for hormone

receptor-positive disease
(HR+ve), even in presence of visceral metastases, unless there
is concern or proof of
endocrine resistance or there is a need for rapid disease
response and/or symptom control.
Recommendations for chemotherapy (CT) should not differ from
those for older patients
with the same characteristics of the metastatic disease and its
extent. Young age by itself
should not be an indication to prescribe more intensive and
combination CT regimens over
the sequential use of monotherapy. Poly(ADP-ribose)
polymerase inhibitors (PARP inhib-
itors) represent an important group of promising drugs in
managing patients with breast
cancer susceptibility gene (BRCA)-1- or BRCA-2-associated
BC. Specific age-related side
effects of systemic treatment (e.g., menopausal symptoms,
change in body image, bone
morbidity, cognitive function impairment, fertility damage,
sexual dysfunction) and the
social impact of diagnosis and treatment (job discrimination,
taking care for children)
should also be carefully addressed when planning systemic
long-lasting therapy, such as
endocrine therapy. Survivorship concerns for young women are
different compared to
older women, including issues of fertility, preservation, and
pregnancy.
Introduction
Breast cancer in young women is a rare condition; how-
ever, in the USA, an estimated 14,000 women under age
40 are diagnosed with breast cancer (BC) annually, and
nearly 3,000 young women die each year from their

disease [1]. BC is the leading cause of cancer death in
young women.
The prognostic relevance of young age (age
G40 years) by itself it is highly controversial. Some data
suggest worse outcome, mainly in age G35 years, while
other propose it is mostly related with biology. Recent
research suggests that age as a prognostic factor differs by
biologic subtype. Young women have increased risk of
psychosocial distress after BC diagnosis, not only due to
less favorable disease on average but also to their stage of
life at diagnosis and need to cope with multiple tasks
linked to a young family, work, and career [2•]. There
are other special areas in young BC patients such as
fertility preservation and family planning, sexual func-
tioning, beauty and body image, launching careers, and
raising young children.
16 Page 2 of 24 Curr. Treat. Options in Oncol. (2015) 16: 16
In recent years, there has been an improvement
in the understanding of the biology of BC in
young women. The most important message is that
although age is an important factor to consider, it
should not be the main or only factor for the
choice of treatment (both for early (early breast
cancer (EBC)) and advanced (advanced breast can-
cer (ABC)) disease). Treatment choices should be
driven by the biological characteristics of the
individual tumor, stage, and characteristics of each
individual young patient [3, 4].

In this review article, we will focus on current treat-
ment modalities recommended for women G40 years
with EBC and ABC. We will also address studies that
allowed us to better understand the biology of BC in this
population. Survivorship with emphasis on fertility
preservation, contraception, and pregnancy after BC di-
agnosis will also be discussed.
Diagnosis and staging
General considerations
Imaging evaluation of breast suspicious abnormalities should be
done as
fast as possible by experienced professionals in departments of
radiology
with expertise of breast diagnostic and interventional
procedures [3, 4].
Mammography should be preferably done during the first 2
weeks of
the menstrual cycle, while ultrasound can be performed at any
time.
Magnetic resonance imaging (MRI) should be performed in the
second
week of the menstrual cycle (to reduce the risk of false
positives)
following the standard technical recommendations [5].
Screening
Women with a family history suggesting a genetic
predisposition to BC
should have their risk assessed by a professional, e.g., a clinical
geneticist
[3, 4]. If they are found to be at high risk (20–30 % lifetime risk
or
higher), they should be given oral and written data regarding
their actual

risk and benefits of mammography and MRI screening
techniques as well
as of prophylactic procedures. Breast cancer susceptibility gene
(BRCA)-1
and BRCA-2 mutation carriers should be offered an annual MRI
screening
starting between age 25 and 29 years or on an individualized
timetable
based on the earliest age of cancer onset in family member.
Tumor protein
p53 (TP53) mutation carriers should start at age 20.
Other subgroups of high-risk women with a predisposition to
BC
should also be offered an annual MRI screening, and they
include first-
degree relatives of BRCA-1, BRCA-2, and TP53 mutation
carriers, wom-
en from families not being tested for BRCA mutation but with a
20–
30 % lifetime risk or greater, women with previous radiotherapy
(RT)
before age 30 (e.g., for Hodgkin lymphoma) starting 8 years
after the
treatment, and women at high risk and being already diagnosed
and
treated for BC. In TP53 mutation carriers of any age, annual
mam-
mography should be avoided due to high risk of radiation-
induced
cancer(s) [3].
After finding suspicious abnormalities with MRI, there is
always a need for
reevaluation with conventional imaging (mammography and
ultrasound). If

Curr. Treat. Options in Oncol. (2015) 16: 16 Page 3 of 24 16
solely MRI discloses the suspicious lesion, MR-guided biopsy
localisation
should be performed [3, 4].
Diagnosis
Because of the challenge that BC diagnosis often represent in
young patients,
imaging evaluation of breast lesions should be performed only
by an experi-
enced professional, and in case of a strong suspicion of BC,
triple assessment
must be done (clinical examination, imaging, and
cytological/histological
confirmation) [3, 4]. When a palpable mass is present, patients
should have
ultrasound followed, in case of Breast Imaging Reporting and
Data System 3-5
(BIRADS 3-5), by core biopsy preferred or fine needle aspirate
cytology. The use
of mammography should be based on the biopsy result; in case
of malignancy,
mammography is indicated to determine the extent of the
disease [3, 4], and
ultrasound of breast and axilla bilaterally should be performed.
It is highly recommended to have a histopathological
confirmation of
malignancy before any surgical procedures, and
immunophenotype of the
disease (estrogen receptor (ER), PR, human epidermal growth
factor receptor 2

(HER-2) status, and Ki-67 index) should ideally be determined
in the core
biopsy [6].
There are no data advising the routine use of MRI in the
preoperative
setting in young women with BC. It should be used for the same
indications as in older patients in case of newly diagnosed
invasive
lobular carcinoma [7], patients being at high risk for BC, those
with a
size discordancy of more than 1 cm between mammography and
ultra-
sound, and expected impact on the surgical intervention.
Multifocality
and/or multicentricity found by MRI should be assessed with
mam-
mography and ultrasound and confirmed by biopsy.
Staging
Age alone should not be an indication for performing additional
staging
procedures in asymptomatic patients [3, 4]. In young women
with BC, the
standard staging procedures for distant metastases should be
used and consist
of thorax x-ray, bone scan, liver ultrasound (US), and blood
tests including a
tumor marker.
Biology
Pathohistological features of BC in young women
Results of the POSH study, the largest prospective
observational study evalu-
ating the pathological characteristics of 2,956 BC women under

age 40, have
recently been reported [8]. The majority had ductal histology
(86.5 %) and
grade III (58.9 %) tumors. Of patients, 50.2 % had node-
positive disease, and
multifocality was observed in 27 % of patients. One third of
tumors were ER-
negative and one quarter were HER-2 positive. Similar results
were found
among the first 399 patients evaluated in the Young Women’s
BC Study [9], also
with high rates of lymphovascular invasion (34 %) and
lymphocytic infiltration
(24 %). Many other retrospective studies have evaluated
differences in patho-
logical features according to age [10]. Gnerlich et al.
demonstrated that young
patients were more often diagnosed with larger tumors, nodal
involvement,
grade III tumors, and ER-negative disease [10]. A population-
based study from
the California Cancer Registry, which included 5,605 patients
aged under 40 at
diagnosis, further showed higher proportion (28.2 %) of HER-2-
positive tu-
mors in the younger population [11]. In addition, it should be
recognized that
there is a rare histological subtype, secretory breast carcinoma,
which is more
common in the (very) young women. Despite the fact that they
belong to the

phenotypic spectrum of basal-like BC, they are associated with
good long-term
survival [12].
Recently published retrospective analysis of prospectively
collected
data by Bayraktar et al. showed that BRCA-1 carriers were more
likely
to have high nuclear grade and triple negative tumors than
BRCA-2
carriers and non-carriers [13]. Moreover, they were more likely
to have
medullary BC. BRCA-1 carriers were also more likely to be
lymph node
negative than non-carriers and BRCA-2 carriers. This is a new
finding
and could be a result of screening differences [13].
Pattern of BC subtypes in young women
The advent of genomic signatures allowed us to better
understand the
biology of BC, and four main intrinsic subtypes of BC with
clinical
implications are now recognized: luminal A, luminal B, HER-2
overexpressed, and basal-like. These subtypes generated by
genomic
signatures are correlated with the classical classification and
have clini-
copathologic surrogates: luminal A-like, luminal B-like, HER-2
positive
(non-luminal), and triple negative. Luminal A type tumors are
charac-
terized by endocrine-responsive disease (ER+ and PR+) and low
prolif-
erative rate (low grade and low Ki-67). Luminal B tumors are
also

endocrine-responsive but have higher proliferative rate and are
associat-
ed with worse prognosis compared to luminal A tumors. HER-2-
positive
disease (as defined by ASCO/CAP guidelines) [14] is
characterized by
more aggressive biological behavior and a usually good
response to anti-
HER-2 therapy. Finally, triple negative disease (ER-negative,
PR-negative,
and HER-2 negative) usually have a very aggressive behavior
being
chemotherapy (CT) the mainstay of treatment [15]. More
recently pub-
lished research has depicted even further the heterogeneity of
breast
cancer recognizing additional subgroups within main intrinsic
subtypes
already described [16, 17].
In the largest published study to date, Azim et al. evaluated
tumors of 3,522
patients in whom 451 were aged ≤40 at diagnosis [18•]. There
was a signifi-
cantly higher proportion of basal-like tumors (34.3 %) in this
cohort compared
to those aged 41–52 (27.7 %). A higher proportion of HER-2-
enriched cancers
was also observed in young patients. On the other hand, young
women were
less likely to have luminal A tumors (17.2 %) compared to other
age groups.
Prognostic genomic signatures in young BC patients
Since genomic assays were mainly developed using populations
of postmeno-

pausal women, there have been concerns about whether they
have the same
prognostic value in young patients. First-generation gene
signatures,
MammaPrint and Oncotype Dx, were evaluated in young
patients in two
studies. The Dutch group reported that 52/63 (82 %) young
patients were
classified as high risk on MammaPrint [19]. The same findings
were observed
for Oncotype Dx, where the majority of patients under age 40
had a high-risk
score (56 %) [20].
An analysis of 755 patients with ER-positive disease, of whom
87 were aged
≤40 years, demonstrated that all three gene expression profiles,
MammaPrint,
genomic grade index, and GENE 76, were significantly
associated with disease-
free survival (DFS) and added significant prognostic
information to clinico-
pathologic parameters (tumor size, nodal status, ER status, and
histological
grade) [18•].
Because of the longer life expectancy of young women, genomic
assays
could be useful not only to decide whether to use adjuvant CT
but also to
identify those who would benefit from extended adjuvant

endocrine treatment
(ET). However, the late recurrence genomic signatures
developed so far have not
yet been validated in patients under 40 years.
Gene expression differences in young BC patients
One of the first analyses of the biology of BC in young women
using gene
expression profiling done by Anders et al. showed a higher
proportion of
phosphatidylinositide 3-kinase (PI3K) and Myc pathway
deregulation [21], but
this analysis was not adjusted for potential differences in BC
molecular
subtypes.
More recently, Azim et al. evaluated the association between
patients’ age
and nearly 50 genes that were identified to be related to early-
onset BC. It was
found that younger patients have higher expression of RANK-
ligand, mammary
stem cell and luminal progenitors, and BRCA-1 mutation
signatures indepen-
dently of grade, stage, and intrinsic subtype of BC [18•]. There
was also more
disruption of MAPK-PI3K pathways and lower expression of
many apoptosis-
related genes, especially FAS.
There is a high prevalence of BRCA-1 mutations in younger
patients [22].
These patients are frequently diagnosed with basal-like tumors
[23].
Age as biomarker (prognostic and predictive)

For a long time, young age at diagnosis of BC has been
considered as
an independent factor associated with higher risk of relapse and
death
[24, 25]. However, several data, namely lower incidence of
luminal A
type tumor and enrichment in aggressive subtypes [26, 27], have
led to
question whether the prognostic significance of age remains
when
stratified on the basis of biologic subtype. In a recent analysis,
Sheridan
et al. [28] suggested that the effect of age varies with subtype.
In this
study, hormone receptor-positive disease (HR+ve) BC in young
women
carried a worse prognosis than in older women. Age G40
predicted
inferior survivals within the luminal subgroup. One must
acknowledge
that an important limitation of the study is the lack of further
subtyping within the luminal group. It is possible that the
inferior
outcomes are driven by luminal B cancer in this group. In the
HERceptin Adjuvant (HERA) trial (HER-2 positive BC), age
G40 years
was not prognostic for DFS or overall survival (OS) in the CT
plus
trastuzumab arm [29]. Such data supports the concept that age
G40 years as a prognostic factor differs by biologic subtype.
Regarding prediction, age is not a discriminative factor between

different
types of CT. Additionally, in the HERA trial, age G40 years did
not predict for
trastuzumab benefit [29].
Treatment
General recommendations
The optimal locoregional and systemic management strategies
should be de-
termined by a multidisciplinary tumor board for every
individual patient with
BC before the start of any therapy including surgery. This
applies to both EBC
and ABC before the start of any therapy [3, 4, 30, 31].
Locoregional treatment
Surgery
Surgical treatment of BC in young women consisted, for many
years, of mas-
tectomy that was considered to be safer leading to less
locoregional recurrences
(LRR) and better OS. In the last decade, this concept was
challenged with the
results from large randomized trials in all age groups [32], and
mastectomy
even in young patients confers no OS advantage when compared
to breast-
conserving treatment (BCT) [33], followed by RT. Young age
however remains
as an independent risk factor for increased LRR after BCT [34]
for both
intraductal and invasive disease [35], despite the use of more
effective adjuvant
therapies [36]. Even considering the higher LRR in young

women compared to
other age groups, BCT if feasible should always be the
preferred option [37]. The
use of oncoplastic techniques is considered safe and seems
particular useful
when more extensive resections are needed. Young age is also a
predictor of a
gradual asymmetry between the treated and non-treated breast
making
oncoplastic techniques more important [38].
Based on current evidence, nipple-sparing mastectomy seems to
have iden-
tical results regarding local recurrences as classic mastectomies,
conveying
higher cosmetic results [39]. Reconstruction options should be
thoroughly
discussed with the patient [37]. Patients should be fully
informed of the impact
of radiotherapy in breast reconstruction. Current evidence
shows similar results
when comparing immediate with delayed reconstruction
regarding complica-
tions. Results favor delaying the procedure when an implant
only based tech-
nique is the selected method.
Regarding axillary approach, indications are identical to other
age groups
with no special indications for the young age group.
Young patients submitted to neoadjuvant CT, with incomplete
pathologic
response, have a higher LRR after BCT [40]. Although surgical
guidelines are
similar to other age groups regarding resection margins and

axillary approach,
there is an unnecessary trend towards mastectomy in younger
patients after
primary systemic treatment [41], eventually explained by a
reported greater risk
of LRR, less imaging accuracy with higher false-positive rates,
and a higher
possibility of hereditary BC [40].
Breast conservation can also be an option in BRCA mutation
carriers with
recently diagnosed BC with the same survival benefit than
mastectomy [42]. A
recent meta-analysis [43] concerning surgical management of
BRCA mutation
carriers concludes however that LRR after BCT is significantly
higher in
mutation carriers when longer follow-up (more than 7 years)
studies were
included. There were no differences in LRR between BRCA-1
and 2 mutation
carriers. Adjuvant radiotherapy, CT, and prophylactic
oophorectomy were all
associated with a significant risk reduction of LRR [44].
The risk for contralateral breast cancer (CBC) is increased in
BRCA
mutation carriers and significantly higher in BRCA-1 mutation
carriers,
but data about an OS benefit of contralateral prophylactic
mastectomy is

not clear [42, 45].
Risk reduction surgery with bilateral mastectomy and eventual
oophorecto-
my should be extensively discussed before initial surgery if
genetic test results
are available at diagnosis. However, adding the impact of a
recently diagnosed
cancer with the complex discussion about harms and benefits of
prophylactic
surgery in mutation carriers can be overwhelming and can be
delayed to a
second phase after the treatment of the recently diagnosed
cancer [46]. If
bilateral mastectomy is indicated, immediate reconstruction
should be offered,
and nipple- or skin-sparing mastectomies are proven good
options regarding
both oncological and cosmetic outcomes [47].
Radiotherapy
Young age is one of the most important risk factors for local
recurrence after
both BCS and mastectomy associated with a higher risk of
distant metastasis
and death [34]. Local recurrence rates are reported three times
higher at
5 years in patients under 40 years [48]. Biological subtypes are
known to
have a great impact on both local control and distant failure in
all BC
patients. Several reports state higher risk for local recurrence
after BCS for
women younger than 50 years and high-grade tumors [34, 48–
50]. There are
several hypotheses to account for the effect of age on local

control. First,
young women may be more likely to have HER-2-positive and
triple nega-
tive BC [51–53]. The reason for association of the HER-2
subtype with
ipsilateral breast tumor recurrence (IBTR) in younger patients is
unclear;
however, some studies suggest that this subtype may be
relatively resistant
to post-lumpectomy RT [54–57]. HER-2 inhibitors can affect
cellular re-
sponses to ionizing radiation by induction of apoptosis and cell
cycle arrest
and by impeding DNA repair [58–63]. Targeting of the PI3K-
AKT-
mammalian target of rapamycin (mTOR) pathway may help to
overcome
resistance to currently available HER-2 inhibitors plus
irradiation. Second,
dense breasts, which are more common in younger women, may
be a risk
factor for local recurrence [64, 65]. The mechanisms underlying
the association
of dense breasts and tumor recurrence are largely unknown,
although previous
research indicated that circulating growth factors and proteins
may influence
breast density and tumor recurrence [64–66]. Moreover, dense
breasts may have
a masking effect on tumor detection by mammography [64].
RT after BCS reduces local recurrence from 19.5 to 10.2 % in
BC patients
40 years and younger (P=0.002) [48]. The 10-year results of the
EORTC 22991/
10883 trial (boost vs no boost trial) demonstrated that

additional radiation had
the largest absolute benefit on local control in younger patients
and reported
that close margin was associated with higher local recurrence
rate only in
younger patients (less than 45 years old), suggesting the
importance of strict
surgical local control for this patient population [67, 68].
Systemic treatment
General recommendations
The indications for and the choice of systemic treatment for
invasive BC (BC)
(both early and advanced disease) should not be based on age
alone but driven
by the biological characteristics of the individual tumor
(including hormone
receptor status, HER-2 status, grade, and proliferative activity),
disease stage,
and patient’s comorbidities [3, 4].
Recommendations regarding the use of genomic profiles such as
MammaPrint, Oncotype Dx, and Genomic grade index in young
women are
similar to the general BC population.
In view of the longer expected life time of young women,
special attention
must be taken into account to potential long-term toxicities of
systemic treat-
ment such as secondary cancers, cardiovascular toxicity, bone

morbidity, cog-
nitive change (“onco-brain”), and irreversible ovarian failure
with consequent
infertility. Young women with BC are also more likely to suffer
from psycho-
social distress and anxiety compared to older patients and are
more likely to be
concerned with maintaining high function at home and/or work,
attractiveness,
and sexual dysfunction [2•].
Young women must be advised to appropriate and early
referrals to
fertility clinics, mental health professionals, and supportive
resources,
and genetic testing must be an integral aspect of caring for the
young
patient with BC [69•].
EBC
Indications for neoadjuvant systemic therapy are the same for
young as in
older women. Neoadjuvant CT approach and subsequent breast
conserva-
tion have no detrimental effect on survival in young BC patients
[3, 4].
It is recommended to start adjuvant systemic CT within 8 weeks
of completion
of surgery. If both chemo- and radiotherapy are indicated in
adjuvant setting,
CT should be given first in young women, as in other age
categories [3, 4].
(Neo)adjuvant chemotherapy
In the (neo)adjuvant setting, there is currently no evidence to

recommend a
specific CT regimen for young women. Therefore, regimens
including
anthracyclines with or without a taxane represent the preferred
standard treat-
ment option [3, 4, 15]. Based on the tolerability profile, and on
the possible
higher efficacy, sequential anthracycline-taxane-based regimens
are the pre-
ferred combination regimens [70]. A combination of a taxane
and cyclophos-
phamide is also an option in case of contraindications for
anthracyclines
(cardiac disease, previous exposure to anthracyclines, etc.).
There are currently
no data supporting the use of platinum in the adjuvant setting.
Young age alone should not be a surrogate factor for use of
dose-dense CT
approach, as it was shown in a systematic review and meta-
analysis that mainly
patients with hormone receptor-negative aggressive biology
disease benefit
from this regimen [71]. The neoadjuvant Gepartrio trial showed
that age below
40 was a significant independent predictive factor for efficacy
of a docetaxel,
adriamycin, and cyclophosphamide (TAC)-based therapy and in
the subgroup
of patients with triple negative or grade 3 tumors [72].
However, TAC regimen is

associated with more grade 3/4 toxicity, mainly as febrile
neutropenia and
diarrhea in comparison with the dose-dense one [70].
Approximately 15 % of triple negative breast cancers (TNBCs)
are BRCA-
mutated [73]. Results of recent randomized phase II trials and
meta-analysis
suggest that TNBC patients who are BRCA carriers and/or those
with a family
history of breast/ovarian (BC/OC) cancer seem to benefit from
neoadjuvant CT
(combination/sequence) incorporating platinum salts [74•, 75,
76•]. These
patients respond better compared with non-TNBC patients and
achieve a
significant improvement in pathologic complete response (pCR)
rates when
platinum salt is added to standard anthracycline- and/or taxane-
based therapy.
However, all these trials had small number of patients, and the
true value of
pCR, particularly in BRCA-mutated tumors, is still unclear.
Therefore, use of
platinum in the early BC setting cannot yet be considered
standard of care.
An indirect endocrine effect of CT in ER-positive BC is based
on the induc-
tion of ovarian function suppression (OFS). Amenorrhea is
associated with
improved treatment outcome, even if transient [77•]. In the
IBCSG trial, 13–93
(adjuvant CT ± tamoxifen) premenopausal patients with node-
positive ER-
positive BC who experienced CT-induced amenorrhea (CIA) had

a significantly
improved outcome (hazard ratio (HR) for amenorrhea vs no
amenorrhea=
0.61), whether they received tamoxifen or not.
(Neo)adjuvant endocrine therapy
Neoadjuvant ET should not be proposed to young women
outside clinical trials
[77•]. In the STAGE study, 95 patients treated with 2 years
neoadjuvant com-
bined therapy with goserelin plus anastrozole achieved a
significantly better
overall response rate (ORR) than 90 patients that were treated
with goserelin
and tamoxifen (70.4 vs 50.5 %; p=0.004) [78].
There are currently many treatment options available for
adjuvant ET for
young patients with HR+ve. According to the 2011 EBCTCG
meta-analysis,
5 years of tamoxifen compared to no ET is associated with a
reduction in BC
recurrence by 39 %, which is translated into a 13 % absolute
reduction in the risk
of recurrence at 15 years (33 vs 46 %) [79]. The risk of BC
mortality is reduced by
30 %, which is translated into a 9 % absolute reduction in BC-
related death (24
vs 33 %). An important issue of adjuvant ET is the so-called
carryover effect,
which means the mortality reduction is significant throughout at
least the first
10 years [79]. The substantial benefit was seen in both pre- and
postmenopausal
women with ER-positive disease regardless of age, stage, and
grade of the disease.

The optimal duration of ET has not been sufficiently studied in
young
women. Extending tamoxifen up to 10 years should be
considered in premen-
opausal patients that are at high risk for late relapse (such as
those with high
tumor burden). The results of the recently published ATLAS
trial showed a
significant reduction in the risk of recurrence, BC-specific
mortality, and overall
mortality in women with ER-positive disease continuing with
tamoxifen treat-
ment up to 10 years [80•]. At 15 years, the recurrence rate for
women treated
with tamoxifen for 5 years was 25.1 vs 21.4 % for women who
received
tamoxifen for 10 years. The rate of BC mortality for women
treated for 5 years
was 15 vs about 12 % for women who received tamoxifen for 10
years (an
absolute gain of 2.8 %). Another “extended” tamoxifen adjuvant
trial (aTTom)
confirmed the ATLAS reduction in recurrence and death from
BC [81]. In both
extended tamoxifen trials, ATLAS and aTTom, the relapse risk
reduction was
time dependent, with practically no benefit seen with longer
treatment on years
5–9, followed by an abrupt significant improvement on year 10
and subse-

quent years [82]. This can be explained by the carryover effect
of the first 5 years
of tamoxifen, extended its benefit to the period of years 5 to 9.
Benefit of luteinizing-hormone releasing hormone (LHRH)
agonists’ use has
also been shown specifically in the absence of CT. In the meta-
analysis by Cuzick
et al. that analyzed the role of OFS in 11,906 premenopausal
women with EBC,
randomized in 16 trials, there was no significant benefit for the
use of LHRH
agonists alone, but adding these agents to CT, to tamoxifen or
both, significantly
reduced recurrence by 12.7 % and death after recurrence by 15.1
% [83].
Moreover, the benefit of LHRH agonists after CT was seen in
women under age
40 but not in older premenopausal patients. The SOFT trial was
designed to
assess the benefit of the addition of OFS to adjuvant tamoxifen
in premeno-
pausal HR+ve BC patients. The results already reported [84]
show a lack of benefit
with the addition of OFS to tamoxifen in the overall population.
However,
prespecified subgroup analysis demonstrates that in the cohort
of patients at high
enough risk to be treated with chemotherapy (and who remained
premeno-
pausal), the addition of OFS to tamoxifen or exemestane led to
an improvement
in 5-year BC-free interval of 4.5 and 7.7 %, respectively. In the
cohort of women
not requiring chemotherapy, no statistically significant
difference in DFS at

5 years (HR=0.83, 95 % confidence interval (CI)=0.66–1.04)
was seen. In an
important subgroup analysis of patients younger than 35 years,
the most striking
advantage from the addition of OFS to endocrine therapy was
seen. The rate of
freedom from BC at 5 years was 67.7 % for patients in the
tamoxifen alone arm,
78.9 % for those in tamoxifen plus OFS arm, and 83.4 % for
those assigned to
exemestane plus OFS. OS data is not mature, and longer follow-
up is needed.
OFS resulted in increased adverse events—menopausal
symptoms, depres-
sion, osteoporosis, and hypertension—and this must be balanced
with the
expected benefits and discussed with each patient.
It is still unknown what is the optimal duration of LHRH
agonists, although
most studies have utilized 2–3 years of LHRH agonists
(monthly injection) with
5 years of tamoxifen. Estradiol levels should be monitored on a
regular basis (at
least every 6 months), always in the same laboratory and
preferably in a central
reference laboratory. In case of insufficient ovarian
suppression, bilateral
ovariectomy or continuation of tamoxifen alone should be
considered [3].
Aromatase inhibitors (AIs) alone are contraindicated in
premenopausal
women because the suppression of peripheral aromatase results
in reduced

feedback to the hypothalamus and consequently ovarian
stimulation occurs
[77•]. Because of this, AIs alone should also not be used in
young women who
have had CIA, unless postmenopausal status is definitively
proven [3]. At ASCO
2014, the combined analysis of the TEXT and SOFT trials,
evaluating the role of
adjuvant AIs in premenopausal BC patients, was presented.
Exemestane (EXE)
plus OFS significantly improved DFS, BCFI, and DRFI in
comparison with
tamoxifen (a 3.8 % absolute difference in DFS in favor of EXE,
no difference in
OS after a median follow-up of 5.7 years). Safety profile of
EXE + OFS was
similar to that seen with AIs in postmenopausal women after a
median follow-
up of 5.7 years. This combination of ET represents a new
treatment option for
premenopausal women with early ER-positive BC [85•],
particularly for those
with contraindications for tamoxifen.
Young women with contraindications for the use of tamoxifen,
intolerant,
or who develop symptoms/signs of hyperestrogenism induced by
tamoxifen,
namely ovarian cyst formation, may also be treated with a
LHRH agonist alone
or in combination with AI; the optimal duration of this
treatment is unknown

[3, 4]. In young women with BRCA-1/2 mutation or in those
patients belonging
to hereditary BC families, prophylactic ovariectomy may be
considered when
adjuvant ET is discussed [77•].
Adjuvant anti-HER-2 therapy
Young women with HER-2-positive early BC should be treated
with standard 1-
year adjuvant trastuzumab treatment [3, 4]. Adjuvant
trastuzumab is indicated
for patients with T1b tumors (more than 5 mm in maximum
size) and for all
patients with node-positive HER-2 positive disease irrespective
of its size [15].
A subgroup analysis of the HERA trial showed that patients
under the age 35
have the same benefit from 1-year trastuzumab treatment as
older ones [29].
Adjuvant bisphosphonates
The meta-analysis of the three largest adjuvant bisphosphonate
trials reported an
apparent harm of these agents in pre- and perimenopausal
women [86]. This
finding had been already previously shown in the AZURE trial,
in which there
was a significant detrimental effect of zoledronic acid (ZA) on
the rate of non-
skeletal metastases in premenopausal women that was
independent of ER status
[87]. An older Finnish study also demonstrated similar
conclusions, when oral
clodronate was given in the adjuvant setting, with non-skeletal
recurrences being

significantly more frequent in the clodronate group vs control
group, especially
in ER-negative disease [88]. The only trial showing a potential
benefit was the
Austrian where ZA at 4 mg per 6 months effectively prevented
bone loss in ER-
positive premenopausal patients whose treatment regimens
included LHRH
agonist or those who developed complete ovarian suppression
following adju-
vant CT [89]. Based on all these data, bisphosphonates should
not be given to
young women in the adjuvant setting independently of “intrinsic
subtype” of BC.
Locally advanced and inflammatory breast cancer
Inflammatory BC is slightly more common in young women,
specially in
women of African descent in the USA and in North African
countries [3, 4]. The
management of inflammatory BC in young women should be the
same as in
the older BC population since there are no data indicating a
different biology or
a different prognosis [90].
ABC
The treatment for a young individual BC patient with advanced
disease
must be determined by a multidisciplinary team as for the
overall ABC
population. Specially in the metastatic setting patient
preferences should
always be taken into account, as the disease is incurable. The
best strategy

for these patients is the inclusion into well-designed,
independent, pro-
spective randomized clinical trials. Metastatic disease should
always be
biopsied whenever feasible for histological confirmation and
reassessment
of biology [3, 4, 30, 91].
Endocrine therapy for advanced disease
Endocrine therapy is the preferred option for HR+ve, even in
presence of visceral
metastases, unless there is concern or proof of endocrine
resistance or there is a
need for rapid disease response and/or symptom control [30,
91].
In young patients with ER-positive MBC, tamoxifen in
combination with
OFS (a LHRH agonist or bilateral ovariectomy) is currently
recommended as
the standard first-line therapy [3, 4, 30, 77•, 91].
AIs in combination with OFS (a LHRH agonist/bilateral
ovariectomy) can
be considered in young patients after progression on tamoxifen
plus OFS based
on the available evidence [3, 4, 30, 91].
Based on findings of the efficacy of fulvestrant in metastatic
setting for post-
menopausal BC patients and its mechanism of action, this drug
should also be

effective in young patients. However, it has not been properly
studied in pre-
menopausal patients. Bartsch et al. demonstrated a clinical
benefit rate of 58 %
with fulvestrant plus goserelin in 26 patients pretreated with
TAM and AIs in
combination with goserelin; median TTP was 6 months and OS
32 months [92].
No specific endocrine resistance mechanisms have been
identified in premeno-
pausal ABC patients. mTOR inhibitors have not been studied in
premenopausal
women. However, from their mechanism of action and in cases
where a OFS is
given (and therefore the patient becomes postmenopausal), it is
acceptable to
consider this treatment option for the same indications of
postmenopausal women.
Chemotherapy for advanced disease
Recommendations for CT should not differ from those for older
patients with
the same characteristics of the metastatic disease and its extent.
Young age by
itself should not be an indication to prescribe more intensive
and combination
CT regimens over the sequential use of monotherapy [3, 4].
Platinum agents are facing a renewed interest in TNBC and
BRCA-1/2-
related BC, based on preclinical and some clinical data and
several studies to
confirm their efficacy is underway. However, in an unselected
TNBC popula-
tion, there are yet no randomized data supporting platinum-

based CT as the
optimal regimen [93]. In BRCA, mutation carrier’s recent
data—TNT
trial—suggests advantage of platinum-based CT over taxane in
first-line meta-
static setting [94]. The TNT trial is a randomized, phase 3 trial,
comparing six
cycles of carboplatin at the full AUC6 vs docetaxel. In the
BRCA-related BC, a
benefit for single agent platinum with an ORR of 68 vs 33 %
(p=0.03) was seen.
Anti-HER-2 therapy for advanced disease
Anti-HER-2 therapy recommendations should not differ from
those for older
patients with HER-2-positive MBC [3, 4].
Systemic treatment of specific sites of metastases
Therapeutic recommendations should not differ from those for
older women
with the same biology of metastatic disease and its extent [3, 4].
In case of bone metastases in young women, a bone-modifying
agent (a
bisphosphonate or denosumab) should be routinely used in
combination with
other systemic therapy, like in older patients [3, 4, 30, 91].
Systemic treatment of locoregional relapse
It has been shown that systemic therapy (both endocrine and
CT) has a
beneficial effect after complete resection of a first isolated LRR

[95]. The
CALOR study, a randomized phase III study, evaluating the role
of CT
after surgery of isolated locoregional recurrence, showed a
significant
reduction in systemic recurrence with the use of CT in this
setting
(HR=0.59; p=0.046). A significant improvement in survival was
seen
only in ER-negative disease. Patients with a HER-2-positive
LRR who
have not received trastuzumab in adjuvant setting or whose
primary
tumor was HER-2 negative should receive trastuzumab for 1
year (“pseu-
do-adjuvant” therapy). These recommendations should not
differ in
young women from older patient population [3, 4].
New targeted treatment options—BRCA carriers
PARP inhibitors
BRCA mutation-associated BCs are characterized by deficient
ho-
mologous recombination of DNA, and most of BRCA-1-
associated
BCs display the basal-like molecular subtype. Traditionally,
BRCA-
associated BCs have been treated with conventional systemic
CT.
With the growing understanding of the functions of BRCA-1/2
pro-
teins in homologous DNA repair, it is recognized that BRCA-
associated breast tumors may have distinct biochemical
characteris-

tics and thus could require tailored treatment strategies. These
tu-
mors were shown to be particularly sensitive to platinum com-
pounds or inhibitors of poly(ADP-ribose) polymerase.
Over the past years, increasingly potent poly(ADP-ribose)
polymerase
(PARP) inhibitors (PARPi) have been developed and their
potential role in
treatment of TN and BRCA-associated tumors evaluated.
Phase II studies evaluating single agent therapy with olaparib
[96] or
veliparib combined with temozolamide [97] in this patient
population
confirmed the activity of this class of drugs with especially
impressive ORR
of 41 % (11 of 27) and an additional 44 % (12/27) rate of stable
disease
(SD) with olaparib monotherapy. Several phase III studies in
ABC and neo/
adjuvant setting are recruiting patients. In the metastatic
setting, the
EMBRACA study is evaluating talazoparib after second line
[98]. Veliparib
is being studied in association with carboplatin and paclitaxel in
first and
second line
(https://clinicaltrials.gov/ct2/show/NCT02163694?term=
Breast+cancer+AND+PARP+AND+BRCA&phase=2&rank=2)
and inaparib
as single agent in the BRAVO study [99].
Imaging for follow-up (EBC and ABC)
General considerations
The aim of follow-up after BC treatment is to detect local
recurrences or

contralateral BC and to evaluate therapy-related complications
[100].
https://clinicaltrials.gov/ct2/show/NCT02163694?term=Breast+
cancer+AND+PARP+AND+BRCA&phase=2&rank=2
https://clinicaltrials.gov/ct2/show/NCT02163694?term=Breast+
cancer+AND+PARP+AND+BRCA&phase=2&rank=2
In women treated for sporadic BC by BCS and adjuvant therapy,
the risk of
ipsi- or contralateral recurrence after 10 years is low (at about
less then 5 %)
[101].
For women diagnosed at the age of 40 years or less, the risk of a
local
recurrence at 5 years is equal to 10 %, and there is currently no
evidence
supporting any differences in follow-up examinations or
imaging based on
patient age alone [3, 4].
Because the risk of ipsi- or contralateral relapse is constant over
time, at least
for the first 14 years after primary treatment, routine long-term
follow-up is
recommended [102].
Conventional breast imaging
In terms of imaging, annual mammography followed by bilateral
breast ultra-
sound, depending on breast density and/or presence of post-
surgical and post-

radiotherapy changes, represents the standard of care in patients
treated for
sporadic BC [3, 4].
Ultrasound could represent the first imaging modality, after
clinical examina-
tion, in patients treated by mastectomy (level of evidence (LOE)
4 and 5) [3, 103].
Ultrasound of the axillary and supraclavicular region is useful
in identifying
nodal recurrence, both in symptomatic and asymptomatic
patients.
Breast MRI
As in older patients, there is not enough evidence to support the
routine use of
MRI in following up young patients treated for sporadic BC.
MRI may be useful if conventional imaging results are
inconclusive for the
differential diagnosis between scar and recurrence, where a
needle biopsy
cannot be performed [3, 4]. If conventional imaging shows a
high likelihood of
recurrence and a needle biopsy can be performed, MRI should
not be used as an
alternative to needle biopsy [5].
MRI imaging should be the first choice in monitoring patients at
high
genetic-familial risk and previously treated BC [3, 4].
MRI has been shown to provide better monitoring of
neoadjuvant CT
(NAC) response than clinical breast examination (CBE) and/or

conventional
breast imaging. It should preferably be performed 2 weeks after
the last NAC
cycle and within 2 weeks before surgery.
Measurements of residual disease after NAC must be performed
according to
RECIST or WHO criteria. Multifocal or multicentric disease
should be evaluated
by summing the largest diameter of the visible tumors [5].
MRI evaluation is not recommended as routine surveillance for
patients
treated for BC with implant prostheses. In asymptomatic
patients, dynamic
contrast-enhanced MRI is recommended only in higher risk
groups that would
qualify for MRI screening. In symptomatic women, non-contrast
and dynamic
contrast-enhanced MRI is indicated when conventional imaging
is negative or
equivocal [5].
Imaging follow-up (other than breast) in patients treated for BC
An annual gynecological examination with cytology and an
endovaginal ultra-
sound are recommended for all patients on tamoxifen (LOE 5).
For patients on
hormone therapy, regular bone density evaluation is indicated:
annually for
patients on AIs and every 2 years for patients on tamoxifen (or

annually for
those with osteoporosis or osteopenia).
Fertility preservation plus pregnancy after BC diagnosis
and treatment
Major concerns in young BC patients who plan to have children
in the future are
treatment-induced premature menopause and accompanying
infertility [104].
Oncofertility is a new discipline born from the junction of
reproductive med-
icine and oncology and stresses the attention that should be
given to child-
bearing desires and preservation options for every BC patient
when her thera-
peutic plan is designed; whenever possible, the patient should
be referred to a
specialized reproductive unit [105–107].
Impact of cancer treatments in gonadal function
Systemic treatments may hasten the quality deterioration
oocytes naturally
suffer during a woman’s fertile lifespan [108].
The total effect of CT on the gonadal function depends on
several factors,
namely the chemotherapeutic agent, the total dose, the dose
intensity, the
treatment duration, the patient’s age, and, of course, the
woman’s innate
ovarian reserve (the latter two being the most important) [109].
The incidence
of treatment-related premature ovarian failure rises with age,
being in the range
of 6–20 % in patients under 31 years, 22–61 % in patients

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