Breast Cancer Survivorship

Melissa Accordino, MD

Assistant Professor of Medicine

Herbert Irving Comprehensive Cancer Center

Columbia University Medical Center

Who are the Cancer Survivors?

• More than 1 in 3 Americans will be

diagnosed with cancer in their lifetime

• 15.5 million Americans have a personal

history of cancer; >4% of the US

population

• More than 28 million survivors worldwide

Cancer Survivorship Facts

• Prevalence will increase sharply during the next

25 years with aging of the population

• 60% of survivors are over the age of 65

• Breast, Prostate, and Colorectal are the 3 most

prevalent cancer sites

• Approximately 14% of survivors were diagnosed

20 years ago

Estimated and Projected # of Survivors

by Year Since Diagnosis in the US

Source: de Moor JS, et al. CEBP Annual Report 2013;22:561-570

Estimated Number of Survivors by

Cancer Site in the US (2012)

Source: de Moor JS, et al. CEBP Annual Report 2013;22:561-570

No Clear Consensus on Survivor Definition

Disease-free after

5 years

Not sure

How do you define a cancer survivor (n=144)

Disease-free after 2-3 years From the moment of

diagnosis and for the

balance of life

From diagnosis to

recurrence Following completion of

active treatment

Source: P De Fusco, et al. SABCS 2007, ASCO 2009

Definition of a Cancer Survivor

“From time of diagnosis, through the balance of his

or her life”

– NCCN

“Anyone with a history of cancer, from the time of

diagnosis and for the remainder of life, whether that

is days or decades.”

– National Coalition for Cancer Survivorship

What Has Led to our Success?

• Earlier detection

• Novel treatments

• Combined modality therapy

• Prolonged adjuvant and/or maintenance

therapies

• Prevention of second malignancies

For Many Patients, Cancer is now a

Chronic Disease…

The Effects of Cancer and Its

Treatment

• Physical and/or psychosocial Effects

• Long-term effects

• Late effects

• Range in severity

• Some improve over time, while others

progress or become permanent

Health Status Significantly Poorer in

Cancer Survivors

Excellent

Very Good

Good

Fair

Poor

Excellent

Very Good

Good

Fair

Poor

31% Fair & Poor 18% Fair & Poor

Cancer Survivors

(n=1,817) Non-cancer Controls

(n=1,817)

Source: Yabroff KR, et al. JNCI 2004;96:1322-30

Loss of Productivity Significantly

Poorer in Cancer Survivors

0

10

20

30

40

50

60

70

80

90

100

Held job in past12 months

Unable to workdue to health

problems

Limited in amountof work due to

health

Lost days fromwork in past 12months (mean)

% o

f patients

with lost pro

ductivity

Breast Cancer Survivors (n=301) Matched Controls (n=1,479)

*

*

* *

* p<0.02

Source: Yabroff KR, et al. JNCI 2004;96:1322-30

IOM Findings: Survivorship Care

• Survivorship care is a

neglected phase of the

cancer care trajectory

• Recurrence, second cancers,

and treatment late effects

concern survivors

• Few guidelines on follow-up

care

• Providers lack education and

training

IOM Findings: Survivorship Care

• Survivors may:

• Be unaware of risk

• Have no plan for follow-up

• Opportunities to intervene

may be missed

• Care is often not coordinated

• Models of survivorship care

not tested

Why is Cancer Different from other

Chronic Diseases?

Cancer treatment is…

Complex

Multi-modal

Multi-disciplinary

Toxic

Expensive

Often poorly coordinated

Cancer treatment usually occurs in isolation from

primary health care delivery

Other Challenges

• Limited systematic study of the late effects of

cancer therapy

• Follow-up care plans have been ad hoc, with

focus on surveillance for recurrence

• When should health promotion and chronic

disease prevention become the focus?

• Infertility?

What is Needed to Implement the

Survivorship Care Plan?

• Acceptance of cancer as a chronic disease – following

an initial period of extraordinarily complex therapy

• Staff support for time required to prepare and

communicate the plan

• Expand the evidence-base of knowledge re: late

effects, follow-up needs, and survivorship care

• Train all health professions in the needs of the

growing number of cancer survivors – how to act on

the care plan recommendations

Survivorship Care Plans: A model for

Integration of QOL & QOC

Quality of Life

Quality of Care

Breast Cancer as a Model for Study of

Late & Long-term Effects

• Most common cancer in women

• Occurs across the lifespan

• Complex treatments, high rates of cure

• Treatment affects menopausal status and

endocrine milieu of the woman

• Potential for substantial impact on physical and

emotional health

Surveillance Testing after Breast Cancer

• Breast cancer adjuvant clinical trials abandoned routine

monitoring with chest, liver, and bone imaging in the

1990s – recurrence detection rare before clinical

symptoms

• Two randomized trials conducted in the 1990s did not find

a difference in survival outcomes in women who had

routine clinical visits and mammograms compared to

women with more intensive surveillance including blood

work, chest films, scans, and ultrasounds

Sources: ASCO Guidelines 2006, 2013

Rojas et al. Cohrane Review 2005

Tumor Marker Surveillance after

Breast Cancer

• No RCT data to support use of tumor markers for breast

cancer monitoring (CEA, CA 15-3, CA 27.29) for effect on

survival outcome, i.e. that detection of recurrence earlier

makes a difference

• The rate of false negative or false findings for these

markers are not known

• Normal or abnormal tumor marker results can contribute

to false reassurance and/or increased anxiety for patients,

as well as unnecessary medical evaluations

Source: Schnipper LE, et al. JCO 2012;30:1715-24

Surveillance Testing Utilization Women with early stage breast cancer diagnosed 2001-2009 (n=258)

at an academic medical center

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

% of sample who received at least one % for pure surveillance testing

Source: Han EE, et al. Cancer 2013;15:4316-24

Surveillance Testing Utilization Women ≥65 with locoregional breast cancer diagnosed 2001-2007

(n=39,650) using SEER-Medicare

Tumor Marker Use

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Months 3-12after

Diagnosis

Months 13-24 after

diagnosis

35% 28%

% In

cre

ase

d C

osts

of C

are

*

Costs of Care Increased in

Patients who had TMs

*

* p<0.001

Source: Ramsey SD, et al. JCO 2015;32:149-55

Common Survivorship Care Concerns

• Pain

• Fatigue

• Depression

• Physical limitations

• Cognitive changes

• Lymphedema

• Sexual dysfunction

• Menopause related symptoms

• Body Image / Weight Gain

• Secondary cancers

• Late effects of therapy

• Osteoporosis, cardiac, infertility

Cancer-related Fatigue

• Most common side effect of cancer and its treatment

• Occurs in 60-96% of patients during treatment (Wagner &

Cella, 2004)

• Fatigue may persist for months or years after successful

treatment completion

• 30% of breast cancer survivors report fatigue 1-5 years

post-diagnosis (Bower et al.;2000)

• 63% of fatigued survivors continue to report fatigue 5-10

years post-diagnosis (Bower et al., 2006)

Cancer-related Fatigue

• Different than “normal” fatigue due to lack of sleep or over-

exertion

• More pervasive, debilitating, longer-lasting

• Involves physical, mental, and emotional components

• Not relieved by adequate sleep or rest

• Fatigue occurs across different types of cancer and different

types of cancer treatment

• Mechanisms underlying cancer-related fatigue have not

been determined

What Causes Fatigue?

Comorbid

medical

conditions

•Cardiovascular

disease

•BMI

Comorbid

symptoms

•Pain

•Menopausal sx

•Sleep disturbance

Fatigue

Biological factors

•Anemia

•Inflammation

Demographic

factors

•Age

•Income

•Marital status

Psychosocial

factors

•Depression

•Catastrophizing

coping style

Health

behaviors

•Physical activity

Cognitive Complaints

• Self-reported complaints don’t always match performance

on neurophysiological (NP) testing

• Tests of memory, attention, reasoning, visual-spatial abilities

• Some studies document impairment on NP tests in cancer

patients that pre-exist cancer treatment

• 20-30% of breast cancer patients

• Biology of cancer (e.g. inflammation related)?

• Common risk factors for both cancer and cognitive impairment (e.g.

poor DNA repair mechanisms?)

• True incidence of cognitive decline is uncertain

• Estimates range from 15-25%; some percentages as high as 61%

Risk Factors

• Age

• Cognitive reserve or

vulnerability

• Age and medication

• Genetic predisposition/

vulnerability to

chemotherapy or

cognitive impairment:

• APOE, COMPT

• Poor DNA repair

• Menopause

• Hormone therapy

• Anxiety/Depression

• Supportive Care meds

• Comorbid medical

conditions

• Surgery and anesthesia

• Sleep disturbance

Candidate Mechanisms for Cognitive

and Brain Changes

Blood-brain

barrier integrity

Changes in cognition, and

brain structure and function

DNA damage

and telomere

length

Cytokine

deregulation

Estrogen or

testosterone

reduction

Genetic

susceptibility

Source: Ahles and Saykin Nature Reviews Cancer 2007;7:192-201

The Effect of Modafinil on Cognitive

Function in Breast Cancer Survivors

Open label cancer survivors >30 days post chemo and/or RT with fatigue

(n=76) those with improvement after 4 weeks (n=68) randomized to

Modafinil vs. Placebo x 4 weeks

Open label portion significant effect on:

• Speed of memory (p=0.007)

• Quality of episodic memory (p<0.0001)

After randomization, relative to placebo, improvement

of:

• Speed of memory (p=0.03)

• Quality of episodic memory (p=0.02)

• Mean continuity of attention (p=0.02)

Source: Kohil S, et al. Cancer 2009;115:2605-16

Patient Factors and Interaction with

Treatment & Survivorship Outcomes

• Effects of tobacco use on drug metabolism and treatment

efficacy

• Weight and weight gain and its effect on treatment efficacy,

comorbid conditions, and survivorship outcomes

• Physical activity influence on survival and other outcomes

• Concomitant medications and their effects on outcomes,

e.g. metformin, aspirin, statins

• Comorbid conditions, e.g., hypertension or DM, and their

effect on outcomes

Obesity at Diagnosis Associated with Inferior

Outcomes in HR+ Breast Cancer (E1199)

N=4,770 node positive & high risk node negative Br CA patients who

received AC, taxanes, and hormonal treatment. Median age 49, 37% obese

DFS for obesity (HR positive/HER-2 negative/unknown

Multivariable analysis HR 1.24 p=0.008

Source: Sparano JA, Cancer 2012;118:5937-46

Obesity at Diagnosis Associated with Inferior

Outcomes in HR+ Breast Cancer (E1199)

N=4,770 node positive & high risk node negative Br CA patients who

received AC, taxanes, and hormonal treatment. Median age 49, 37% obese

OS for obesity (HR positive/HER-2 negative/unknown

Multivariable analysis HR 1.37 p=0.002

Source: Sparano JA, Cancer 2012;118:5937-46

Lifestyle Modifications & Br CA Prognosis

• Observational studies suggest:

• Higher physical activity may improve survival

• High fruit/veg and low fat diet may improve

survival

• Higher BMI is associated with poorer outcomes

• Clinical trials suggest:

• High fruit/veg and low fat diet may improve

survival in ER- Br CA (WINS)

• Potential mechanisms include insulin-IGF-1 axis,

inflammatory pathways, and hormonal pathways

Chlebowski JCO 2002, Holmes JAMA 2005, Pierce JCO 2007, Chlebowski JNCI 2006

Physical Activity & Mortality After BC Diagnosis

Nurses’ Health Study (n=2,987)

MET-hrs/wk RR (95% CI)*

<3 Ref

3-8.9 0.71 (0.56-0.89)

9-14.9 0.59 (0.41-0.84)

15-23.9 0.56 (0.41-0.77)

24+ 0.65 (0.48-0.88)

*Adjusted for age, time since

diagnosis, smoking, BMI,

menopausal status, HRT use, age at

1st birth, parity, OC use, energy

intake, stage, treatment

Source: Holmes MD, et al. JAMA 2005;293:2479-86

Diet, Physical Activity and Survival Women’s Healthy Eating and Living (WHEL) Study (n=1,490)

Source: Pierce JP, et al. JCO 2007;25:2345-51

Women’s Intervention Nutrition Study (WINS) (n=2,437)

Chlebowski JNCI 2006

ER+ subjects

ER- subjects

Insulin and Breast Cancer Prognosis

0

0.5

1

1.5

2

2.5

3

3.5

< 27 27-35.3 35.3-51.9 > 51.9

HR

Distant Recurrence p=0.007

Insulin Quartiles (pmol/L)

Death p=0.001

Source: Goodwin PJ, et al. JCO 2002;20:42-51

SUMMARY

• Increasing number of cancer survivors

• Breast, Prostate, and Colon = 50%

• Successes in outcome have come at a cost:

• Financial

• Physical

• Functional

• Psychological

• Much research to be done!

THANK YOU