The Breast 48S1 (2019) S103–S109

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The Breast
j o u r n a l h o m e p a g e : w w w. j o u r n a l s . e l s e v i e r . c o m / t h e - b re a s t

Breast cancer survivorship care beyond local and systemic therapy

Jennifer Y. Sheng, Kala Visvanathan, Elissa Thorner and Antonio C. Wolff*,†
The Johns Hopkins University School of Medicine, The Johns Hopkins Bloomberg School of Public Health, and The Johns Hopkins Sidney Kimmel Comprehensive Cancer Center,
Baltimore, MD, USA

K E Y W O R D S A B S T R A C T

Breast cancer Despite persistent inequities in access to care and treatments, advances in combined modality care have led to a
Survivorship steady improvement in outcomes for breast cancer patients across the globe. When estimating the magnitude of
Therapy clinical benefit of therapies, providers and patients must contend with a multitude of factors that impact
Toxicity treatment decisions and can have long-term effects on quality of life and survival. These include commonly
Access to care described early toxicities, like aromatase inhibitor-associated musculoskeletal syndrome and neuropathy. But
longer-term comorbidities often observed among cancer survivors including weight gain, obesity, infertility,
psychological distress, sexual dysfunction, second cancers, bone loss, and body image issues can have lasting
effects on quality of life. Equally important, system-level factors such as access to care and resource allocation
can have a systemic impact on survival and on the quality of survivorship. Financial toxicity including
underemployment can have a lasting impact on patients and caregivers. The resulting disparities in access to
treatment can help explain much of the observed variability in outcomes, even within high-income countries
like the US. This article revisits some of secondary effects from therapies discussed in a prior 2015 review article,
along with other impediments to the optimal delivery of breast cancer care that can affect patients anywhere.
© 2019 Elsevier Ltd. All rights reserved.

Introduction As overall cancer burden broadens and treatment options advance,

The global burden of cancer is growing with 18.1 million new cancer
cases and 9.6 million cancer deaths expected in 2018 [1]. And despite
improvements in survival outcomes for most cancers [2], patients in
pocket areas within high income countries and in widespread areas
in low income countries are at risk for poor care due to inadequate
availability and distribution of resources. Each year, more than 2
million women worldwide are diagnosed with breast or cervical
cancer, and where a woman lives and her socioeconomic status have a
disproportionate impact on her chances of survival [3]. While
adjuvant chemotherapy for breast cancer has significantly improved
the outcomes of patients in developed countries, fragmented health
systems contribute to poor survival outcomes observed in regions
with scarce resources [4]. For instance, biomarkers such as hormone
receptor status or access and standard routine pathology expertise
are essential to stratify care needed and are imperative across all
health systems, even before new and more costly molecular assays are
considered [5–7].
the growing numbers of survivors led us to expand our efforts, and
focus not only on disease biology and therapy efficacy but also on
issues of therapeutic effectiveness, quality of life, cost of care, and
access. ASCO’s 2015 guidance statement on a conceptual framework,
which was developed to assess the value of cancer treatment
options and guide physicians and patients towards shared decision,
encourages us to consider issues such as high-quality evidence,
measures of clinical benefit and toxicity, palliation of symptoms
including treatment breaks, how to communicate absolute benefits,
and cost of therapy [8]. Care can be optimally delivered once we have
a better understanding of the factors that drive cancer care costs, can
assess the effectiveness of oncology therapies and diagnostics, and
allow improved patient-physician communication for optimal
exchange of information [9]. In this article, we review factors that
impact cancer survivorship both at an individual and at a societal
level.
Updates on standardized late effects from adjuvant chemotherapy

In a previous review article, we reviewed acute and chronic issues,

including fatigue, alopecia, musculoskeletal pain, chemotherapy-
*Corresponding author at: 201 N Broadway, Viragh 10-289, Baltimore, MD 21287, USA. induced peripheral neuropathy, neurocognitive dysfunction, cardio-
Tel: +1-410-614-4192; fax: +1-410-614-9421.
† myopathy, neurocognitive dysfunction, psychosocial impacts, second
E-mail address: awolff@jhmi.edu (A. C. Wolff).
This article was published as part of a supplement sponsored by St. Gallen Oncology cancers, early menopause, and infertility [10]. Here, we reassess some
Conferences. of them and summarize a few important new findings.

0960-9776 / © 2019 Elsevier Ltd. All rights reserved.

S104 J.Y. Sheng et al. / The Breast 48S1 (2019) S103–S109
Infertility
As the prognosis of breast cancer in women of reproductive age
improves, concerns about fertility greatly affect treatment decisions
and quality of life [11]. As opportunities for survival improve, we
must ensure discussions about fertility occur so that we can effectively
counsel younger patients [12,13]. The updated 2018 ASCO guidelines on
fertility preservation note that sperm, oocyte, and embryo cryopreser-
vation are considered standard practice [14]. Gonadotropin releasing
hormone (GnRH) agonists may be offered with the primary goal of
reducing the risk of chemotherapy-induced ovarian insufficiency, but
not as a replacement for established fertility preservation methods.
Emerging assisted reproductive techniques include in vitro maturation,
ovarian tissue collection and ovarian tissue cryopreservation [15]. But, a
recent survey of oncologists including attendees of the 2017 St Gallen
Breast Conference showed that many practitioners still offered
recommendations that were not guideline concordant [16].
Treatment associated myeloid neoplasms
It is now accepted that the risk of therapy-related marrow neoplasm
(including myelodysplastic syndrome) is at least twice than previ-
ously reported, especially after exposure to anthracyclines [17, 18],
and rates in some series are as high as 1.8% after 5–10 years of follow-
up [19–21]. Survival is poor after these events with only 9% still alive
after 10 years [19].While oncologists are increasingly aware of these
risks and of the need for upfront counseling, questions remain about
the baseline risk observed in carriers of germline mutations in DNA
repair genes. But a more thoughtful and selective approach towards
the use of anthracyclines may reduce the frequency of these
complications.
New insights on survivorship
As access to care improve and treatment options increase, so do the
growing list of factors that could influence the quality of survivorship.
Many are interconnected, affect individual patients and their
Fig. 1. Taxonomy of Cancer Care. Inspired by the paper by Tran et al, Taxonomy of the burden of treatment, a multi-country web-based qualitative study of patients with chronic con-
ditions. BMC Med 2015 PMID 25971838.
caregivers, and can be the intended and unintended result of policy
decisions. Therefore, it is critical to first understand them so as to
effectively intervene (see Figure 1).
Obesity
Obesity is one of the most prevalent health problems worldwide [22–
25] and a major risk factor for many cancers including postmeno-
pausal breast cancer [26]. Among breast cancer survivors, obesity is
also associated with worse quality of life, a higher risk of adverse
treatment effects including self-esteem [27], sexuality [27, 28],
neuropathy [29–31], lymphedema [32], chronic fatigue [33, 34],
and worse survival. Chemotherapy-associated weight gain is experi-
enced by most patients in the year after diagnosis [35, 36], and while
efforts at weight management directed at lifestyle changes through
caloric restriction and increased physical activity are effective they are
often not sustainable [37–41]. Exercise interventions alone may not
help [42], so trials like the Breast Cancer Weight Loss study
(NCT02750826) are investigating the combined effects of physical
activity as part of a telephone-based weight loss program interven-
tion on long term survival among women with a BMI ≥27 kg/m2
diagnosed with stage 2 and 3, HER-2 negative breast cancer [43].
Equally important, scalable and sustainable weight loss strategies for
broad implementation are needed.
Sleep and mood disorders
Sleep and mood disorders are highly prevalent, but under recognized.
Rates of sleep disturbance in cancer survivors can be two to three
times higher than in the general population [44]. Early recognition is
key and new effective delivery strategies including internet-delivered
[45] and group-based cognitive behavioral therapy (CBT) have been
reported [46], along with other methods such as Tai Chi Chi [47].
Mental health illness, such as mood and psycho-affective disorders
often go undetected after a cancer diagnosis and may be associated
with increased all-cause mortality if not properly addressed [48, 49].
Predictors of psychological distress (anxiety or mood disorders) in
 SGIBCC Proceedings Supplement / The Breast 48S1 (2019) S103–S109
women with newly diagnosed breast cancer include young age,
axillary surgery, underlying connective tissue disorders, and appear
to be more common among patients who report increased meno-
pausal symptoms, have greater need for stronger pain medication,
and have more acute care interactions with the health system during
follow-up [50]. These associated factors may help increase awareness
and improve recognition of patients who might benefit from timely
referrals for appropriate care.
Sexual function and body image
Sexual dysfunction after a cancer diagnosis and treatment is common
and often compounded by anxiety, fear, and preexisting issues [51]. A
decline in sexual function has been reported regardless of the type of
breast surgery [52] and is particularly prevalent in resource limited
settings [53]. Recent studies exploring varying approaches to
treatment of sexual dysfunction and body image seem promising.
As one example, a four session couple-based intimacy enhancement
telephone intervention demonstrated feasibility, acceptability, and
promise in addressing breast cancer survivors’ sexual concerns and
enhancing their and their partners’ intimate relationships and
psychosocial well-being [54] An online single session writing
exercise may help reduce body image distress and enhance body
appreciation [55], and therapeutic effects on body appreciation were
maintained for three months. Additionally, internet-based CBT with
weekly therapist guided sessions for up to 24 weeks benefits sexual
functioning, body image, and menopausal symptoms in survivors
with sexual dysfunction [56], which suggests the potential for non-
pharmacologic treatment approaches for sexual dysfunction and
poor body image.
Musculoskeletal syndromes
Aromatase inhibitors (AIs) are integral to endocrine therapy in
postmenopausal women with hormone receptor positive (HR+)
breast cancer [57]. However, over 30% of women receiving an AI as
adjuvant therapy stop it or are non-adherent due to toxicity [58–61].
Retrospective analyses reported that half of women on an AI develop
musculoskeletal toxicity, often early on [62–66], which in some cases
can severely impact quality of life [67, 68], adherence, and efficacy
[69]. Ultimately, about 25% of patients discontinue adjuvant AIs
within two years [58], and nonsteroidal anti-inflammatory drugs
offer limited relief [70]. More management strategies are now
available, including pharmacotherapy, acupuncture, dietary supple-
mentation and physical activity. For instance, a 12-week course of the
serotonin norepinephrine reuptake inhibitor duloxetine improved
average and worst joint pain, joint stiffness, pain interference, and
functioning compared with placebo [71]. Acupuncture also resulted
in a significant reduction in joint pain after six weeks of twice weekly
sessions compared to sham acupuncture or waitlist control [72].
Studies of oral supplements have by in large been negative [73].
However, exercise is a safe alternative and an adjunct in the
management of moderate to severe musculoskeletal symptoms,
and a 6-week, self-directed walking program of more than 150
minutes per week yielded significantly increased the number of
minutes walked per week, reduced stiffness and improved the
performance of activities of daily living [74]. For acute management,
loratadine can help prevent bone pain in patients receiving
chemotherapy and pegfilgrastim [75].
Bone health
Bone loss, including osteoporosis, is consistently reported among
older breast cancer survivors [76]. Risk factors include chemother-
apy-induced premature menopause and use of GnRH analogues and
S105
AIs, in addition to other prevalent risk factors like age, prior fracture
history, and family history. A recent study demonstrates that breast
cancer survivors age 50 and younger are at higher risk for osteopenia
and osteoporosis compared to cancer-free women [77], and this is
particularly important as the treatment of AIs plus ovarian suppres-
sion expands among younger women.
Complementary, alternative, and integrative medicine
Integrative health care is a term not universally accepted, but that
attempts to bring conventional and complementary approaches
together in a coordinated way. This encompasses a broad category of
interventions that includes dietary supplements (like vitamins,
minerals, botanicals, and other natural products) and mind-body
practices (like yoga, meditation, qi gong, acupuncture, and massage).
Estimates suggests that over 80% of patients with early stage breast
cancer employ one or more integrative approaches at any given time
[78, 79], with the purpose of symptom relief, wellness promotion, or
just to offer them a greater sense of hope and control [80]. In
response to this growing interest, in 2018, the American Society of
Clinical Oncology endorsed several integrative modalities including:
music therapy, meditation, stress management, and yoga for
anxiety/stress reduction; meditation, relaxation, yoga, massage,
and music therapy for depression/mood disorders; meditation and
yoga to improve quality of life; and acupressure and acupuncture for
reducing chemotherapy-induced nausea and vomiting [81].
Therefore, oncologists should recognize that the use across the
whole trajectory of breast cancer care is prevalent and should offer
their patients some guidance in the context of existing evidence. At
the same time, use of unapproved pharmacotherapy (including so-
called “natural products”) has been associated with delayed
initiation of adjuvant chemotherapy that in some cases could
prove deleterious [78, 82, 83].
Global cancer survivorship
Inadequate care due to limited resources and coverage
To improve survivorship outcomes, we must ensure appropriate
access to treatment worldwide. Many of the chronic issues described
above are a function of receiving appropriate care and surviving a
breast cancer diagnosis. While individual practitioners focus on the
patient at hand, societal and structural issues play an often not so
visible and critical role, sometimes even in high income countries,
leading clinicians to offer less-than-optimal care when diagnostic or
treatment resources are lacking or access to care is hampered by
cultural or economic issues (including inadequate insurance). In low
income countries, breast cancer mortality rates are substantially
higher and this is largely attributable to health system factors that
often result in late-stage presentation [84]. It is therefore important
to identify which resources might most effectively fill health care
needs in limited-resource regions and to provide guidance on how
new resource allocations should be made to maximize improvement
in outcome (See Table 1) [85].
Access to care in countries like the US
Individual financial struggles are still present in high income
countries and continue to be a major problem in low income
countries. In the US, cancer patients without insurance or covered by
Medicaid seem to experience inferior quality of care compared with
those with private insurance [86]. Federal response to expand care
with purchase of a new insurance category created by the US
Affordable Care Act (“Obamacare”) had the intended effect to
improve the quality of care for breast cancer patients who would
S106 J.Y. Sheng et al. / The Breast 48S1 (2019) S103–S109
Table 1
Breast cancer care resources for low, intermediate, and high income countries.
Low income countries
Detection Self-breast exam
Targeted outreach
Diagnostic ultrasound
Diagnosis Breast exam
Surgical biopsy, FNA
Pathology Interpretation of biopsy
Tumor size, lymph node status, histology, grade,
margins, ER/PR
Other workup Diagnostic breast ultrasound
Plain chest radiograph
Liver ultrasound
Cell blood count and chemistries
Stage I-III Modified radical mastectomy
locoregional Rx
Stage I-III Ovarian ablation, tamoxifen
adjuvant Rx CMF, AC, EC or FAC*
*AC, doxorubicin and cyclophosphamide; CMF, cyclophosphamide, methotrexate, and 5-fluorouracil; EC, epirubicin and cyclophosphamide; FAC, 5-fluorouracil, doxorubicin, and
cyclophosphamide; LH-RH, luteinizing hormone–releasing hormone.
Adapted from Anderson and Carlson (BHGI), JNCI 2007 PMID 17439758.
otherwise be uninsured or underinsured without purchasing
insurance [87]. Unfortunately, only about 40% of plans in the
federal exchange network allow access to NCI-designated cancer
centers and opportunities to participate in clinical trials [88].
Additionally, medically underserved individuals are often not
afforded the option to have access to germline counseling and
BRCA1 and BRCA2 mutation testing [89]. Even among Medicare
beneficiaries, test uptake in ovarian and breast cancer survivors was
low at just about 50% for those who met clinical criteria [90].
Reduced access to care due to financial toxicity
Providing high‐quality patient care should include communicating
treatment costs to patients, as the expense of therapy vary widely
across regimens and patients bear substantial out‐of‐pocket burden
[90]. Physicians should involve value-based care, which is defined as
services that improve health at a reasonable cost, and guideline-
concordant local therapy options [91]. For example, mastectomy plus
reconstruction can be associated with almost twice the risk of
complications and higher total cost as lumpectomy plus whole breast
irradiation [92]. Out-of-pocket costs for adjuvant therapy for
hormone sensitive breast cancer were significantly associated with
adherence and persistence to the therapy [93, 94]. Low-income
subsidy for the Medicare Part D (an optional United States federal-
government program to help Medicare beneficiaries in the US pay for
self-administered prescription drugs through prescription drug
insurance premiums) was associated with improved persistence on
hormonal therapy [95].
A Patient Decision Aid tool may help reduce costs by individu-
alizing aftercare based on an assessment of their preferences for
modality of conversations [96]. Significantly, patients using them
more often chose less intensive aftercare (telephonic or on-demand
consultations) over intensive (face-to-face consultations), leading to
a small reduction of hospital costs and a large increase in average
consultation time. Other decision aids have involved patient
ascertainment of breast cancer risk factors, a description of differing
guidelines, a comparison of mortality reduction and other out-
comes, and listing the factors most important to them [97].
Consideration of both patient and financial outcomes will be
important as health systems increase the emphasis on guideline‐
based care.
Intermediate income countries High income countries
Diagnostic mammography Mammographic screening
needle localization bx under Stereotactic biopsy
US guidance Sentinel node biopsy
On-site pathologist HER2 status
Bone scan CT scan
PET scan
Breast MRI
Breast conserving Rx Sentinel node biopsy
Breast RT Reconstructive surgery
Chest wall/regional RT
Taxanes Growth factors
Aromatase inhibitors Dose-dense chemo
LH-RH agonists Anti-HER2 therapy
Cancer in the workplace
Breast cancer or its treatment may adversely impact everyday
functioning, including employment. In North America and Europe,
return‐to‐work rates vary among breast cancer survivors, from 82% to
as low as 53% at 36 months after diagnosis [98, 99]. Rates in South
America were 60.4% at 24 months after diagnosis, which is similar to
the rates among low‐income Americans [100]. Higher income, breast‐
conserving surgery, endocrine therapy, and absence of depression are
factors associated with the likelihood of returning to work.
Returning to and maintaining employment after treatment may be
important, not only for social connection and financial support but
also for regaining a sense of normalcy and personal satisfaction [101].
At time of breast cancer diagnosis, a large proportion of patients
work. However, among patients treated with contemporary adjuvant
chemotherapy, persistent symptomatology was associated with
negative employment outcome [102], and figures worsened with
longer follow-up [101]. For instance, one study in Israel showed that
after 8 years of follow-up about 33% of those employed (median age
at diagnosis 56 and at time of survey 65) prior to their diagnosis
stopped working or retired, 48% downgraded to part-time, and only
19% had no change in their work situation. Breast cancer survivors
with characteristics pointing at underprivileged social circumstances
more often experienced changes in work status after surviving breast
cancer, irrespective of diagnosis, comorbidity or treatment. Thus,
breast cancer patients with immigrant status or lower educational
attainment require greater support to keep their jobs.
An international survey of 500 executives conducted by The
Economist Intelligence Unit identified several approaches employed
to strengthen support in the workplace for those affected by cancer,
like coaching, support groups, and case managers [103]. Employers
also need more training, support and resources to facilitate return to
work for employees [104]. A stronger global effort by payers and
policy makers is necessary to provide greater support to patients and
families [105].
Globally, metastatic breast cancer is associated with a substantial
economic burden. In the United States, these families incurred almost
40% higher indirect costs than families of patients with early stage
disease [106], and the national economic burden of metastatic
disease due to lost productivity in the US was almost $3 billion over 5
years. The majority of these patients are unable to continue with paid
 SGIBCC Proceedings Supplement / The Breast 48S1 (2019) S103–S109
employment, due to rigid work environments and lack of flexible
schedules or home-working options. One global survey found that
half of all patients with advanced disease who returned to work left
the job within one year [107].
Measuring financial toxicity
Nearly half of cancer survivors experience financial distress even
among those who are insured [108, 109]. Health insurance does not
eliminate financial distress or health disparities among cancer
patients [110]. Consumer credit may reflect financial hardship that
breast cancer patients face due to treatment, which in turn may
impact ability to manage health after cancer [111]. Better credit was
associated with over 7 times higher physical health score, and a
significant change in psychosocial stress. Other tools, such as the
COST (Comprehensive Score for financial Toxicity) measure, may be
reliable and valid measures of financial toxicity [112]. Stabilizing and
monitoring financial toxicity may be a potential intervention for
mitigating economic burden after breast cancer, and oncologists
should focus on delivering value-based care, encouraging discussions
about cost, and educating patients on costs of treatment [113].
Patients also need better understanding of the costs of treatments
(cost-related health literacy) to make shared decision about high-
value care.
Impacts of economic burden on morbidity and mortality
Cancer-related financial burden is also associated with greater
physical and mental health challenges (depressed mood and
frequency of fear of recurrence) and lower quality of life [114].
Cancer survivors’ risk of bankruptcy in the US is 2.65 times higher
than those with no cancer history [115]. Among patients with a
history of cancer, bankruptcy has been associated with a greater risk
of mortality [116]. Compared with guideline-concordant treatments,
non-concordant treatment can be seen in about one sixth of adults
≥65 with early stage breast cancer and is associated with higher costs
and rates of healthcare utilization [117]. Lastly, non-concordant
treatment can be seen in about a fifth of patients with de novo
metastatic breast cancer and is also associated with higher costs [118].
With the growing costs of cancer treatment, both patients and care
teams must address factors contributing to economic burden through
direct conversations about the cost and value of cancer treatment,
availability of and access to resources, and assessment of financial
toxicity as part of comprehensive cancer care [119].
Conclusions
As survival improves in breast cancer survivors, the risk for
treatment-related complications rises. Oncologists have a responsi-
bility towards their patients and the medical profession, but most
have had limited to no training on how to deal with the economic
aspects of modern cancer care delivery and on how to help patients
transition into long term survivorship and best coordinate care
among various specialists including primary care [120]. Improved
strategies are needed to facilitate shared decision marking and allow
for patient-centered care. Finally, as ethical and societal issues arise
regarding allocation of resources, we cancer specialists must engage
with policy makers to address structural issues and best advocate on
behalf of our patients.
Authorship
All authors have directly participated in the planning and data
collection. The first author wrote the first draft and all authors edited
and approved the final version submitted.
S107
Conflict of interest statement
The authors have no conflict of interest to disclose.
Acknowledgement of Support
Supported in part by National Cancer Institute CA006973 (institu-
tional grant) and by Susan G. Komen Scholar Grant SAC170001
(ACW).
Ethical Approval
This work did not require approval from an institutional review board
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