Cancer Risk Assessment - bentonfranklincms.com
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Cancer Risk
Assessment
REBECCA JOHNSON, MD
MARCH 4, 2016
Objectives
Review current recommendations for cancer
screening for average risk patients by age
Identify high risk patients who are candidates for
cancer risk assessment with a genetic counselor
Discuss
screening tests available for that
assessment
Objectives
Cancer screening for average risk patients
Identifying patients at high risk for cancer
Role
of PCPs in cancer screening
Cancer
predisposition syndromes: identifying high
risk patients
Screening
Genetic
for high risk patients in your clinic
referral/testing
Cancer in the US
Second leading cause of death
Lifetime risk: 1 in 3 for men,1 in 2 for women
Decreasing mortality since early 1990’s
Down 22.9% in men and 15.3% in women) Mostly among common cancers (lung, breast,
colorectal and prostate)
Due to better therapies, reduction in smoking, and cancer screening
In the last four decades, the number of cancer survivors has quadrupled; now >12
million
> 30% of cancer deaths could be prevented by modifying risk factors alone
e.g modifying obesity, physical activity; vaccinations, antibiotics for H. Pylori, tamoxifen
and other preventive meds
At least half of all new cancer cases can be prevented or detected earlier by
screening
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.
Cancer screening for average risk patients
Death from cancer is the leading cause of death before the age of 85 years and
the leading cause of premature mortality
A person dying from cancer loses on average15.5 years of life— 25% more than
with heart disease (11.7 years).
5 cancers breast, cervix, colon and rectum, lung, and prostate account for
>50% of all new cancer diagnoses
47% and 40% of the cancer deaths in men and women, respectively
PCP recommendation is the most important predictor of whether or not a patient
has a cancer screening test done
We will review screening recommendations for:
Breast
Cervical
Colorectal (CRC)
Lung
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.
Cancer screening- considerations at the
population level
• Important public health problem
• Detectable preclinical phase of disease
• Treatment benefit to early detection
• Data-driven consensus strategy for
• age to begin screening, screening
interval
• Accurate, safe
• Relatively easy to administer and
inexpensive
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in
Primary Care. Lippincott, Williams and Wilkins.
Breast Cancer Screening
Not a single disease- wide variation in tumor growth and spread
Treatment based on risk of recurrence; avoid overtreatment
Screening most beneficial for slow growing cancers
Aggressive cancers
May grow quickly
More common in young women
A negative mammogram should not deter full workup
in a patient with a new lump
Benefit of early diagnosis of premalignant lesions is unclear
less aggressive approaches need to be studied
Mammogram every other yearlikely to have the greatest screening benefits
Harmony with European guidelines
3% increase locally advanced cancers (NS)
Chance of biopsy in 10 year period decreased from 61% to 42%
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.
Screening for Gynecologic Malignancies
Of gynecologic malignancies, only cervical cancer has an evidence-based early detection
screening program that has led to reduced incidence
90% of HPV does not progress to precancerous state
Of cervical intraepithelial neoplasia grade 3 (CIN 3) lesions:
20% progress to invasive carcinoma within 5 years, 40% within 30 years
Cervical cancer screening
Liquid cytology=conventional cytology sensitivity for detecting CIN3- highest incidence in women
aged 25-29
Start screening at 21 y.o., stop at age 65
3 year interval if cytology alone used; 5 years if cytology+oncogenic HPV contesting (3X increase in
cost; 4X false negative rate)
HPV vaccination may decrease abnormal cytology screens and need for
colposcopy/excisional procedures
Gardasil protection for > 5 years HPV-6 and -11, the major causes of genital warts
Cervarix protection for > 9.4 years against seven oncogenic cervical and 5 vulvar/vaginal HPV
types; 100% effective in one dose
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.
US Cervical Cancer Screening Guidelines
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.
CRC Screening Recommendations
Have an office screening policy that has at least two options for
patients— colonoscopy and a sensitive fecal occult blood test/ fecal
immunochemical test (FOBT/ FIT)
FIT preferable: unaffected by diet or meds
Clearly recommend screening for all eligible patients
Use office systems and technology to track screening results, identify
care gaps, and issue reminders
Develop an “open access” colonoscopy system with your
colonoscopist partners
Monitor practice-wide screening rates strive for 80%
Decreasing death rates largely due to screening
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.
CRC screening
Average-risk men and women aged 50+
Colonoscopy every 10 years or a sensitive stool blood test every year
Proven value: Annual FOBT 33% reduction in mortality
Colonoscopy <age 70, ~1/1000 have complications within 30 days, more if
polyps removed
Five key points to maintaining a high-quality screening program:
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.
CRC screening
Lung Cancer Screening
Do not screen for lung cancer with chest radiography
Screening with annual low-dose computed tomography
reduces mortality from lung cancer by 20%
Follow National Lung Screening Trial (NLST) screening protocol
Ideally, care from an experienced multidisciplinary team
PCPs should inform patients eligible for screening of the
benefits, limitations, and potential harms before screening is
initiated
All screening discussions should be accompanied by a
discussion of smoking cessation
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.
No
screening
Summary:
Screening and
Risk Reduction
Options for
Average Risk
Patients
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA
(2013). Oncology in Primary Care. Lippincott, Williams
and Wilkins.
Objectives
Cancer screening for average risk patients
Identifying patients at high risk for cancer
Role
of PCPs in cancer screening
Cancer
predisposition syndromes: identifying high
risk patients
Screening
Genetic
for high risk patients in your clinic
referral/testing
Role of Primary Care Provider (PCP) in
Cancer Prevention and Treatment
Risk Assessment
Take detailed family history
Know risk factors
Refer appropriately for genetic
counseling
Follow up with surveillance, risk
reduction recommendations
Use national screening
guidellines
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.
Inherited cancer predisposition
Goal: Identify people with elevated risk and then appropriately manage the risk
New cancer diagnoses
90% caused by de novo somatic mutations
10% due to inherited genetic traits
Cancer predisposition syndromes
Increased risk for cancer
Younger average age of onset
Cancer genetics screening
Identifies individuals at high risk of cancer
May help target therapies
Patients with a 5-10% chance of a genetic condition warrant genetic evaluation
Offer testing only if the results beneficially influence the medical management of the
patient and/or family members
Saletta F et al. (2015) Transl Pediatr 4:67-75
J Clin Oncol 1996; 14:1730-1736
Strahm B and Malkin D (2006) Int. J. Cancer 119: 2001–2006
Myths about
cancer
genetic
counseling
Psychological, insurance
concerns are less of a risk
than wrong genetic test
being ordered and/ or
results misinterpreted
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.
Most Cancer Susceptibility Genes Are Dominant With
Incomplete Penetrance
Normal
Susceptible Carrier
Carrier, affected
Ca
Sporadic Ca
•
Mutation present in all cells of the body, including germ cells
transmitted to offspring
•
Individuals inherit cancer susceptibility genes, NOT CANCER
•
Incomplete penetrance May appear to “skip” generations
•
Start by testing a family member with cancer
Potential pitfalls in family history assessment
Lack of awareness of cancer types associated with predisposition
syndromes
Importance of ancestry
Factors that can falsely lower risk assessment
Small
Little
family
knowledge of family history
Artificial
alteration of cancer risk (e.g., total hysterectomy at young
age, reducing risk for ovarian, uterine, and breast cancers)
Changes in family history over time- update at each visit!
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.
Physician barriers
to collecting/using family history data
Personal/family history data not collected nor used effectively in either
oncology primary care
Lack of time, reimbursement, and confidence
Clinical guidelines valuable but increasingly detailed, rapidly changing
50–90 % of patients with increased cancer risk are not recognized and are
potentially mismanaged
Two studies:
Only 19 % of PCPs consistently recognized patients appropriate for a genetics
evaluation for Hereditary Breast and Ovarian Cancer (HBOC) syndrome
Only 31 % of Canadian Oncologists appropriately referred their patients for (free)
genetic counseling
Baumgart LA et al. (2015) Familial Cancer
Cancer Risk Assessment:
PCP practice patterns
83%- take detailed family cancer history
33%- obtain three generation pedigree
8%- get details necessary for accurate risk assessment
Key questions: which family member, cancer type, age at diagnosis
Some clinicians can devote only 2 to 3 minutes to a family history
discussion
Most not confident in taking a detailed family history.
Consider screening for strong cancer histories by having all patients
complete a family history worksheet at each visit.
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.
PCPs and family risk assessment
Despite high levels of confidence in assessing breast cancer risk
48% incorrectly categorized a high-risk breast cancer scenario as low-risk breast cancer
19% identified all increased risk and no low-risk scenarios for BRCA1 and 2 testing
Use of genetic risk calculators is complicated
91% PCCs agree with national recommendations for pre-test genetic counseling but
one study showed that 30% of PCCs had ordered their own genetic testing in the
past year.
Genetic testing companies market directly to PCPs- and medical and legal liability
lies solely with the PCC.
Patients do not expect their PCCs genetics experts but want them to play a key role
in referring them for genetic services
PCPs should:
know the risk factors that increase hereditary cancer risk
ask these questions
refer patients who appear to be at increased risk to a qualified cancer genetic counselor
Referrals historically more likely if genetic counselor is within a 10 mile radius- remote
services now available
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.
Risk factors that warrant cancer genetics
counseling
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.
Genetic Testing: myths and facts
Oncology in Primary Care (2013) Rose MG et al. eds. Lippencott, Williams and Wilkins.
Genetic testing: myths and facts (2)
Objectives
Cancer screening for average risk patients
Identifying patients at high risk for cancer
Role
of PCPs in cancer screening
Cancer
predisposition syndromes: identifying high
risk patients
Screening
Genetic
for high risk patients in your clinic
referral/testing
Hereditary breast-ovarian cancer syndrome
Germline mutations in the BRCA1 or BRCA2 tumor suppressor gene
Autosomal dominant
Penetrance varies considerably between mutations
Increased risk:
Women- breast and ovarian cancer
Men- prostate cancer
Cumulative cancer risk by age 70 in females with:
BRCA1breast 65%, ovarian 39%
BRCA2 breast 45%, ovarian11%
Relative risk
BRCA1: highest at 30-39 years of age, ovarian cancer when older
BRCA2: relative risk for breast cancer does not vary with age.
Other rare loss-of-function variants confer moderate increased risk:
PALB2, ATM, BRIP1, CHEK2 and RAD51C, and the p53 inducible
protein phosphatase PPM1D in a mosaic form
Saletta F et al. (2015) Transl Pediatr 4:67-75
BRCA1-Associated Cancers: Lifetime Risk
Breast cancer 60%-80% (often early age at onset)
Second primary breast cancer 64%
Ovarian cancer 20%-40%
In men: Increased risk for prostate cancer
BRCA2-Associated Cancers: Lifetime Risk
breast cancer
(50%-80%)
male breast cancer
(7%)
contralateral breast
(50%)
ovarian cancer
(10-30%)
Prostate cancer
(10-20%)
pancreatic cancer (3%)
Genetic referral is indicated…
• …when there is >20% chance of finding a BRCA mutation
Asymptomatic patients
Cancer patients
Case Study: Ruth
Ruth, a 35 year old Ashkenazi Jewish woman, comes because she is anxious
about her family history of cancer. You inquire about family health history and find
out the following information:
– Family history :
•Paternal grandmother diagnosed with ovarian cancer at age 63
•Paternal aunt diagnosed with breast cancer age 42
Ruth has no other risk factors or pertinent family history
Case Study
- Ruth, a 35 year old Ashkenazi Jewish woman, presents because she is anxious
about her family history of cancer.
- Ruth has no other risk factors or pertinent family history
Polish Jewish
Russian Jewish
Dx 63
82 yrs
Dx 42
60
58
Key
64yrs
41
Ruth
35
38
-Ov Ca
-Br CA
Assessment
• Ruth is in “Moderate risk” category
•Ethnicity is important as she is of Ashkenazi Jewish descent
• Refer to genetics clinic
• Moderate risk screening for breast cancer arranged
• Genetic testing for 3 common ‘Jewish Mutations’
Identifying Patients at High Risk for
CRC
Hereditary non-polyposis colon cancer,
(Lynch syndrome)
Increased risk for early onset colorectal, stomach and
pancreatic cancer
2-4% of all colorectal cancers
Autosomal dominant, high penetrance
Germline mutations in DNA mismatch repair genes (such
as MLH1, MSH2, MSH6 and PMS2)
Age-specific cumulative risk varies with specific mutation
Defective mismatch repair microsatellite instability and
frame-shift mutations
Lifetime risk for colorectal cancer for mutation carriers:
38-100% (men)
24-54% (women)
Typical age of cancer onset is 40-50 yrs
Polyps may be present (onset in teens), multiple primaries
common
Saletta F et al. (2015) Transl Pediatr 4:67-75
HNPCC, lifetime cancer risks:
–
–
–
–
–
–
–
–
Colorectal
Endometrial
Gastric
Ovarian
Biliary tract
Urinary tract
Small bowel
Brain/CNS
80%
20-60%
13-19%
9-12%
2%
4%
1-4%
1-3%
High risk for CRC: who needs screening?
•
•
•
•
Patient or first degree relative with:
– CRC <50yrs
– 2 or more primary CRCs any age
– Colorectal cancer and a related cancer* any age.
2 first degree relatives with CRC or related cancer* at any age
3 relatives affected with CRC or related cancer* at any age, one of
which must be a first degree relative.
History of polyposis (e.g. Familial adenomatous Polyposis)
– *related cancers- endometrial, ovarian, small bowel, ureter,
renal pelvis and stomach
Familial Adenomatous Polyposis (FAP)
Caused by mutations in APC gene
Thousands of colon polyps
Early onset colon cancer
Hepatoblastoma- APC mutation in 15%
Desmoid tumors- APC mutation in 15%
MAP (MYH associated polyposis)
– Autosomal recessive
– Median number of polyps = 55
– Mean age of polyp diagnosis = 30-50 years
– Polyps mainly small, mildly dysplastic tubular adenomas
• 30% of individuals with 15-100 polyps have homozygous mutations in the
MYH gene
• Genetic testing should be offered if >10-15 polyps (and APC gene testing
negative)
Many possibilities
Other
Cancer
Predisposition
Syndromes
Rose MG, DeVita VT,
Lawrence TS, Rosenberg
SA (2013). Oncology in
Primary Care. Lippincott,
Williams and Wilkins.
Li-Fraumeni Syndrome
Associated Tumors:
Adrenocortical carcinoma
Sarcomas of soft tissue and bone
Brain tumors
Leukemia
Germ cell tumors, Melanoma
Breast cancer
- 42% risk of developing cancer by age 16
- Frameshift mutations worse than missense
D’Orazio JA (2010) J Pediatr Oncol 32: 195-228
Criteria for P53 testing:
Chompret’s Criteria:
Proband with tumor in LFS spectrum <age 46 AND at
least 1 first or second degree relative with LFS-type
tumor < age 56
Proband with multiple tumors <age 46
Adrenocortical carcinoma or choroid plexus
carcinoma at any age, irresepctive of family history
Eeles' definition of LFL:
Two first- or second- degree relatives with LFS-related
malignancies at any age
Cancer risk in P53 mutation carriers
Female carriers are at high risk for early breast
cancer
Avg. age of diagnosis 34 years
Screening should begin in early 20’s- MRI
Affected patient has 15% risk of developing a second
primary malignancy
Carriers need annual screening
Objectives
Cancer screening for average risk patients
Identifying patients at high risk for cancer
Role
of PCPs in cancer screening
Cancer
predisposition syndromes
Screening
Genetic
for high risk patients in your clinic
referral/testing
Considerations prior to testing
Careful family history and physical exam
Pretest Counseling- implications of testing for the patient and relatives
Written consent (documentation now usually from provider)
Consider predictive testing in children only when it will
immediately affect their clinical care
It takes time
Risk screening tools
in the primary care setting
Population-based cancer screening programs may cause harm (over-diagnosis, false positive)
Risk-stratified screening
May reduce harm and identify patients at higher risk
Used in many countries to assess cancer risk:
Breast
CRC
Cervical
Guide primary preventive measures or chemoprevention (breast, CRC)
Tools identify an individual’s risk of developing cancer, carrying a cancer predisposition
syndrome or both
Newer risk models incorporate genomic profiles and environmental, behavioral risk factors
Use in UK
Increased appropriate referrals
Led to improvements in diet and physical activity
Walker et al. (2015) Ann Fam Med 13: 480-489
Systematic review of cancer risk assessment tools
11 published randomized controlled trials (RCTs) using 7 tools
Use by patients was greater when:
Initiated by patients
Used by a dedicated clinician
Combined with decision support
Improved patient
Risk perception
Knowledge
Screening intentions, (not necessarily screening behavior)
No increase in cancer worry
Walker et al. (2015) Ann Fam Med 13: 480-489
Success of recruitment strategies
Low- Phone contact
High- (>93%) Approach by dedicated research
assistant or practice nurse in waiting room before
primary care appointment
When intervention was delivered by a practice nurse,
75% of patients completed a risk assessment
Only 12% of general practitioners attended training
Walker et al. (2015) Ann Fam Med 13: 480-489
Sample family cancer history checklist
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.
Health Heritage, a patient-facing tool for
personal and family history collection and
cancer risk assessment
Clinically validated tool to:
Identify patients appropriate for further genetic evaluation
Accurately stratify cancer risk
Instrument development
Retrospective chart review on 100 patients who presented to adult genetics
clinic with concern for an inherited predisposition to cancer
Relevant personal and family history collated, algorithm developed
Concordance between Health Heritage and :
National eligibility guidelines for genetic evaluation
Agreement was 97 % (sensitivity 98 % and specificity 88 %) overall
Risk stratification by geneticist: 90 , 93, and 75 % agreement for breast, ovarian and
colorectal cancer
Baumgart LA et al. (2015) Familial Cancer
Cancers and hereditary cancer
syndromes evaluated by Health Heritage
Breast cancer
Attenuated Familial
Adenomatous Polyposis (AFAP)
Colorectal cancer
Classic Familial Adenomatous
Polyposis (FAP)
Melanoma
Cowden syndrome
Ovarian cancer
Familial Atypical Multiple Mole
Melanoma syndrome (FAMMM)
Pancreatic cancer
Hereditary Breast and Ovarian
Cancer syndrome (HBOC)
Prostate cancer
Hereditary Diffuse Gastric Cancer
syndrome
Uterine cancer
Hereditary Pancreatitis
Juvenile Polyposis syndrome
Li-Fraumeni syndrome
Lynch syndrome
Peutz–Jeghers syndrome
Serrated Polyposis syndrome
Objectives
Cancer screening for average risk patients
Identifying patients at high risk for cancer
Role
of PCPs in cancer screening
Cancer
predisposition syndromes
Screening
Genetic
for high risk patients in your clinic
referral/testing
How to find a
genetic
counselor for
your patient
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA
(2013). Oncology in Primary Care. Lippincott,
Williams and Wilkins.
Sequencing Panels
Screens simultaneously for many potential cancer predisposition genes
Hereditary breast cancer genes: BRCA1/2, p53, CHEK2, PALB2, and PTEN, etc.
Colon cancer: MSH2, MLH1, MSH6, EpCAM, PMS2, MYH, APC, and SMAD4, etc.
Simplifies workup of cancers/traits seen in multiple cancer syndromes
Cancers: thyroid, sarcoma, pancreatic, adrenal cortical carcinoma
Noncancerous findings: autism, benign skin findings, speckled genitalia
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.
Gene Panels-
UW BROCA and ColoSeq
BROCA suspected hereditary cancer predisposition
Focus on syndromes that include breast or ovarian cancer; may co-occur with
other cancer types (such as colorectal, endometrial, pancreatic, endocrine, or
melanoma)
Next-generation sequencing for 51 (and counting) genes
Assay completely sequences all exons, non repeating introns, and select
promoter regions of these genes AND detects large deletions, duplications, and
mosaicism
Lab can also do single gene testing for any gene on the panel, as well as
BRCA1/2 founder mutation testing for Ashkenazi Jewish patients
ColoSeq suspected hereditary colon cancer syndrome
http://tests.labmed.washington.edu/BROCA accessed 2/28/16
Test results- potential gray areas
1. Deleterious mutation. Cancer risk for patient is within published range
test both parents— whenever possible
2. True negative
patient tests negative for the familial mutation, which segregates with the cancer family
history.
Risk = general population
3. Negative. Mutation not detected
4. Uninformative negative
Patient tests negative, but no mutation has been identified in the family.
Families with significant personal and family history may still be high risk
5. Variant of uncertain significance
Genetic change found, but unclear if deleterious or benign. Interpretation based on
personal and family history.
Don’t test unaffected family members for VUS
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.
When the test results come back…
Next steps for asymptomatic carrier and their PCP
Patient
Take time to consider options
Review information from genetic counselor on
Support options
Cancer risks
PCP
Consider referrals to psych, reproductive counseling, gynecology (if considering BSO)
Follow up (along with support person) in 4-6 weeks to discuss
Plan for the next year
Patient contacting family members who may be at risk
Periodic tumor surveillance (See NCCN guidelines) or consider referral
Rose MG, DeVita VT, Lawrence TS, Rosenberg SA (2013). Oncology in Primary Care. Lippincott, Williams and Wilkins.