We have studied the Tyrer-Cuzick model in women with atypical hyperplasia. Overall the Tyrer-Cuzick model overpredicted the number of breast cancers within the first 10 years in this group of women by a factor of almost two. The individual specific agreement between the 10-year Tyrer-Cuzick predictions and the individual patient breast cancer outcomes was low, with a c-statistic of 0.54.
The Tyrer-Cuzick model includes a comprehensive family history as part of its risk assessment. We therefore hypothesized that this model would perform better in women with a strong family history of breast cancer. However, this subgroup analysis within our atypia cohort did not show any improvement in risk prediction. Among our 331 women with atypical hyperplasia, only 68 women had a strong family history of breast cancer. The small number of patients with strong family history may have an impact on the ability to detect an improvement in model performance in this patient subgroup.
Looking at aggregate predictions for the group of women with atypia, the Gail 10-year risk estimates proved to be well calibrated with the number of cases of invasive breast cancer that developed in our cohort. However, the individual concordance between observed cancer status and the Gail model 10-year predictions was still poor. Thus, while the Gail model did well at predicting average group risk at 10 years, it did not predict an individual woman's breast cancer outcome better than chance alone and thus does not have clinical superiority over the Tyrer-Cuzick model.
What are the alternatives for predicting risk of individual women with atypical hyperplasia? The 10-year risk of 9.2% observed in this study is a reasonable estimate of the absolute risk of invasive breast cancer among women with atypia. shows the cumulative risk of breast cancer, corrected for the competing risk of death, among women with atypia. The figure is augmented with absolute risk estimates shown at 5-year intervals. This figure, and the corresponding cumulative risk estimates, can be used by clinicians who counsel women with atypia regarding their risk of subsequent breast cancer.
Cumulative risk of breast cancer after breast biopsy for women with atypical hyperplasia. The dotted lines indicate the upper and lower 95% point-wise confidence bands.
One limitation of this study relative to the Tyrer-Cuzick model pertains to the assessment of family history. In patients with a family history of breast cancer, the exact pedigree was not always available; in earlier years, family history was not documented as clearly in the clinical record because of less frequent use of genetic counselors and in-depth questioning of explicit family history (eg, which aunt—maternal or paternal—had breast cancer). However, we did not observe a major difference in model performance among groups on the basis of degree of family history, suggesting that the overestimation of risk by the Tyrer-Cuzick model was not due to any limitations of our family history data. We also acknowledge that the Tyrer-Cuzick model was not designed to predict risk after 10 years of follow-up. In our effort to extrapolate beyond 10 years, we noted that the model produced risk estimates for some women that exceeded 100%, suggesting that such a linear extrapolation may not be appropriate for the long follow-up times available for many of the women in our cohort. Thus, the extrapolated risk predictions beyond 10 years should be viewed with some caution.
It is theoretically possible that the overestimated risk predictions seen in this group of women with atypia were due to an overall lower breast cancer risk in our cohort. This is unlikely because the relative risk of breast cancer in these women with atypical hyperplasia is 4.2,1
which is concordant with other established estimates of breast cancer risk for women with atypical hyperplasia.2,15,16,18,19
The representativeness of this cohort of women with atypia, with surgical biopsies performed from 1967 to 1991, could be questioned in the modern era of mammographic screening. However, the impact of mammographic screening is already apparent in this cohort, with 72% of patients accrued in 1982 to 1991 (), when mammography was used more frequently. A mammographic abnormality was the most frequent indication for biopsy. Regarding the use of surgical versus core biopsies, most atypias on core biopsy today are still removed via surgical excision.
Despite these limitations, this study was carried out on one of the largest cohorts of women with atypical hyperplasia confirmed by contemporary pathology review.12,15
The cohort has been followed for a considerable length of time, with data available from medical records and from study-specific questionnaires providing an average length of follow-up of more than 14 years.
Accurate risk prediction is vital to help guide clinical risk assessment and to assist patients with their risk reduction options, which can vary from close observation to medical therapy or surgical procedures such as bilateral mastectomy. With ongoing debate surrounding the recommendations for mammographic screening,20
accurate prediction of an individual woman's risk of breast cancer development would enable physicians to personalize recommendations for breast cancer screening with mammograms as well as individualize risk reduction strategies. Overprediction of breast cancer risk could lead to unwarranted use of risk-reduction strategies. Alternatively, significant underprediction can leave patients without intervention who might have benefited from appropriate management of their increased risk.
Although the Tyrer-Cuzick model uses more variables than the Gail model, it does not improve breast cancer risk prediction for women with atypia. It is likely that the risk inherent in a new variable may already be accounted for in features present in an existing model. This phenomenon may be more likely when tissue features are available, such as atypia. As an example, we and others have shown that a positive family history does not convey additional risk in women with atypia.15,21
In this instance, endogenous hereditary risk is presumably one driver of the development of atypia; hence, the presence of atypia already incorporates the risk of a positive family history. It is sobering that neither major risk factors like breast density nor recently identified common genetic variants associated with breast cancer risk have added significantly to current risk prediction models.22–24
In the future, other novel biomarkers of breast cancer risk will likely be identified that may improve breast cancer risk prediction. Previous studies from our group have shown that the number of foci of atypical hyperplasia, the extent of lobular involution, cyclooxygenase 2 overexpression, and proliferation extent can further stratify risk in women with atypical hyperplasia.15,25–27
Our study shows that the Tyrer-Cuzick model significantly overpredicts the risk of breast cancer development at 10 years in women with atypical hyperplasia, and that it is not able to accurately classify women into higher and lower risk groups. Neither the Tyrer-Cuzick model nor the Gail model predict individual risk in women with atypia better than chance alone. Therefore, when counseling women with atypical hyperplasia, we suggest that physicians use cumulative incidence data that reflect actual breast cancer events.