Transcript Clinical Conundrums in Cancer Chemoprevention: What Should

Clinical Conundrums in Cancer
Chemoprevention: What Should
You Recommend to Your
Patients?
Susan Hingle, MD, FACP
Professor of Medicine
Division of General Internal Medicine
Interim Chair
SIU School of Medicine
Session Objectives
 Identify the cancers in which aspirin therapy may
play a role in prevention.
 Learn if aspirin therapy is indicated for cancer
prevention.
 Learn about data on use of 5-alpha reductase
therapy in prostate cancer prevention.
 Recognize the indications for SERMs and AIs in
breast cancer prevention.
Aspirin and Cancer
Chemoprevention
Will an aspirin a day keep the oncologist away?
What you should tell your patients about
aspirin use for cancer chemoprevention.
Case #1
A 52 year-old man with a past medical history of GERD and
hypertension on omeprazole and lisinopril presents to the
clinic for routine follow up. He read on an internet blog that
he should start taking a baby aspirin weekly to reduce his risk
of colon cancer. He asks for your input.
He had a screening colonoscopy at age 50 during which a
small (<0.5 cm) tubular adenoma was removed. Family
history is negative for colon cancer. On physical exam BP is
122/72. The remainder of his exam is normal.
What is your advice for this patient?
Aspirin and Cancer Chemoprevention
 Potential mechanisms of action:
 Induction of cell apoptosis
 Inhibition of cyclooxygenase-mediated PG production
 PGs are associated with:
 Tumor angiogenesis
 Cell proliferation
 Inhibition of immune surveillance & apoptosis
ASA Use and the Incidence of Cancer
 Colorectal cancer:
 Numerous studies suggest ASA may reduce risk of CR
adenomas and CR cancers (post hoc analyses):
 C. Dubé et al (2007):
 22% risk reduction in CRC incidence
 Physicians’ Health Study Research Group (1989) & Cook et al (2005):
 No reduction in CRC incidence at 10 years
 Rothwell et al (2010):
 Follow-up of above at 20 years showed decreased incidence of CRC
 Rothwell et al (2012):
 Analysis of 4 RCTs for ASA prevention of vascular disease, ASA therapy
reduced 20-year colon cancer risk, with reduction of colon cancer risk not
occurring until 8-10 year point
Special Populations
 Lynch syndrome:
 There is only one randomized placebo-controlled trial of aspirin
(CAPP2) in which colorectal cancer was a primary endpoint:
 NO benefit from aspirin (600 mg/day) in 937 patients with Lynch
syndrome (hereditary nonpolyposis colon cancer)
 Short study time (2-4 years)
 Different cancer mechanism for Lynch syndrome??
 Familial adenomatous polyposis (FAP):
 83 patients with FAP were randomly assigned to celecoxib (100
or 400 mg twice daily) or placebo
 After six months, patients receiving the higher dose had a
modest (15 percent) but statistically significant reduction in the
extent of duodenal polyposis as assessed in blinded reviews of
endoscopy videotapes.
ASA Use and the Incidence of Cancer
 Other cancers:
 Meta-analyses of numerous RCTs
 Daily aspirin therapy:
 Was associated with a reduction in all cancers (up to 12% relative risk
reduction)
 Benefit after 4 years, independent of age, gender, tobacco use history
 Reduction in female reproductive tract cancers, lymphoma, and sarcoma
 Long-term aspirin use may reduce cancer mortality
 Several ongoing trials to be completed between
now and 2019 may give us more information on
this subject
And Here Is the Bad News . . .
Adverse effects of aspirin:
 Increased risk of bleeding:
 GI bleeding
 Intracranial hemorrhage
 Other major bleeding
 Possible 50% increase in the RR of major non-fatal
extracranial bleeding
 Associated risk factors:
 Age, prior history of PUD
 Mitigators:
PPIs
Recommendations for the PCP
 Benefits of daily aspirin (75-100 mg) for cancer prevention
may outweigh the risks in select patients:
 Requires individualization and clinical judgment
 Age >50
 Patient with estimated high cancer risk (e.g., using colorectal and
breast cancer risk calculators) or with specific cancer syndromes
[Lynch syndrome, FAP (celecoxib)]
 No concomitant use of medications that increase bleeding risk
IMPORTANT: There are no official
guidelines that recommend aspirin therapy
for primary cancer prevention at this time
Back to Case #1
A 52 year-old man with a past medical history of GERD and
hypertension on omeprazole and lisinopril presents to the
clinic for routine follow up. He read on an internet blog that
he should start taking a baby aspirin weekly to reduce his risk
of colon cancer. He asks for your input.
He had a screening colonoscopy at age 50 which showed one
small (<0.5 cm) tubular adenoma. Family history is negative
for colon cancer. On physical exam BP is 122/72. The
remainder of his exam is normal.
What is your advice for this patient?
5-Alpha Reductase Inhibitors and
Prostate Cancer Prevention
5-alpha reductase inhibitors make the urine
flow and the hair grow, but . . .
Should primary care physicians prescribe
them for prostate cancer prevention?
Case #2
A 55-year-old man with hypertension, dyslipidemia, and
glaucoma presents for routine follow up to his PCP. He
voices no complaints at the visit and has a negative ROS.
Although he has no family history of it, he is concerned about
getting prostate cancer, as he had a colleague who was
recently diagnosed with it. VS and exam are normal.
He hands you an article on prostate cancer that he cut out of a
magazine and inquires whether he can take any medications
to reduce his risk of prostate cancer.
What is your advice for this patient?
Prostate Cancer
2nd most common cancer in men
Increasing incidence since PSA
screening initiated
Most cancers are clinically indolent
Early treatment not proven to improve
survival
Why Chemoprevention
 Long latency period
 Progression from PIN to invasive cancer takes many years
 Chemoprevention might delay progression to invasive cancer
 Androgen dependency
 Men with congenital 5-alpha reductase deficiency do not develop
prostate cancer
 Blocking androgens shown to affect PIN and prostate cancer
 Drugs are available that are antiandrogenic
5-Alpha Reductase Inhibitors
 Agents: finasteride & dutasteride
 Block conversion of testosterone to DHT
 Prostate Cancer Prevention Trial:
 1994-97 with reanalysis of data through 2011
 ~19K men at increased risk of prostate cancer
 Finasteride 5 mg daily versus placebo
 Decrease in incidence of prostate cancer in finasteride-treated group
 Increased risk of high-grade prostate cancer in finasteride-treated
group however
 10-year survival rate after prostate cancer diagnosis in finasteridetreated group was no different than placebo-treated group
5-Alpha Reductase Inhibitors
 REDUCE Trial
 ~8400 men at increased risk of prostate cancer
 Dutasteride 0.5 mg daily versus placebo
 Reduced incidence of prostate cancer in dutasteride-treated group
 Increased incidence of cases with Gleason score of 7 to10
 Author’s explanation: due to the drug’s ability to reduce the volume of the
prostate, which in turn improves the ability to identify high-grade tumors in
biopsy samples. They did not exclude the possibility, though, that the drug
could be responsible for some high-grade tumors.
REDUCE = Reduction by Dutasteride of Prostate Cancer Events
Summary:
Prostate Cancer Chemoprevention
 5-AR inhibitors appear reduce risk of prostate cancer
 Increased risk of high-grade cancer in the treated groups
 No conclusive data that these agents reduce risk of death or increase
survival
 Side effects may not be tolerable for most men (e.g., ED,
gynecomastia, decreased libido)
 No FDA approval to use either drug for prostate cancer prevention
 AUA: “Asymptomatic men with a prostate-specific antigen (PSA) ≤3.0
ng/mL who are regularly screened with PSA or are anticipating
undergoing annual PSA screening for early detection of prostate cancer
may benefit from a discussion of both the benefits of 5-ARIs for 7 years
for the prevention of prostate cancer and the potential risks (including
the possibility of high-grade prostate cancer). Men who are taking 5ARIs for benign conditions such as lower urinary tract [obstructive]
symptoms (LUTS) may benefit from a similar discussion, understanding
that the improvement of LUTS relief should be weighed with the
potential risks of high-grade prostate cancer from 5-ARIs (although the
majority of the Panel members judged the latter risk to be unlikely).”
Other Agents for Prostate Cancer
Chemoprevention
 Vitamin E and selenium:
 SELECT trial (selenium & vitamin E)
 Vitamin E increased incidence of prostate cancer
 Selenium and selenium + Vitamin E increased incidence of prostate cancer (not
statistically significant)
 Physician’s Health Study II
 Vitamin E (nor beta-carotene, ascorbic acid, or MVI) did not reduce incidence of
prostate cancer

NSAIDs:

Planned trial with rofecoxib was canceled when rofecoxib was pulled from
market
SELECT = Selenium and Vitamin E Cancer Prevention Trial
Back to Case #2
A 55-year-old man with hypertension, dyslipidemia, and
glaucoma presents for routine follow up to his PCP. He
voices no complaints at the visit and has a negative ROS.
Although he has no family history of it, he is concerned about
getting prostate cancer, as he had a colleague who was
recently diagnosed with it. VS and exam are normal.
He hands you an article on prostate cancer that he cut out of a
magazine and inquires whether he can take any medications
to reduce his risk of prostate cancer.
What is your advice for this patient?
SERMs and AIs in Breast Cancer
Chemoprevention
SERMs and AIs:
What are good for fighting cancer are
also good at preventing it, right?
Case #3
A 52-year old postmenopausal caucasian woman with no
significant past medical history comes for her annual exam.
She voices no concerns, and ROS is negative. Family
history is positive for breast cancer in her mother (diagnosed
at age 60). She had menarche at age 11, has never been
pregnant, and has never smoked. She has been getting
mammograms regularly since age 40. She had one breast
biopsy for a lesion seen on screening mammography at age
42, but the pathology was proliferative benign breast disease
without atypia.
Her VS and physical exam are normal. She is concerned
about getting breast cancer and wants to know if there is any
medical therapy that can reduce her risk.
What advice do you give this patient?
Breast Cancer
 Most common nonskin cancer in women
 ~232,000 women diagnosed with invasive breast cancer and
~40,000 died of breast cancer in 2013
 Risk factors:
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


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Age
Age at menarche
Race
Age at first childbirth
Family history (of breast OR ovarian cancer)
History of atypical hyperplasia
Previous breast biopsy
Dense breast tissue
 Risk assessment models are, in general, better at predicting
at-risk study populations rather than at-risk individual women
Selective Estrogen Receptor
Modulators (SERMs) Studies
 Agents: tamoxifen & raloxifene
 Randomized controlled trials have shown they reduce the risk for
ER-positive breast cancer
 Selection criteria:
 Age > 60
 Age > 35 with h/o LCIS, DCIS, or atypical ductal or lobular hyperplasia
 Women between 35 and 59 with ≥1.66% 5-year risk
 Reduced incidence by 7-9 events per 1000 postmenopausal
women over 5 years
 Tamoxifen reduced incidence more than raloxifene
 Tamoxifen also reduced incidence of invasive breast cancer in
premenopausal women
SERMs
 At-risk women were more likely to benefit from
chemoprevention:
 Highest benefit in women who had ≥ 3% 5-year risk
 e.g., NCI Breast Cancer Risk Assessment Tool (based on Gail model)
http://www.cancer.gov/bcrisktool/
 Not recommended for women with PMH of breast cancer, history of chest
radiation, or with possible family history of BRCA1 and BRCA2 mutations
 Minimal benefit in women who were not at increased
risk
Adverse Effects of SERMs
 Deep-venous thromboses
 Endometrial cancer (tamoxifen)
 Cataracts (tamoxifen)
 Hot flashes
 NOTE: no increased risk of CAD or stroke was seen
Tamoxifen versus Raloxifene
 Tamoxifen slightly more effective
 Raloxifene has lower risk of DVTs, endometrial cancer, and
cataracts
Recommendations for SERMs
 ASCO & USPSTF:
 Both recommend SERMs for breast cancer prevention in highrisk patients ≥ 35
 ASCO:
 USPSTF:
≥ 1.66% 5-year risk (or with LCIS)
≥ 3% 5-year risk
 Tamoxifen 20 mg daily for 5 years
 Pre- and postmenopausal women
 Raloxifene 60 mg daily for 5+ years*
 Postmenopausal women only
* can be used longer than 5 years in women with osteoporosis, in
whom BC risk reduction is a secondary benefit.
 Contraindications:
 History of DVT/PE, stroke, transient ischemic attack, or during prolonged
immobilization.
 Combination with hormone therapy
 Pregnant women, women who may become pregnant, or nursing mothers
Aromatase Inhibitors
 Agents: anastrozole & exemestane
 Mechanism of action: inhibit aromatase, which is responsible
for conversion of androgens to estrogens, and hence, will
reduce plasma estrogen levels
 Are regularly used in breast cancer treatment
Aromatase Inhibitors Studies
 NCIC Clinical Trials Group Mammary Prevention.3 Trial,
2011:


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~4,500 women at high risk for breast cancer
Received exemestane or placebo
65% relative reduction in invasive breast cancer with exemestane
Reduction in DCIS seen, too
 International Breast Cancer Intervention Study (IBIS-II),
2013:
 ~4,000 postmenopausal women at high risk for breast cancer
 Received anastrozole or placebo
 50% reduction in number of invasive breast cancer and DCIS
with anastrozole compared to placebo
 Side effects: musculoskeletal pain, hypertension, vaginal
dryness, vasomotor symptoms,
SUMMARY:
ASCO Recommendations for
Breast Cancer Prevention
 Tamoxifen (20 mg per day orally for five years) should be discussed as
an option to reduce the risk of invasive, estrogen receptor (ER)-positive
breast cancer in premenopausal or postmenopausal women. . . .
 Raloxifene (60 mg per day orally for five years) should also be
discussed as an option to reduce the risk of invasive, ER-positive breast
cancer. . . . Its use is limited to postmenopausal women.
 Exemestane (25 mg per day orally for five years) should be discussed
as an alternative to reduce the risk of invasive, ER-positive breast
cancer in postmenopausal women. . . . . . While exemestane is
approved for the treatment of breast cancer, the FDA has not yet
approved its use in breast cancer prevention. This recommendation is
based on encouraging data from a single clinical trial that showed up to
a 70 percent reduction in overall and ER-positive invasive breast cancer
incidence with exemestane compared to placebo over a three year
period.
 All three agents should be discussed (including risks and benefits)
with women aged 35 years or older without a personal history of
breast cancer who are at increased risk of developing invasive
breast cancer (5-year risk ≥ 1.66%), based on risk factors such as
the woman’s age, race, and medical and reproductive history.
SUMMARY:
USPSTF Recommendations for
Breast Cancer Prevention
 “. . . recommends that clinicians engage in shared, informed
decision making with women who are at increased risk for
breast cancer about medications to reduce the risk. For
women, who are at increased risk for breast cancer and at
low risk for medication side effects, clinicians should offer to
prescribe risk-reducing medications, such a tamoxifen or
raloxifene. (B recommendation)”
Back to Case #3
A 52-year old postmenopausal caucasian woman with no
significant past medical history comes for her annual exam.
She voices no concerns, and ROS is negative. Family history is
positive for breast cancer in her mother (diagnosed at age 60).
She had menarche at age 11, has never been pregnant, and
has never smoked. She has been getting mammograms
regularly since age 40. She had one breast biopsy for a lesion
seen on screening mammography at age 42, but the pathology
was proliferative benign breast disease without atypia.
Her VS and physical exam are normal. She is concerned about
getting breast cancer and wants to know if there is any medical
therapy that can reduce her risk.
What advice do you give this patient?
Breast Cancer Risk Assessment Tool
Take-Home Points
 Aspirin may be beneficial for colorectal adenoma and cancer
prevention in certain populations
 No formal recommendations to use aspirin for cancer prevention
yet
 5-alpha reductase inhibitors appear to reduce the incidence
of prostate cancer at the risk of increasing high grade
cancers
 ASCO/AUA guidelines suggest consideration in select men
 SERMs are recommended for breast cancer prevention in
high-risk women ≥ 35 by ASCO & USPSTF:
 Tamoxifen: pre and postmenopausal women
 Raloxifene: postmenopausal women only
 AIs can be considered for breast cancer prevention in highrisk women ≥ 35:
 Exemestane: postmenopausal women (not FDA approved)
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