Tailor Breast Cancer Prevention Strategies to Individual Risk

CHICAGO—Until findings from two recent clinical studies were released, there was no clear indication about the effectiveness of tamoxifen (Nolvadex) or prophylactic mastectomy for reducing the risk of invasive breast cancer in high-risk women.

However, initial results from the NSABP P-1 trial 2 years ago showed that a 5-year course of tamoxifen could reduce the incidence of invasive breast cancer by 49% and ductal carcinoma in situ (DCIS) by 50% among women at increased risk for breast cancer.

A 1999 retrospective study of moderate- and high-risk women who were followed for 14 years after undergoing prophylactic mastectomy at the Mayo Clinic indicated that the surgical procedure reduced breast cancer incidence and death by 90% (Hartmann LC et al: N Engl J Med 340:77, 1999).

Nevertheless, no single preventive strategy is appropriate for every woman at increased risk for breast cancer. “Both tamoxifen and prophylactic mastectomy have their uses in highly selected patients,” Monica Morrow, MD, said at the Second Annual Lynn Sage Breast Cancer Symposium.

These preventive options also have associated risks, such as an increased incidence of endometrial cancer, thrombotic events, postsurgical complications, and reoperations.

Clinicians therefore need to integrate breast cancer prevention into their practices by selecting a prophylactic measure in keeping with the magnitude of a woman’s risk, the potential side effects of the treatment option, and the timing of the intervention, said Dr. Morrow, professor of surgery and director of the Lynn Sage Comprehensive Breast Center, Northwestern University Medical School.

Dr. Morrow pointed out that making preventive care decisions on the basis of breast cancer risk was difficult in the past because of disagreement about the role of individual risk factors as well as their dependence on age and their interactions with one another.

The Gail Model

The Gail model, which was used in the NSABP P-1 study of tamoxifen in the chemoprevention of breast cancer, has resolved some of these concerns because it considers a woman’s age, age at menarche, age at first birth, number of first- degree relatives with breast cancer, history of previous breast biopsies, and history of atypical hyperplasia.

The Gail model, in fact, was one of the most useful pieces of information to come out of the NSABP tamoxifen prevention trial, Dr. Morrow said. During the 5 years of the study, the Gail model predicted that 159 invasive breast cancers would occur, and 155 did occur.

The model underestimated risk for women in the lowest risk group by about 30%, and it overestimated risk in the highest risk group by 20%. However, none of the over- or underestimates reached traditional statistical significance according to confidence intervals.

“Something to keep in mind is that the Gail model is an estimate, not an absolute number, and at either end of the spectrum of risk, there is room for variability,” Dr. Morrow said.

The Gail model also was accurate in predicting the risk of invasive breast cancer on the basis of some individual risk factors, such as age at menarche. The model was less successful in determining risk for young women who had two or more breast biopsies.

For women over the age of 50, the model accurately predicted breast cancer risk; the rate of expected-to-observed cases (E/O) was 1.07 when atypical hyperplasia was absent. For women under the age of 50, it overestimated the development of breast cancer whether atypical hyperplasia was present (E/O 2.00) or absent (E/O 1.76).

This finding is not surprising, Dr. Morrow said, because breast biopsy is no longer restricted to clinically apparent mass lesions; some clinicians count cyst aspiration as a biopsy or insert biopsy needles into bumpy areas to reassure both the patient and themselves that no cancer is present.

In addition, improvements in mammography are revealing more suspicious lesions that are subjected to image-guided biopsy. Clinicians consequently should be wary when applying the Gail model to younger women whose major component of breast cancer risk is a history of multiple breast biopsies.

“The number of breast biopsies may very well reflect the patient’s anxiety or the physician’s anxiety about the level of risk as much as any biological process,” she said.

The Gail model should not be applied to other patient populations, such as women with a personal history of breast cancer, DCIS, or lobular carcinoma in situ, or a strong family history suggestive of a genetic predisposition to breast cancer.

“From the NSABP, we know that tamoxifen reduces risk due to a family history, histological precursors, and other risk factors, but we do not have data to say whether or not it reduces risk due to genetic mutation,” Dr. Morrow said. “There is no definitive information to say that tamoxifen works, and no information to say it doesn’t work.”

Finally, she said, the Gail model should be used with caution when assessing the risk of breast cancer in nonwhite women. Only 99 black women were included in the placebo arm of the NSABP P-1 trial, and the number of women from other racial groups was even smaller.

The decision to use tamoxifen in breast cancer prevention must balance the chance that it may reduce the risk of invasive disease against the potential for causing life-threatening side effects, such as endometrial cancer and thrombotic vascular events.

Risk of Endometrial Cancer

The NSABP P-1 trial found a 2.5 overall relative risk of endometrial cancer in postmenopausal women taking tamox-ifen. A case-controlled study refined the assessment of endometrial cancer risk from tamoxifen according to hormone exposure and body mass index (BMI) (Bernstein ML et al: J Natl Cancer Inst 91:1654-1662, 1999).

This study of 324 women who were treated with tamoxifen for breast cancer and 671 matched controls showed an overall 1.5 rate of increased risk of endometrial cancer among women who used tamoxifen.

The risk of endometrial cancer was greater among women who had taken estrogen previously (3.53) than among those who had not (1.14), and it was highest among women who had taken estrogen previously and had a high BMI (3.95).

“It is the obese woman with a prior history of estrogen use who has a substantial elevation in her risk of endometrial cancer,” Dr. Morrow said.

For the woman with low BMI and no prior estrogen use, she pointed out, there was no statistically significant elevation of risk in this study. “So we can say that tamoxifen definitely increases the risk of endometrial cancer, and patients need to be informed about that. But this risk needs to be modulated by other known risk factors, and in talking to women, we need to try to individualize our estimates of risk,” Dr. Morrow said.

The other important complication of tamoxifen use is thrombotic vascular events, which appears to be age related; the only statistically significant increase in risk for stroke, pulmonary embolism, and deep-vein thrombosis occurs in women over the age of 50, she observed.

Risk-Benefit Studies

Findings from risk-benefit studies, are beginning to suggest when tamoxifen may be used to reduce the risk of breast cancer. The findings “don’t mean that every premenopausal woman with a risk level for breast cancer greater than 1.5 needs to be treated,” she said. “It means that the likelihood of significant complications is extremely low.”

The choice for a postmenopausal woman seems to revolve around the issue of whether she has a functioning uterus. “As a woman gets older,” she said, “she needs a higher level of breast cancer risk to offset the risk of deep-vein thrombosis and endometrial cancer. So knowing whether or not a woman has her uterus is a clinically important piece of information in postmenopausal women.”

Prophylactic Mastectomy

According to the Hartmann study, prophylactic mastectomy may be appropriate for women at high risk of breast cancer because of a strong family history of the disease, which suggests a genetic predisposition. However, the procedure is associated with surgical complications.

Also, the first breast reconstruction after mastectomy often is not the last operation. The incidence of unplanned reoperations within 5 years is about 30% for implants and 10% for tissue flap reconstruction.

Dr. Morrow noted that “not all women at increased risk for breast cancer require treatment, nor will they all benefit from treatment because of other comor-bid conditions. Not all women who will benefit from treatment want treatment. We must regard risk as a personal decision. Undertaking risk reduction is something a women does when she finds her level of risk to be unacceptable, not necessarily when we find her risk to be unacceptable.”