• Most women don't know what their true risk of breast cancer is.  As many women underestimate it as overestimate it.
• Linda McCartney, a long-time vegetarian, recently died of breast cancer.
• National news magazines cover stories touted "miracle drugs" that cure cancer.  Patient's hopes were dashed when they read that these only worked in mice.
• Studies showing that tamoxifen and raloxifene reduce breast cancer by almost 50% were released in May.  Wary patients focus on the side effects.

 

     Relative risk refers to the chances or frequency of an event in one group compared to that of another group whose incidence is given a value of 1.0.  The bar in the middle is 1/3 greater (RR = 1.33) than the control group; the bar on the right 1/3 less (RR =.67)  If the incidence of breast cancer in the control group were (for example) 12 women in 100, then a RR of 1.33 would be 16 in 100; a RR of .67 would be 8 of 100.  Note that if the middle bar were assigned a relative risk of 1.0, the bar on the right would have a relative risk of 2.0 or twice as much rather than 1/3 more.  It is important to know what the control group is to understand the significance of relative risk.

     A more useful way of considering risk is to look at it in absolute terms (how many women out of 1000 would be affected) and put it in the context of other information.  To understand the true impact of tamoxifen one must know that also that  breast cancer is 100 times more common than uterine cancer (100/1000 women vs. 1/1000).  Thus, tamoxifen  causes 1 case of uterine cancer in 1000 women and prevents 50 cases of breast cancer in that same 1000 women.
     Because of the focus on cancer, the relative risks of other health events may be overlooked.    In fact, a woman's risk of heart disease is almost 5 times as great as for breast cancer (1 in 2 vs. 1 in 9.)  Her risk of dying from heart disease is 9.7 times greater than from breast cancer.  Other events, like auto accidents, skull fractures, even injuring oneself on a chair or in bed, are more common than getting breast cancer.  (See Fig. 2.)
 
 

Fig. 2                        Putting Risk in Perspective

    The biggest risk for breast cancer is birthdays; i.e., age. (See Figures 3 and 4.)  This is much more important than having a first degee relative (mother or sister) with breast cancer, or hormone use, or any other factor except certain specific precancerous lesions on breast biopsy and certain specific genes that can be measured (BRCA 1 or 2).
 

Fig. 5

    Tamoxifen Breast Cancer Prevention Trial
 
     This study included 13,388 women, ages 35 and older.  To be eligible a woman needed a risk of breast cancer equal to a average 60 year old, about 5% in 10 yrs.  Factors considered in determining risk included age, number of first degree relatives with breast cancer, number of prior breast biopsies, atypical hyperplasia or LCIS on biopsy, age at menarche, and age at first live birth.  Half the women received 20 mg Tamoxifen for average 3.6 yrs, half got placebo.  Forty percent of women were between ages 35-49; 30% were 50-59; 30% were 60 or older.
 

Fig. 6

RESULTS OF TAMOXIFEN TRIAL
	Placebo 6707 subj.	Tamoxifen 6801 subj.	Comments
Breast Cancer	154	85	45% less
Non invasive Breast Ca	59	31	48% less
Fractures	71	47	34% less
Endometrial Cancer	14	33	135% more*
Vascular Events	70	99	41% more#

              *In Tamoxifen group, all cancers were stage 1, no deaths; In control group 1 death.  #Vascular events: no difference in fatal strokes or fatal MI; 2 fatal pulmonary embolus in   tamoxifen group.  More blood clots in legs with tamoxifen group, RR 1.6

     Tamoxifen cut the risk of both invasive and non-invasive (ductal carcinoma in situ) breast cancers in half.  For a 60 year old woman facing a risk of 5% over 10 years, this would reduce it to 2.5%, or the risk of a woman 15-20 years younger.  For a 45 year old woman whose mother had post menopausal breast cancer this would balance or neutralize the increased risk.
     The was a greater danger of endometrial (uterus) cancer.  More than twice as many women on tamoxifen got uterine cancer than on placebo, raising the incidence from 1/1000 to approximately 2/1000.  Because women taking tamoxifen were carefully watched, all these cancers were discovered while stage 1 and cured with simple hysterectomy.  The only woman to die of uterine cancer was in the control group.
     Venous blood clots were more common with tamoxifen by a factor of 2.  In the general population the incidence of blood clots increases with age.  For women not taking hormones the incidence of either thrombophlebitis or pulmonary embolus is .5-1/1000 ages 50-59, 1.5-3.5/1000 ages 60-69, and 3.5-6/1000 ages 70-79. Hence, with tamoxifen, venous blood clots occur in 2/1000 to 10/1000 women depending upon age.  Both conditions are treated with anticoagulants.  Thrombophlebitis, while uncomfortable, is life threatening only if the blood clot leaves the legs and goes to the lungs (pulmonary embolus).  In this study, 2 women taking tamoxifen died of pulmonary emboli.  Women with a history of blood clots should be cautious about taking tamoxifen.
     Arterial blood clots (strokes, TIA's, heart attacks) were the same in both control and tamoxifen groups.
     Other studies of tamoxifen compared with placebo showed significant increases in hot flashes and vaginal discharge but no differences in bone pain, joint pain, indigestion, nausea, vomiting, headache, insomnia, irritability, depression, or fatigue.  In another study there was no difference between placebo and tamoxifen in the quality of life or activity level.  The control group, not the tamoxifen group, reported feeling less feminine and having less sexual desire.

    Raloxifene Prevention Trials
  The following data are from a series of studies, with varying numbers of subjects and varying follow up times.  In general the studies have been 2 to 3 years long.  They were limited to older women, generally with a diagnosis of osteoporosis.  Raloxifene is a relatively new drug.  The following results are likely to be confirmed in other studies though the magnitude of the effect may not be as great.

Fig. 7

RESULTS OF RALOXIFENE TRIAL
	Placebo 2560 subj.	Raloxifene 5140 subj.	Comments
Breast Cancer	21 (.81%)	11 (.21%)	74% less
Vascular events	1.43/1000	3.08/1000	RR = 2.2**
Endometrial Cancer			RR .38***

  *This is an early study.  The group, mainly women over age 60, would be expected to have more benefit than the younger group in the tamoxifen trial.  It is premature to conclude that raloxifene is better than tamoxifen in preventing breast cancer.
**Like tamoxifen, there is a higher incidence of blood clots.
***Though less than control, the result is not statistically significantly different. There is, however,  not expected to be an increased risk of uterine cancer.
 
 

 Gilda Radner, the comedienne from Saturday Night Live, who died of hereditary ovarian cancer, wrote a book titled, "It's Always Something."  In spite of a search for a risk free life, certain events occur.  Linda McCartney's impeccable lifestyle did not prevent her breast cancer.   There is a benefit and a risk to almost every action.  There is also a risk of not acting and "letting nature take its course."  A deer caught in the headlights of an oncoming car must overcome its fear and jump to one side to avoid being hit.
 Figure 8 is compiled from various sources and is a comparison of the effects of placebo, estrogen, tamoxifen and raloxifene.  In order to make the comparisons between drugs simpler I have had to assume that the control groups are similar, which is not always exact.  The relative risks should be considered approximate.

Fig. 8

+ increase, - decrease

Footnotes
    1     There is controversy whether hormone replacement increases the risk of breast cancer.  Most of the data showing an increased risk comes from Europe where doses of estrogen are 2 times what are used in the US (Premarin .625mg or Estrace 1mg).  If there is an increased risk, it probably applies only to women with a strong family history of breast cancer or to women who use estrogen for more than 5 years continuously.
    2     Because the data on Raloxifene are limited further studies are likely to show the effect closer to that of Tamoxifen.
    3     Does not apply to women with hysterectomy.  Hormone replacement therapy should include progesterone if the uterus is intact.  The increased risk with Tamoxifen only applied to post menopausal women.
    4     Estrogen reduces the risk of heart attack and heart disease by about 50% by improving the ratio of total cholesterol to HDL.  Studies using Tamoxifen for adjuvant therapy for breast cancer showed a decrease of 33-63% in fatal heart attacks but were not controlled for heart disease risk factors.  Most authorities feel Tamoxifen will be almost as good as estrogen and that Raloxifene will be about the same as Tamoxifen in this regard.
    5     The chances of venous blood clots (thrombophlebitis and pulmonary emboli) increase with age.  The rate varies from 1/1000 for women age 50-60 to 3-6/1000 ages 70-80.  Estrogen, Tamoxifen and Raloxifene all increase the chances of blood clots by about 2 or up to 1/100 women.
    6     Osteoporosis occurs mainly after menopause when bone density decreases approximately 1-2%/year.  Risk factors for osteoporosis include a positive family history, low calcium intake, sedentary life style, and smoking.  Osteoporotic hip fractures cause 65,000 deaths/year compared with 43,000/year from breast cancer (RR 1.5).  Estrogen is the standard treatment for osteoporosis.  Alendronate (Fosmax) increases bone density comparably to premarin, 3.3% at the hip and 5.8% in the lumbar spine.
 

     Diet and exercise have long been known to influence the risk of cancer.  Epidemiologic and experimental studies have shown that the chances of breast cancer are directly proportional to animal fat intact.  Populations with low fat diets (e.g., Japan) have 1/4 to 1/10 the incidence of breast cancer as in the US.  When these populations increase their fat intake (e.g., Japanese in Hawaii), the incidence increases to that of Caucasians.  Experimental studies show that it is necessary to reduce dietary fat significantly, to 15% of total calories, to get a measurable effect.  Less strict dietary restriction (e.g., to 20%) may not be as effective.
     It is believed that a decreased total fat intake could slow breast development by restricting the caloric energy needed for tumor growth, decreasing the levels of circulating sex hormones, removing or reducing the levels of certain potentially tumor stimulating fatty acids and by reducing exposure to lipid-soluble carcinogens that may be present in animal fat.
     In January, 1998, a group of doctors gathered at the Commonweal Conference on New Directions in Cancer Care and developed a consensus statement about dietary prevention of breast cancer.  Their recommendations were for a diet of no more than 15% of calories from fat.  The majority of the fat should come from omega-3 fats (from fish and/or fish oil) and omega-9 fats (from olive oil).  Monounsaturated fats should take precedence over polyunsaturated and saturated fats within the 15% goal.  As a rough estimate, for a woman 5'6" tall, age above 50, a 15% fat diet would be 30 grams of fat.  For women younger than 50, 33 grams would be allowed.
     There should be 10-12 servings daily of whole vegetables and fruits.  This provides
approximately 20-24 grams of fiber along with many potentially helpful cancer-protective chemicals.  There should also be 4-6 servings of whole grains (or one serving of a high fiber cereal as an alternative) daily.  A serving of vegetables, fruit or pasta is approximately the size of a tennis ball (6 oz).
     The data showing exercise reduces cancer is even more compelling.  Studies consistently show that people who exercise regularly have less cancer than those with sedentary lifestyles.  The more exercise, the greater the reduction in cancer risk.  The mechanism by which exercise reduces breast cancer is not established but is felt to involve changes in body fat and fat metabolism.

Fig. 9

 

LIFESTYLE PREVENTION OF BREAST CANCER: EXERCISE*
4 hr/wk walking	RR .76-.98
4 hr/wk aerobics	RR .67
Competitive sports	RR .48

*Four exercise levels for women in Finland were determined based upon the amount of activity at work and in leisure time.  1) Sedentary: leisure-TV, work-desk, RR 1.0;    2) Moderate: leisure- 4hr/wk walking, bike etc., work-walking  RR .76-.98;  3) Regular exercise: leisure 4hr fitness exercise, work-lifting, walking RR .67;  4) Heavy exercise: leisure-competitive sports, work-manual labor, RR.48.  The strongest effects for premenopausal women, for those who were overweight when they started exercise, and for those who continued to exercise.
 

2     What are your goals of treatment?  Is it to prevent breast cancer, prevent other diseases (heart attacks, osteoporosis, etc.), or some combination of them?  Is your goal more to reduce your anxiety about cancer or to change your statistical chances?  If the primary problem is anxiety about cancer, then address that directly with either support from friends, counselors, or with specific treatment for anxiety.

3     What is your personal style of health care?  If you wish to prevent disease, do you rely primarily on lifestyle or medication/vitamins?  Do you have limitations on your lifestyle that would prevent you from maintaining a rigorous exercise and nutritional program?  These might include a preference for a sedentary lifestyle, prior failed attempts to change diet, physical limitations preventing vigorous exercise, etc.  Consider your current lifestyle (family and professional demands) and whether this could accommodate another change.  If you rely primarily upon taking pills (and are taking vitamins and supplements for disease prevention), consider the scientific basis for your choices and whether that provides adequate assurance of their effectiveness.

4     What level of risk are you willing to tolerate?  Are you satisfied only if you are doing everything possible?  Recognizing that it is not possible to guarantee that you won't get cancer, where is your comfort zone?  What compromises are you willing to make between what is practical and what is ideal?  You may wish to set a series of small goals and then reevauate them each three months.

5     How do you make decisions?  When you play cards or a game, do you play to win (and take chances) or do you play not to lose (avoid taking risks)?  Do you tend to make decisions after careful analysis of all the facts or more intuitively, trusting your gut feelings?  (A balance between both styles is best.)  Are you more likely to take a "wait and see" position or act quickly and decisively?  You may wish to get feedback from your friends about your plans and decsion making process.
 

1     Laura is a 42 year old, premenopausal manager in a computer company.  Her mother had breast cancer at age 38 and a maternal aunt had breast cancer at age 50 and a second breast cancer at age 58.  There is a moderate family history of heart disease on her father's side.  Laura's menses started when she was 12 had her only child at age 32.  Laura is on a low fat (20-25%) diet, drinks 2 glasses of wine with dinner and exercises 3 days/wk at the gym, keeping her close to her ideal weight.  Professional and family demands are stressful, leaving her little free time.
     After examining her risks, she correctly concludes that she is at high risk for breast cancer.  She prefers not to take medicine and considers what changes in lifestyle she could make to get a 50% decrease in risk.  Realistically, she could not devote the time to exercise at marathon-runner levels.  She is willing to make additional changes in diet to achieve an 18-22% fat diet and reduce her wine to 4 glasses/wk.
     Laura recognizes that these changes will help but will not give her the sense of security she wishes.  She is not particularly anxious, her style is analytical and she tries to avoid risks if possible.  Based upon the evidence from the tamoxifen trial she decides to use this medicine for 5 years.  She recognizes that in 5 years new information will be available and she will consider her options then.

2     Sandra is a 51 year old perimenopausal writer.  Her older sister had bilateral breast cancer at ages 54 and 59.  One brother had a heart attack at age 45, another brother at age 47.  Sandra's menses started when she was 11; she had her first child at age 24, her second at age 26.  She has had 2 breast biopsies, both abnormal but not cancer.  Her cholesterol is high, her blood pressure is controlled on medication.  She does not drink alcohol.  She is 20 pounds overweight; she tries to stay on a low fat diet with only modest success.  She walks 2 miles daily with her Dalmatian.
     At her doctor's suggestion she tried hormone replacement but could not tolerate the side effects.  She is more concerned about breast cancer  (several friends have recently been diagnosed) than she is about heart disease.  She tends to make decisions intuitively and senses that she must do something but is not sure what. She has read about both tamoxifen and raloxifene and can't decide between them.  She would prefer the one that would give her the most certain protection
     After discussing her situation with her doctor she gets a bone density test which shows no evidence of osteoporosis.  She chooses tamoxifen because it has been used longer and its side effects are better known.  She agrees to continue annual gynecology exams and to report any signs of bleeding or blood clots.  She is willing to switch to raloxifene if there is any evidence of abnormal uterine bleeding.

3     Rosa is a 64 year old grandmother and retired dentist.  Her mother died of a stroke at age 52.  Two aunts had postmenopausal breast cancer and osteoporosis.  Her father died of heart disease in his 60's.  Rosa's menses started when she was 10 1/2 and she went thru a natural menopause at age 56.  She took estrogen for 6 years and stopped when she had a breast biopsy which showed atypical cells.  Her cholesterol has come down from 280 to 220 because she follows a low fat (20%) diet carefully and swims 45 minutes 4 days/week.
     Rosa tends to be anxious and wants to avoid cancer if at all possible.  She took the estrogen because it was recommended to prevent osteoporosis.  A bone density test at age 55 showed a marked increased risk of both spine and hip fracture.  Her bones had improved on the test done at age 57 so she was willing to continue the estrogen.  When she had the abnormal breast biopsy, however, she quickly stopped it and started taking multiple vitamins, minerals, and herbs.
     When tamoxifen was suggested as a replacement she was grew concerned about the increased risk of uterine cancer and refused to consider taking it.  She has read about raloxifene and wants to try it.  She is reassured by its demonstrated effect on osteoporosis and its lack of effect on the uterus.  She chose raloxifene over other drugs for osteoporosis because she also wanted breast cancer protection.

4     Elizabeth is a 55 year old homemaker who had breast cancer when she was 43.  The original tumor was 1.8 cm, negative nodes, and estrogen/progesterone receptor negative.  She received CMF chemotherapy which precipitated menopause.  She started menstruation at age 12 and had the first of her 3 children when she was 24.  There were no relatives with cancer of any kind but both her mother's and father's families have had premature heart disease.  Her grandmother had osteoporosis and died after a broken hip at age 73.
     Elizabeth has an active lifestyle though she does not exercise regularly.  She quit smoking when she was diagnosed with breast cancer.  She has multiple food intolerances and avoids red meat and spicy foods, preferring vegetables and fruit.  With pressure from her doctor she takes calcium supplements and is on medication for high cholesterol and high blood pressure.  She would prefer to just "get on with her life" and not think about either past or possible future health problems.
     Her doctor persuaded her to get a bone density test which showed osteoporosis.  Now he suggests that Elizabeth take either tamoxifen or raloxifene, not as adjuvant treatment for her original cancer, but to treat her established osteoporosis, reduce her risk of heart disease (she has multiple risk factors including family history, prior smoking, etc.), and reduce her risk of a second breast cancer.  Elizabeth doesn't think she will get another cancer (though her risk is about 10% over the next 25 years) but is willing to "take something to avoid a dowager's hump" like her grandmother's.  Her doctor chooses raloxifene though he equally could have selected tamoxifen.

     Minimum recommendations for breast cancer prevention include a fat-reduced diet, exercise at least 4 times/week, and less than 1 alcoholic drink per day.  The information in this paper should help you understand whether you should consider medication as part of your strategy.  This paper is not a substitute for seeing a physician knowledgeable about cancer prevention.  Use it as a starting point for an ongoing conversation with her or him.  As an informed patient you will be in a better position to ask the correct questions and reach the best decisions.
 
 

CURRENT AGE_______    Name_______________________________

Hormone and Reproductive History
1     Age when menstrual periods started: 10-12yo (RR 1.3)___;  above 12 (RR 1.0)___
2     Age when you delivered first child: 15-19yo (RR 0.5)___;  20-24yo  (RR 1.0)___
              25-29yo (RR 1.5)___;   30-35yo  (RR 1.9)___
              after 35  (RR 2-3)___;   no child. (RR 3.0)___
3     How many children have you had? ____  (More children, esp. while young, lowers risk.)
4     Approximately how long (total) did you nurse them? 0 mo____; 1-6mo___; 7-12 mo___
         more than 12 mo___.  (Longer time nursing lowers risk.)
         (The use of birth control pills does not influence the incidence of breast cancer.)
5     Have you gone thru either natural or surgical menopause?  Yes___;  If not, skip Quest. 6.
         age 35-40 (RR  0.5)__; age 40-50 (RR 1.0)__; age 50-55 (RR 1.3)__; age >55 (RR 1.5)__
6     Have you taken estrogen replacement?  Never__; 1-5 yr (RR 1.2) __; >5 yr. (RR 1.4)__
 
Family History
     For parents, brothers and sisters (first degree relatives), note whether they have had any of the following diseases and when they first were diagnosed.  For grandparents, aunts and uncles (second degree relatives), note how many had these diseases.
                  Breast Cancer Other cancer Heart Disease Osteoporosis Hi BP Hi Cholesterol
Mother      ___________ __________ ___________ __________ _____ ____________
Father        ___________ __________ ___________ __________ _____ ____________
Sister         ___________ __________ ___________ __________ _____ ____________
Sister         ___________ __________ ___________ __________ _____ ____________
Sister         ___________ __________ ___________ __________ _____ ____________
Brother      ___________ __________ ___________ __________ _____ ____________
Brother      ___________ __________ ___________ __________ _____ ____________
Brother      ___________ __________ ___________ __________ _____ ____________
Grandparent __________ __________ ___________ __________ _____ ____________
Aunt           ___________ __________ ___________ __________ _____ ____________
Uncle         ___________ __________ ___________ __________ _____ ____________
No first degree relative (RR 1)
1 or more first degree relative, premenopausal  (RR 2.0-3.1)
1 or more first degree relative, premenopausal, bilateral (RR 8.5-9.0)    1 or more first degree relative, postmenopausal  (RR 1.5) 1 or more first degree relative, postmenopausal, bilateral (RR 4.0-5.4)

Personal History (check all that apply to you)
 Breast biopsy, benign (RR 1.5)__ abnormal, not cancer (RR 1.5-2.0)__
 Non-invasive cancer, carcinoma in situ (RR 7-12) Breast cancer ____
 High Blood Pressure__ High Cholesterol__ Heart disease__
 Osteoporosis___ Blood clots in legs___  Blood clots in lung___
 Significantly overweight/obese (RR 1.3-1.7) __

Lifestyle
 Diet: Vegetarian__ meat 2-4/week___ meat 5 or more/week__
 Alcohol  Avg. <1/day__  Avg. 1/day (RR 1.0)__  Avg. 2+/day(RR1.3-1.8)__
 Exercise  Sedentary (RR 1.0)__  4 hr/week walking, biking (RR .76-.98)__
  4 hr/week aerobics (RR .67)__    competitive sports training (RR .48)__
 

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