Clinical Conundrums in Cancer Chemoprevention: What Should You Recommend to Your Patients? - PowerPoint Presentation

Slide1

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 MedicineSlide2
Slide3

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.Slide4

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.Slide5

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?Slide6

Aspirin and Cancer ChemopreventionPotential 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 & apoptosisSlide7

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 pointSlide8

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. Slide9

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 historyReduction 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 subjectSlide10

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

: PPIsSlide11

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 judgmentAge >50Patient 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 timeSlide12

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?Slide13
Slide14

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?Slide15

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?Slide16

Prostate Cancer

2

nd

most common cancer in men

Increasing incidence since PSA screening initiated

Most cancers are clinically indolent

Early treatment not proven to improve survivalSlide17

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 antiandrogenicSlide18

5-Alpha Reductase InhibitorsAgents

: 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 finasteride-treated group was no different than placebo-treated groupSlide19

5-Alpha Reductase InhibitorsREDUCE 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

=

Re

duction by

Du

tasteride of Prostate

C

ancer

E

ventsSlide20

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 5-ARIs 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

).”Slide21

Other Agents for Prostate Cancer ChemopreventionVitamin 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 IIVitamin 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 =

Sel

enium

and V

itamin

E

C

ancer Prevention

T

rialSlide22

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?Slide23
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SERMs and AIs in Breast Cancer Chemoprevention

SERMs and AIs:

What are good for fighting cancer are also good at preventing it, right

?Slide25

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?Slide26

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:

Age

Age at menarche

RaceAge at first childbirthFamily 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 womenSlide27

Selective Estrogen Receptor Modulators (SERMs) Studies

Agents

: tamoxifen &

raloxifene

Randomized controlled trials have shown they reduce the risk for

ER-positive

breast cancerSelection 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

post

menopausal women over 5 years

Tamoxifen reduced incidence more than

raloxifene

Tamoxifen also reduced incidence of invasive breast cancer in

pre

menopausal womenSlide28

SERMsAt-risk women

were

more likely to benefit from

chemoprevention:

Highest benefit in women who

had

≥ 3% 5-year riske.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 riskSlide29

Adverse Effects of SERMsDeep-venous thromboses

Endometrial cancer (tamoxifen)

Cataracts (tamoxifen)

Hot flashes

NOTE

: no increased risk of CAD or stroke was seenSlide30

Tamoxifen versus RaloxifeneTamoxifen slightly more effective

Raloxifene has lower risk of DVTs, endometrial cancer, and cataractsSlide31

Recommendations for SERMs

ASCO & USPSTF

:

Both recommend SERMs for breast cancer prevention in high-risk patients ≥ 35

ASCO: ≥ 1.66% 5-year risk (or with LCIS)

USPSTF:

≥ 3% 5-year riskTamoxifen 20 mg daily for 5 yearsPre- 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 mothersSlide32

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 treatmentSlide33

Aromatase Inhibitors Studies

NCIC Clinical Trials Group M

ammary

Prevention.3

Trial

, 2011:

~4,500 women at high risk for breast cancerReceived exemestane or placebo65% 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, Slide34

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

pre

menopausal or post

menopausal

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

post

menopausal 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

post

menopausal

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.Slide35

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)”Slide36

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 ToolSlide37

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 high-risk women ≥ 35:

Exemestane

: postmenopausal women (not FDA approved)Slide38

Bibliography

Chen WY. Selective estrogen receptor modulators and aromatase inhibitors for breast cancer prevention

. In: UpToDate, Basow DS (Ed), UpToDate, Waltham, MA. (Accessed on January 15, 2014.)

Cook NR et al. Low dose aspirin in the primary prevention of cancer: the Women’s Health Study: a randomized controlled trial. JAMA 2005;294:47.

Cook NR et al. Alternate-day, low-dose aspirin and cancer risk: Long-term observational follow-up of a randomized trial. Ann Intern Med 2013;159:77-85.

Crawford ED . Chemoprevention strategies in prostate cancer.

In

: UpToDate, Basow DS (Ed), UpToDate, Waltham, MA. (Accessed on

January 15

,

2014.)

Dubé C et al. The use of aspirin for primary prevention of colorectal cancer: a systematic review prepared for the US Preventive Services Task Force. Ann Intern Med 2007;146:365.

Final report on the aspirin component of the ongoing Physicians’ Health Study. Steering Committee of the Physicians’ Health Study Research Group. N Engl J Med 1989;321:129.

Fortmann SP et al. Vitamin and mineral supplements in the primary prevention of car

Goss PE. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med 2011;364:2381-91.

Klein EA et al. Vitamin E and the risk of prostate cancer: the selenium and vitamin E cancer prevention trial (SELECT). JAMA 2011;306:1549.

Moyer VA. Medications for risk reduction of primary breast cancer in women: US Preventive Services Task Force recommendation statement. An Intern Med. 2013;159:698-708.

Rothwell PM et al. Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomized trials. Lancet 2010;376:1741.

Rothwell PM et al. Short-term effects of daily aspirin on cancer incidence, mortality, and non-vascular death: analysis of the time course of risks and benefits in 51 randomized controlled trials. Lancet 2012;379:1602.

Spencer FA and Guyatt G. Aspirin in the primary prevention of cardiovascular disease

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Thompson IM et al. Long-term survival of participants in the prostate cancer prevention trial. N Engl J Med 2013;369:603.

Visvanatha K et al. Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guidelines. J Clin Oncol 2013 Aug 10;31(23):2942-62.

Wolin KY and Colditz GA. Cancer prevention. In

: UpToDate, Basow DS (Ed), UpToDate, Waltham, MA. (Accessed on

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