Ambi Journal Club June 14th 2006 Breast Cancer

1. Ambi Journal ClubJune 14th 2006Breast Cancer Case Report Screening / Mammography Epidemiology Risk Factors Diagnostic Approaches Therapy Evidence Based Medicine / Literature Analysis Ambreen Ijaz, M.D.

2. ACADEMIC APPROACH TO BREAST CANCER IN LITERATURE Drug Therapy: Treatment of Breast CancerHortobagyi G. N. N Engl J Med 1998; 339:974-984, Oct 1, 1998. Review Articles Primary Care: Assessing the Risk of Breast CancerArmstrong K., Eisen A., Weber B. �N Engl J Med 2000; 342:564-571, Feb 24, 2000. Review Articles Primary Care: Reducing the Risk of Breast CancerChlebowski R. T. �N Engl J Med 2000; 343:191-198, Jul 20, 2000. Review Articles

3. CASE REPORT PRESENTATION: 39 year old Hispanic young female otherwise healthy. Regular PCP visit with some cough and chest congestion. No H/O fevers/ chills/ SOB/ fatigue, otherwise healthy. PMHx: Insignificant for any long standing disease. ALL: NKDA. SHx: Cholecystectomy 2002 BTL 2002. FHx: non � contributory , no family h/o cancers. SoHx: married for 13 years, lives with husband and two kids. Never smoked, No EtOH , No IVDA. Work related increased physical activity , works in a five star hotel (house keeping). Average Fat intake with no night hours at work.

4. OBGYN Hx Age of Menarche: 13 years. Sexually active with one partner x 13 years . LMP: May 22nd � 2006. Menses are regular with average flow. Pt does develop mid cycle and pre menstrual breast tenderness and engorgement. Has two children , 9 and 3 years of age , born as a result of NVD . Abortions: nill Contraception : condoms / depo provera shots 5 yrs back x 6yrs, and then finally had the BTL in 2002.

5. GPE BP: 104/60 PULSE:80 TEMP: 98.7 R/R : 18 Gen: well built , completely oriented in time place and person. HEENT: sclera clear, mmm, EOMI , B/L PEARL .No throat congestion . NECK: supple, no JVD, no Thyromegaly , no LAD . CHEST: CTA B/L . CVS: S1, S2 with no G/R/M. ABD: soft , NT, ND , BS+ EXT: Pulses positive , no O/C/C noted NEURO : non focal .

6. BREAST EX: Pt examined on lying down and while sitting. INSPECTION: Symmetrical with no disparity in sizes , no skin changes noted . Moving with the movement of the chest wall. PALPATION: All 4 quadrants and area under the areola palpated with the pt lying down, with her hands under the head and then in sitting position, consistency felt like breasts with fibrocystic texture, no clear demarcation of any mass or lump noted , Ex was not painful for the pt . No discharge from the nipple noted. Both the AXILLARY AREAS were palpated well for any LAD, No palpable lymph nodes. GENITOURINARY EX: Vaginal speculum was introduced after placing the pt in lithotomy position, cervix visualized, clean, smooth, posteriorly placed .Specimen for the Pap smear obtained and sent for the cytology. Bimannual exam after the Pap smear was not suggestive of any adenexal tenderness or mass.

7. LABS CBC and the LIPID panel were ordered but pt didn�t get the blood work done. Pathology report for the Pap smear is normal, negative for any intraepithelial lesion or malignancy. MAMMOGRAPHIES: Suggestive for 12mm rounded focal asymmetrical density in the left slightly Inner breast, spot compression imaging was suggested. Spot compression imaging obtained , suggestive of the same findings, an Ultrasound was suggested to complete the work up. US: two contiguous solid masses in the inner left breast at 10:00 o�clock Versus a single lobulated solid mass. Findings were c/w Fibro adenoma, Biopsy was suggested. Successful left breast Bx done. Pathology results from the Bx show that this is possibly a cellular fibro adenoma , although the possibility for a benign Phyllodes tumor cannot be ruled out and an excision for the density has been suggested .

8. INTRODUCTION Breast cancer is the most common female cancer in the United States, the second most common cause of cancer death in women (after lung cancer), and the main cause of death in women ages 45 to 55. Up to 55 percent of cases can be explained by known risk factors, such as: age at menarche first live birth, and menopause proliferative breast disease socioeconomic situation. an additional 10 percent of breast cancers are associated with a positive family history. Understanding the risk factors for breast cancer permits us to identify women at increased risk, and intervene to modify that risk, either individually or societally.

9. Screening mammography The U.S. Preventive Services Task Force recommends screening mammography, with or without clinical breast examination, every one to two years for women aged 40 and older. The USPSTF found fair evidence that mammography screening every 12 to 33 months significantly reduces mortality from breast cancer. Evidence is strongest for women aged 50 to 69, the age group generally included in screening trials. For women aged 40 to 49, the evidence that screening mammography reduces mortality from breast cancer is weaker, and the absolute benefit of mammography is smaller, than it is for older women. Most, but not all, studies indicate a mortality benefit for women undergoing mammography at ages 40 to 49, but the delay in observed benefit in women younger than 50 makes it difficult to determine the incremental benefit of beginning screening at age 40 rather than at age 50. The absolute benefit is smaller because the incidence of breast cancer is lower among women in their 40s than it is among older women. The USPSTF concluded that the evidence is also generalizable to women aged 70 and older (who face a higher absolute risk of breast cancer) if their life expectancy is not compromised by comorbid disease. The absolute probability of benefits of regular Screening for Breast Cancer U.S. Preventive Services Task Force mammography increases along a continuum with age, whereas the likelihood of harms from screening (false-positive results and unnecessary anxiety, biopsies, and cost) diminishes from ages 40 to 70. The balance of benefits and potential harms, therefore, grows more favorable as women age. The precise age at which the potential benefits of mammography justify the possible harms is a subjective choice. The USPSTF did not find sufficient evidence to specify the optimal screening interval for women aged 40 to 49.

11. Epidemiology The incidence of breast cancer increases with age, although the rate of increase slows after menopause.Early menarche, late menopause, and nulliparity increase the risk of breast cancer. Atypical lobular or ductal hyperplasia also increases the risk, and benign breast disease does so marginally. Other risk factors are early exposure to ionizing radiation, long-term postmenopausal estrogen-replacement therapy, and alcohol consumption. The most important risk factor is a family history of breast cancer. About 5 to 10 percent of all breast cancers occur in high-risk families, and there are several familial breast cancer syndromes, including the breast�ovarian cancer syndrome, the Li�Fraumeni syndrome, and Cowden's disease.

12. EPIDEMIOLOGY INCIDENCE � It is estimated that approximately 211,240 American women will be diagnosed with breast cancer in the year 2005, and 40,410 women will die from this disease. (SEER) program of the National Cancer Institute indicate that the lifetime probability of developing breast cancer is one in six, and for invasive breast cancer, it is one in nine . However, more recent data from the SEER program suggest that the incidence of estrogen (ER) and/or progesterone (PgR) receptor-negative breast cancer is declining while that of ER/PgR-positive disease is increasing. At least some of this increase may be attributable to increased use of hormone replacement therapy (HRT) GLOBAL VARIATION � Breast cancer incidence is highest in North America and Northern Europe, and lowest in Asia and Africa. Incidence rates in Japan and urban China have been rising in recent years. These international differences are thought related to societal changes occurring during industrialization (eg, changes in fat intake, body weight, age at menarche, and/or lactation). MORTALITY� Overall breast cancer mortality rates have declined since 1975, attributable to the increased use of screening mammography and the aggressive use of adjuvant therapies. However, this trend has not been seen in all subgroups. While breast cancer-specific mortality rates have declined in women under the age of 70, they have been stable (in women 70 to 79 years old) or increasing (in women over the age of 80) over time in elderly women, and in African-American women of all ages. Mortality rates are highest in the very young (less than age 35) and the very old (greater than age 75).

13. A: SOCIODEMOGRAPHIC RISK FACTORS � surrogates for lifestyle, hormonal, and/or reproductive factors. Gender � Breast cancer occurs one hundred times more frequently in women than in men. Age � Incidence rates rise very sharply with age until about the age of 45 to 50 when the rise is less steep. At age 75 to 80, the curve flattens and decreases slightly thereafter Socioeconomic status � Women of higher socioeconomic status are at greater risk for breast cancer. Area of residence � Incidence and mortality rates vary throughout the United States, with the highest reported incidence in Hawaii (128 per 100,000 women) and lowest in Utah (98 per 100,000 women) . Urban rates exceed those of rural areas. Race/ethnicity � In the United States, breast cancer is the most common cancer among women of every major ethnic group, although there are interracial differences. As an example, in California the highest rates occur in Caucasians (110.6 cases per 100,000 women). The rates in African-American women (96 per 100,000), Latina women (59.2 per 100,000), Asian-Americans (58.2 per 100,000), and others are all less.African-American women have more high grade cancers, which are known to be associated with a higher mortality rate. RISK FACTORS

14. RISK FACTORS��..cont B: HEREDITARY RISK FACTORS � Hereditary risk factors for breast cancer are complex, and involve more than the passage of genetic material. Family history � Family history is an important risk factor, but only 10 percent of women diagnosed with breast cancer have a positive family history. In a meta-analysis using data from over 50,000 women with breast cancer and 100,000 controls, the risk of breast cancer for a woman with one affected first degree relative was increased 1.80 fold. With two affected first degree relatives, the risk is increased 2.93 fold. The risk ratios were highest for women with young affected relatives. Thus, the risk was increased 2.9 fold for a woman whose relative was diagnosed before age 30, but only 1.5 fold increased if the affected relative was diagnosed after age 60 . Similarly, the risk of breast cancer before age 40 was increased 5.7-fold if one relative had breast cancer before age 40. Genetic mutations � specific genetic mutations that predispose to breast cancer are rare. It is believed that only 5 to 10 percent of all breast cancers are associated with a specific gene mutation, such as BRCA1, BRCA2, p53, ATM, PTEN, MLH1, or MSH2. Breast density � In at least 15 independent epidemiologic studies, the risk of breast cancer is four to five times greater in women with mammographically dense breasts compared to women of similar age with less extensive dense tissue. C: BREAST CONDITIONS � Proliferative lesions without atypia � The proliferative lesions without atypia include fibroadenoma, moderate or florid hyperplasia, sclerosing adenosis, and intraductal papillomas. Women with these lesions typically have an increased risk of breast cancer of only 1.3 to 2 times that of the referent group . Proliferative lesions with atypia � Proliferative lesions with atypia (both lobular and ductal) possess one or more characteristics of carcinomas in situ. They are associated with a higher relative risk of breast cancer development . Malignant breast conditions � ; the risk of developing contralateral breast cancer in women with an invasive cancer is 1 and 0.5 percent per year for pre- and postmenopausal women, respectively.

15. RISK FACTORS���..cont D: REPRODUCTIVE FACTORS � The key reproductive factors that influence breast risk are age at menarche, age at first live birth, age at menopause, and possibly parity and breast-feeding. Age at menarche � Younger age at menarche is associated with a higher risk for developing breast cancer. Age at first pregnancy � The younger a woman is at first full term pregnancy, the lower her breast cancer risk . However, women who give birth to their first child after the age of 30 have a higher risk than nulliparous women. Age at menopause � The later a woman undergoes menopause the higher her risk for breast cancer. Bilateral oophorectomy before the age of 40 reduces lifetime risk by 50 percent �Parity � Nulliparous women are at increased risk for breast cancer compared with parous women. �Abortion � Since abortion disrupts the maturation process of the breast, it has been hypothesized to increase breast cancer risk. One meta-analysis of case-control studies supports this theory , but a second does not. Pregnancy � Full term pregnancy itself is associated with an increased breast cancer risk. The protective effects of pregnancy are not seen until after ten years following delivery Breast Feeding � In the largest case-control study that included individual data from 47 epidemiologic studies including 50,302 women with invasive breast cancer and 96,973 controls, the relative risk of breast cancer was reduced by 4.3 percent for every 12 months of breast feeding, in addition to a decrease of 7 percent for each birth . The mechanism postulated for the protective effect of breastfeeding is that it may delay the reestablishment of ovulatory cycles. Other mechanisms may be the increase in prolactin secretion and the concomitant decrease in estrogen production.

16. Risk factors���cont E:ENDOGENOUS HORMONE FACTORS � Prolonged exposure to and higher concentrations of endogenous estrogen increase the risk of breast cancer. Reducing estrogen levels (by castration or use of antiestrogens such as tamoxifen) lowers breast cancer risk. The data for postmenopausal women are better : A review of nine prospective epidemiologic studies found a positive relationship between serum estradiol concentration and breast cancer risk. Similar findings were noted in a later study of 7705 postmenopausal women enrolled on the Multiple Outcomes of Raloxifene Evaluation (MORE) trial: women with the highest tertile of serum estradiol levels (>12 pmol/L) had a two-fold higher risk of invasive breast cancer than women with lower levels . Furthermore, women in the highest estradiol tertile tended to have a greater reduction in the risk of breast cancer with raloxifene compared to women in the low estradiol subgroup . Bone mass: In one report, elderly women with high BMD had an greater risk of breast cancer (relative risk 2.7 for women in the highest compared to the lowest quartile of BMD), compared with women with low BMD, particularly advanced disease .

17. RISK FACTORS���.cont F: NOCTURNAL LIGHT EXPOSURE: It is postulated that exposure to light at night suppresses the normal nocturnal production of melatonin by the pineal gland , which in turn, could increase the release of estrogen by the ovaries. In one of the above studies, the risk of developing breast cancer was significantly higher in women who did not typically sleep between 1 AM and 2 AM, the nighttime period when melatonin levels are at their highest. G: EXOGENOUS HORMONE FACTORS � Oral contraceptives � a large meta-analysis calculated a small but significant increase in relative risk of breast cancer (RR =1.24) in current oral contraceptive users . Hormone replacement therapy � Women's Health Initiative trial, the relative risk of breast cancer was increased 1.24-fold (95% CI 1.01-1.54) when women taking combined estrogen/progesterone for an average of 5.2 years were compared to those receiving placebo. Infertility treatment � Whether ovulation induction for the treatment of infertility increases the risk of breast cancer is a matter of debate. H: DIETARY FACTORS Height and weight � Fat and dairy product intake � Micronutrients � Alcohol � Caffeine � NSAIDs � PHYTOESTROGENS :Two phytoestrogens, the isoflavones genistein and daidzein, are an important component of soy. These compounds are weak estrogens compared to estradiol. The low rates of breast cancer in Asia and the high soy intake in China and Japan have led to the hypothesis that soy consumption can decrease breast cancer risk by displacing estradiol and functioning as relative antiestrogens. I: MISELLANEOUS Ionizing radiation � Physical activity:. The benefit of physical activity was most pronounced when performed at age 35 (RR 0.86, 95% CI 0.78-0.95) as compared to a younger (age 18) or older (age 55) age, and in women who currently engaged in the equivalent of 10 hours or more per week of brisk walking, particularly if they were in the lowest tertile of BMI (RR 0.63 for the combination).

18. Biology Germ-line mutations in BRCA1 and BRCA2 are associated with a 50 to 85 percent lifetime risk of breast cancer, ovarian cancer, or both. In sporadic breast cancer, abnormalities have been identified in several genes (including p53, bcl-2, c-myc, and c-myb), and in some cancers normal genes or gene products (HER-2/neu and cyclin D1) are overexpressed. Gonadal steroid hormones (estrogens, progestins, and androgens), growth factors (epidermal growth factor, transforming growth factors and , and insulin-like growth factors I and II), and various cytokines and lymphokines influence the behavior and phenotypic expression of breast cells.

19. Diagnostic Approaches Systematic screening by means of mammography and clinical examination results in early diagnosis of breast cancer and a 25 to 30 percent decrease in mortality due to breast cancer in women over the age of 50 years and probably also in women between the ages of 40 and 50 years. The American Cancer Society and the National Cancer Institute recommend annual screening mammography for women older than 40 years who have a standard risk of breast cancer. In women from high-risk families, especially those with BRCA1 or BRCA2 mutations, screening should start at 25 years of age, or 5 years earlier than the earliest age at which breast cancer was diagnosed in a family member. Additional improvements are expected to result from : 1. Digital mammography 2. Breast MRI 3. Technetium-99m sestamibi imaging 4. Fine needle aspiration 5. Core needle biopsy 6. Stereotactic biopsy 7. MRI directed biopsy

21. Therapy A: Primary Breast Cancer a) Local and regional treatment: For most women with early breast cancer, lumpectomy (wide excision of the tumor with preservation of the breast) with radiotherapy is the preferred treatment. Noninvasive (in situ) ductal and lobular breast cancer can also be treated adequately with lumpectomy and radiotherapy. b) Axillary Lymph-Node Dissection: It is responsible for most of the morbidity associated with breast surgery. Sentinel-lymph-node mapping is a procedure in which a radioactive substance or a blue dye is injected into the area around the tumor; a short time later, the lower ipsilateral axilla is explored through a small incision and the lymph node that has taken up the dye or radioactive substance (i.e., the sentinel node) is excised. If it is histologically negative, the rest of the axillary lymph nodes are also likely to be negative. The positive predictive value of a successful sentinel-node biopsy approaches 100 percent, whereas its negative predictive value exceeds 95 percent. Many patients with clinically negative axillary lymph nodes could be spared an axillary dissection if the sentinel node was found to be negative. An alternative approach is to analyze the primary tumor for nuclear or histologic grade, kinetics of cell growth and division, hormone-receptor expression, markers of invasive or metastatic capability, or blood-vessel content. Axillary dissection remains the standard of care for all women with invasive breast cancer or large noninvasive tumors (>2.5 cm).

23. Therapy����cont A: Primary Breast Cancer (cont) c) Radio Therapy: A recent randomized trial showed that administering chemotherapy before radiotherapy resulted in higher survival rates when both chemotherapy and radiotherapy were given postoperatively. Radiotherapy after mastectomy is indicated only for women at high risk for local or regional recurrence (patients with large tumors invading the skin of the breast or the chest wall or those with many positive axillary lymph nodes). d) Systemic Hormone Therapy or Chemotherapy: For adjuvant therapy, combination chemotherapy is more effective than single-drug therapy, reducing the annual risk of death by about 20 percent. Adjuvant tamoxifen therapy significantly reduces the risks of recurrence and death in women in all age groups. The benefit is greater when tamoxifen is administered for about five years, rather than one to three years, and when it is given to women with estrogen-receptor�positive tumors. Treatment for more than five years is no more effective than treatment for five years.

25. A: Primary Breast Cancer (cont) e) Preoperative Chemo Therapy: Several reports have indicated that close to 90 percent of primary operable tumors decrease in size by more than 50 percent after chemotherapy, thus making lumpectomy a possibility for many women who would otherwise have required a mastectomy. In terms of survival, there is no apparent advantage to preoperative chemotherapy as compared with postoperative chemotherapy. f) Duration of Chemo Therapy: In several trials, combination treatment for less than three months was inferior to treatment for four to six months, whereas treatment with a single combination-chemotherapy regimen, such as cyclophosphamide, methotrexate, and fluorouracil (CMF), for longer than six months was no more effective than treatment for four to six months.The combinations used most often are: fluorouracil, doxorubicin, and cyclophosphamide (FAC); fluorouracil, epirubicin, and cyclophosphamide (FEC); doxorubicin and cyclophosphamide (AC); and CMF. These combinations are administered intermittently at intervals of three to four weeks. Six cycles of FAC or FEC (duration, 18 to 24 weeks), six cycles of CMF (duration, 18 to 24 weeks), or four cycles of AC (duration, 12 to 16 weeks) are considered standard therapy. A recent report of the preliminary results of a large randomized trial suggested that the addition of four cycles of paclitaxel (duration, 12 to 16 weeks) to four cycles of AC improved both disease-free survival and overall survival rates. Therapy����cont

26. Therapy����cont A: Primary Breast Cancer (cont) g) Combination Chemo Therapy and Hormone Therapy: The combination of tamoxifen (or ovarian ablation for premenopausal women) and chemotherapy is more effective than either alone. h) Dose-Intensive and High-Dose Chemotherapy Regimens i) Locally Advanced and Inflammatory Breast Cancer : Stage III breast cancer includes tumors larger than 5 cm in the largest diameter, tumors of any size with direct invasion of the skin of the breast or the chest wall, and any tumors with fixed or matted axillary lymphadenopathy. Women with stage III or locally advanced breast cancer should be treated with preoperative chemotherapy or hormonal therapy, surgery, and radiotherapy. In more than 65 percent of such women, the tumors shrink by more than 50 percent with preoperative chemotherapy. Excellent local control can be achieved in 80 to 90 percent of women, and about 30 percent of women with stage IIIB tumors (tumors with direct invasion of the skin of the breast or the chest wall) or inflammatory breast cancer remain free of cancer after 10 years.

27. Therapy����cont B: Metastatic Breast Cancer:

28. Therapy����cont B: Metastatic Breast Cancer: (cont) Eventually, in most women, metastatic breast cancer becomes refractory to hormonal treatment, at which time the women should receive chemotherapy (CMF or FAC). Vinorelbine, paclitaxel, and docetaxel given alone result in response rates similar to those associated with CMF as first-line treatment. Combinations of taxanes and anthracyclines result in responses in 40 to 94 percent of women in first-line treatment and complete remissions in 12 to 41 percent. Bone is the most common site of metastases in breast cancer, and bone metastases are the cause of substantial morbidity and complications. Bisphosphonates (pamidronate and clodronate [clodronic acid]) added to chemotherapy or hormonal therapy reduce pain and the incidence of complications, and they prolong survival free of bone-related events. High-Dose Chemotherapy

29. Chemoprevention The administration of adjuvant tamoxifen for five years after primary therapy reduces the incidence of contralateral breast cancer by 47 percent. In a recently completed randomized study, more than 13,000 women at high risk for breast cancer received daily tamoxifen (20 mg) or placebo. After a mean follow-up of 3.5 years, there was a 45 percent decrease in the incidence of breast cancer in the tamoxifen group. Endometrial cancer developed in twice as many women in the tamoxifen group as in the placebo group. There was also an increase in thromboembolic events in the tamoxifen group. These adverse effects occurred predominantly in women older than 50 years. Overall, the beneficial effects of tamoxifen outweighed its adverse effects. The results of two other studies of chemoprevention with tamoxifen and one of fenretinide are not yet available.

30. Novel Therapies Anthrapyrazoles, liposomal anthracyclines, gemcitabine, several novel anti�folic acid compounds, and new thymidylate synthase inhibitors. Among the new hormonal agents, pure antiestrogens, aromatase inhibitors (anastrozole, letrozole, and vorozole), and selective estrogen-receptor modulators are causing great excitement. Monoclonal antibodies against the extracellular domain of the HER-2/neu oncoprotein with cisplatin.

38. AS PER USER�S GUIDE TO MEDICAL LITERATURE: A: ARE THE RESULTS OF THE STUDY VALID? Sample no : Design, Setting, and Participants� Following breast cancer risk assessment, 10�739 postmenopausal women aged 50 to 79 years with prior hysterectomy were randomized to CEE or placebo at 40 US clinical centers from 1993 through 1998. Mammography screenings and clinical breast examinations were performed at baseline and annually. All breast cancers diagnosed through February 29, 2004, are included. Inclusion criteria: The WHI Estrogen-Alone trial enrolled 10�739 postmenopausal women with prior hysterectomy from 1993 through 1998 at 40 US clinical centers. Women were recruited primarily by mass mailings and were eligible if they were aged 50 to 79 years at study entry, postmenopausal, and likely to reside in the same area for 3 years. Special attempts were made to recruit minority women in an effort to study the effects of hormone therapy in a cohort that reflected the ethnicity/racial diversity of postmenopausal women aged 50 to 79 years in the US population.

39. Exclusion criteria: The study exclusions included prior incidence of breast cancer and medical conditions likely to result in death within 3 years. Menopausal hormone use at screening required a 3-month washout before enrollment. All women had a baseline mammography screening and a clinical breast examination; suspicious findings required clearance before study entry.

40. PRIMARY GUIDES: 1). was the assignment of patients to treatments randomized? 2). a. were all the patients who entered the trial properly accounted for? b. was follow up complete? c. was this an intention to treat analysis? (i.e. were the patients analysed in the group to which they were initially randomized?) SECONDARY GUIDES: 1) Were the patients� health care workers and study personnel �blind� to treatment? 2) Were the groups similar at the start of the trial? 3) Aside from the experimental intervention, were the groups treated equally? 4) Do the statistics used appear to be appropriate for the data?

41. B: WHAT WERE THE RSULTS? C: 1) Is the study objective / null hypothesis accepted or rejected ? 2) How large was the treatment effect ? a) Risk without therapy ( baseline risk): X b) Risk with therapy : Y c) Absolute risk reduction ? X-Y d) Relative risk reduction (RRR): { 1-(Y/X)} x 100%

42. D: How precise was the estimate of treatment effect ? a) What are the CI�s? b) Are the p � values significant? c) will the results help me in caring for my patients ? Can the results be applied to my patient care? Were all clinically important outcomes considered? Are the likely treatment benefits worth the potential harms and costs?

45. Invasive Breast Cancers (Annualized %) by Baseline Characteristics and Randomization Assignment

47. Conclusions:� Treatment with CEE alone for 7.1 years does not increase breast cancer incidence in postmenopausal women with prior hysterectomy. However, treatment with CEE increases the frequency of mammography screening requiring short interval follow-up. Initiation of CEE should be based on consideration of the individual woman's potential risks and benefits.

48. Thank You & A Very Happy Father�s DayTo All of Us!