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Clinical Reviews


Reducing the risk of breast cancer: Key trials and their impact on practice

An expert sifts the data regarding chemopreventive options and expands on current guidelines for endometrial cancer screening of tamoxifen users.

July 2003 · Vol. 15, No. 7

KEY POINTS

  • In the Breast Cancer Prevention Trial, women taking tamoxifen experienced a 49% overall reduction in invasive breast cancer; the relative risk of endometrial cancer was 4.01 for women over 50 and 1.21 for women younger than 50.
  • The risk of serious adverse effects with tamoxifen use appears to be lower in women under age 50.
  • Preclinical animal data suggest that, like tamoxifen, raloxifene has potent antiestrogen effects on breast tissue.
  • Because aromatase inhibitors block the peripheral conversion of androstenedione to estrogens, they inhibit both initiation and promotion of breast cancer. Thus, they may be more effective than selective estrogen receptor modulators in preventing the disease.

More than 28,000 additional breast cancers could be prevented over 5 years if all eligible women were given tamoxifen.1

This is just one of several important findings highlighted in the studies covered in this review of breast cancer risk assessment and chemopreventive options.

Because Ob/Gyns often treat tamoxifen users who experience uterine bleeding and worry about their risk of endometrial cancer (see “Endometrial screening and tamoxifen users: Going beyond the ACOG opinion,”), it is crucial that we have the latest data on preventive therapies for breast cancer—which include not only tamoxifen, but also, potentially, raloxifene and aromatase inhibitors—so that we may facilitate proper work-up and monitoring.

Endometrial screening and tamoxifen users: Going beyond the ACOG opinion

With the rising use of tamoxifen has come an increased need for vigilance for signs of endometrial cancer. To address the issue, the American College of Obstetricians and Gynecologists (ACOG) released a committee opinion on the subject in April 2000.1

In the opinion, ACOG observed that screening tests have not increased the early detection of endometrial cancer in women using tamoxifen and may lead to more invasive and costly diagnostic procedures. ACOG also recommended that Ob/Gyns:

  • Educate women taking tamoxifen on the risks of endometrial proliferation, hyperplasia, and cancer and stress the importance of annual gynecologic exams.
  • Closely monitor these patients for signs of endometrial hyperplasia or cancer.
  • Encourage patients to promptly report abnormal vaginal symptoms, including bloody discharge, spotting, staining, or leukorrhea.
  • Investigate any abnormal vaginal bleeding, bloody discharge, spotting, or staining.
  • Limit tamoxifen therapy to 5 years, as no benefit has been established beyond this time frame.
  • Initiate proper gynecologic management and reassess the use of tamoxifen if the patient develops atypical endometrial hyperplasia.
  • Consider resuming tamoxifen therapy following hysterectomy for endometrial carcinoma, in consultation with the physician responsible for the woman’s breast care.1

Screening tests help determine risk. In light of data published over the last 5 years, I now perform endometrial screening on patients about to begin tamoxifen therapy—a practice that differs from the ACOG opinion outlined above. Here is why:

Work published by Berliere et al2 in 1998 and updated in 20003 suggest that, among women on tamoxifen therapy, there exists a group at high risk and a group at low risk for developing complex atypical hyperplasia of the endometrium.

Berliere and her group studied 575 asymptomatic postmenopausal women with recently diagnosed breast cancer about to begin tamoxifen therapy. Each woman received transvaginal ultrasound; if the endometrial echo was greater than 4 mm, office hysteroscopy was performed. Of the study population, 17.4% had initial benign polyps of the endometrium. All polyps were removed, tamoxifen therapy initiated, and follow-up carried out through 5 years.

Among the women with no initial polyp (whom I would classify as “squeaky clean”), 0.7% developed atypical hyperplasia over the 5-year study period—compared with 11.7% of those who had an initial polyp removed. In addition, 11.7% of squeaky clean patients experienced polyp formation, compared with 17.6% of those with initial polyps. Thus, the 17.4% with initial benign polyps had 18 times the risk of the squeaky clean group for developing atypical hyperplasia while on tamoxifen therapy.

These findings have caused me to rethink my approach toward endometrial surveillance for women taking tamoxifen.4

Here is my current practice:

  • When patients are diagnosed with breast cancer and scheduled to begin tamoxifen therapy, I perform pretreatment screening.
  • If no initial endometrial polyps are found, I follow ACOG’s recommendations. Further interventions are unnecessary (unless abnormal symptoms develop), since these patients are at no more risk for endometrial cancer than women not taking tamoxifen.
  • For patients with an initial polyp (ie, the high-risk group), I remove the polyp prior to starting tamoxifen treatment and monitor them throughout the course of therapy, periodically utilizing transvaginal ultrasound and saline infusion sonohysterography.

REFERENCES

1. Committee on Gynecologic Practice, American College of Obstetricians and Gynecologists. ACOG Committee Opinion #232: Tamoxifen and Endometrial Cancer. Washington, DC: ACOG; April 2000.

2. Berliere M, Charles A, Galant C, Donnez J. Uterine side effects of tamoxifen: a need for systematic pretreatment screening. Obstet Gynecol. 1998;91(1):40-44.

3. Berliere M, Radikov G, Galant C, Piette P, Marbaix E, Donnez J. Identification of women at high risk of developing endometrial cancer on tamoxifen. Eur J Cancer. 2000;36(suppl 4):S35-S36.

4. Goldstein SR. Controversy about uterine effects and safety of SERMs: the saga continues. Menopause. 2002;9:381-384.

Assessing risk: The need for a new model

Although a number of breast cancer riskassessment models are available based on individual risk factors (TABLE 1), estimates based on combinations of factors are preferable. The Gail model,2 widely used to determine breast cancer risk, takes into account nongenetic (nulliparity, age at menarche) and genetic (family history) factors, as well as the number of previous breast biopsies. It assigns a smaller relative risk to women over age 50. A Web-based version, available at bcra.nci.nih.gov/brc, is useful for calculating a woman’s risk of developing invasive disease over the next 5 years, as well as over her remaining lifetime.

Limitations of the Gail model. Unfortunately, the data on which the model is based were collected in the late 1970s and early 1980s. Today, the greater ease of breast histopathologic assessment by fine-needle aspiration and outpatient core-needle biopsy has increased the rate of tissue sampling, creating confusion as to what constitutes a biopsy. Thus, the cutoff of 1.66% for high risk—the threshold adopted for the Breast Cancer Prevention Trial (BCPT)—loses some credibility.

Consider this example: A 50-year-old nulliparous Caucasian woman experienced menarche at age 11, has no first-degree relatives with a history of breast cancer, and has never had a breast biopsy. The Gail model would assign her a risk of developing breast cancer of 1.2% in the next 5 years and 10.8% over her lifetime. However, if the same patient had had 3 breast biopsies, her risk would rise to 1.8% in the next 5 years and 15.8% for her lifetime (placing her in the high-risk category), even if none of the biopsies revealed hyperplasia.

Biomarkers. Objective findings that are patient-specific but which correlate closely with breast cancer development are needed.

Biomarkers have been proposed; among them: ultrasensitive measurement of serum estradiol levels in postmenopausal women.3 In the Multiple Outcomes of Raloxifene Evaluation (MORE),4 the women who had the greatest reduction in breast cancer during treatment had the highest baseline serum estradiol levels (FIGURE 1)—although the baseline levels of all subjects were well within the postmenopausal range of 20 pmol/L or less.

TABLE 1

Breast cancer risk factors and their relative risks19

RELATIVE RISK <2

RELATIVE RISK 2–4

RELATIVE RISK >4

  • Age 25 to 34 at first live birth
  • Early menarche
  • Late menopause
  • Proliferative benign disease
  • Postmenopausal obesity
  • Alcohol use
  • Hormone replacement therapy
  • Age >35 at first birth
  • First-degree relative with breast cancer
  • Nulliparity
  • Radiation exposure
  • Prior breast cancer
  • Gene mutations
  • Lobular carcinoma in situ
  • Ductal carcinoma in situ
  • Atypical hyperplasia

FIGURE 1 Breast cancer risk in raloxifene users


Reprinted with permission from: Cummings SR, Duong T, Kenyon E, et al. Serum estradiol level and risk of breast cancer during treatment with raloxifene. JAMA. 2002;287:216-220. Copyright © 2002 American Medical Association. All rights reserved.

Chemoprevention: The rationale for tamoxifen

Data from preclinical animal and in vitro studies led to the use of tamoxifen, a selective estrogen receptor modulator (SERM), for primary prevention of breast cancer in healthy women. The drug was shown to inhibit mammary tumors in mice and rats and suppress hormone-dependent breast cancer cell lines in vitro.5

Clinical data from the Early Breast Cancer Trialists Collaborative Group also helped spur prevention trials with tamoxifen.6 Besides decreasing the risk of recurrent breast cancer, tamoxifen reduced the risk of contralateral, new-onset breast cancer by 47% after 5 years of adjuvant treatment (P = .00001) and by 26% after 2 years of treatment (P = .004). This, along with tamoxifen’s favorable effects on skeletal remodeling and lipid levels, led to a series of chemopreventive trials in the United States and Europe (TABLE 2).

TABLE 2

Results of tamoxifen trials

 

BREAST CANCER PREVENTION TRIAL7

ROYAL MARSDEN10

ITALIAN11

Number of participants

13,388

2,471

5,408

  Age ≤50

40%

62%

36%

  One first-degree relative with breast cancer

55%

55%

18%

  >2 first-degree relatives with breast cancer

13%

17%

2.5%

  HRT users

0%

42%

8%

Woman-years of follow-up

46,858

12,355

20,731

Cancer incidence/1,000

  Placebo

6.8

5.0

2.3

  Tamoxifen

3.4

4.7

2.1

Breast Cancer Prevention Trial: Tamoxifen reduces cancer incidence

In 1992, the National Surgical Adjuvant Breast and Bowel Project launched a prevention trial using tamoxifen: the Breast Cancer Prevention Trial.7 A total of 13,388 women aged 35 or older and at high risk for breast cancer were enrolled at numerous sites throughout the United States and Canada.

The Gail model was utilized to determine which women had sufficient risk—that is, a risk of developing invasive breast cancer within the next 5 years of 1.66% or greater—to be included in the trial.2 Subjects were randomly assigned to receive placebo or tamoxifen (20 mg/d) for 5 years.

The trial was terminated in April 1998, 14 months before its planned completion, due to the striking reduction in new-onset breast cancer in the tamoxifen group. The data safety monitoring board felt it would be unethical to allow one half of the participants, who were deemed to be at high risk, to continue taking placebo in light of the dramatic reduction in both invasive and noninvasive breast cancer with tamoxifen use.

The overall incidence of breast cancer in the tamoxifen group was 3.4 cases per 1,000, compared with 6.8 cases per 1,000 in the placebo group. Overall, the reduction in invasive breast cancer was 49% (P<.000001). The reductions were 44% for women in the group aged 35 to 49 years, 51% for those aged 50 to 59, and 55% for those 60 years and older (FIGURE 2).

Tamoxifen decreased the incidence of noninvasive breast cancer (ductal carcinoma in situ) by 50%. (Expanded use of mammography has led to greater detection of this cancer. Most such lesions are estrogen-receptor–positive.8) In addition, tamoxifen reduced breast cancer risk in women with a history of lobular carcinoma in situ by 56% and atypical hyperplasia by 86%. Overall, tamoxifen decreased the occurrence of estrogen-receptor–positive tumors by 69%, but had no impact on tumors that were estrogen-receptor–negative.

Tamoxifen’s other effects in healthy women. The BCPT offered the first largescale data on the effects of tamoxifen in healthy women.7 (All previous studies included only women with breast cancer.) Several secondary endpoints merit consideration.

  • Endometrial cancer risk. Researchers found the relative risk (RR) of endometrial cancer associated with tamoxifen therapy in healthy women was 2.53 (95% confidence intervals [CI], 1.35, 4.97). When this figure was calculated for the different age groups, it rose to 4.01 (95% CI, 1.70, 10.90) in women over 50, and declined to 1.21 for women ages 49 and under (95% CI, 0.41, 3.60).
  • Thromboembolic event risk. The same age distinction was seen in relation to thromboembolic events. There were no statistically significant increases in pulmonary emboli or deep venous thrombosis in women 49 years of age or under. Although it is unclear whether the trial was sufficiently powered for this particular endpoint, the likelihood that serious adverse events will limit the potential benefits of tamoxifen appears to be lower in women under the age of 50. This has significant clinical consequences for physicians caring for perimenopausal patients.
  • No change in incidence of other cancers. Overall, the incidence of invasive cancers other than those of the breast and uterus was the same for the tamoxifen and placebo groups.
  • Other outcomes. The relative risk of death from any cause was 0.81 (95% CI, 0.56–1.16).

There was a slight increase in the risk of myocardial infarction (RR, 1.11; 95% CI, 0.65–1.92) and a slight decrease in the development of severe angina (RR, 0.93; 95% CI, 0.40–2.14) in tamoxifen users, although neither of these was statistically significant.

The overall relative risk of fractures at various sites (hip, spine, radius) was 0.81 (95% CI, 0.63–1.05).

A statistically significant increase was found in the number of women with cataracts who then underwent cataract surgery. That relative risk was 1.57 (95% CI, 1.16–2.14).

Continued...
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