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Breast Cancer Radiotherapy: Safe for All?

The Cleveland Clinic Foundation Cleveland, OH

To the Editor:Dr Obedian et al have provided a valuable addition to the literature concerning second malignancies in breast cancer patients treated with radiotherapy.¹ The message of their report seems clear: for the majority of patients with early-stage breast cancer, rates of second malignancies (including second breast cancer) seem to be equivalent in groups of patients treated with lumpectomy and radiation versus those who received mastectomy without adjuvant radiotherapy. This should be welcome news for patients and practitioners alike. However, clinical outcomes analyzed for large, inhomogeneous groups may not have the statistical power to rule out the existence of a treatment-related second cancer link for patients who are in atypical high-risk groups. We thus must be careful not to overinterpret the data.

This point is underscored in an article on prophylactic mastectomy in variable-risk patients that was coincidentally published in the June 2000 issue of the Journal of Clinical Oncology.² In this article, Meiser et al show that patients with variable-risk profiles should probably receive different counseling in terms of likelihood that a safety intervention such as prophylactic mastectomy will be justified based on future cancer risk. Thus, generalizations and recommendations for heterogeneous risk groups may be perilous and incomplete, leading to inappropriate counseling.^3,4

Obedian et al¹ noted that patients in their study group who were younger than 45 years of age at the time of treatment demonstrated a 10% incidence of contralateral breast cancer when treated with lumpectomy and radiotherapy, compared with a 7% risk when treated with mastectomy (P = not significant). Acquisition of family history data has been incomplete in much of the published literature. The article by Obedian et al lacks specific information on the number/percentage of women in the less than 45 years old age group who are family history–positive and/or BRCA1/BRCA2-positive. On the basis of the data available from the articles reviewed, among 1,007 patients who developed a contralateral breast cancer, 213 were positive for family history, and among 9,227 patients who did not develop a contralateral breast cancer, 1,708 patients were positive for family history.^5-9 The family history status was unknown for approximately 40% of the patients. Despite this deficiency, family history was associated with an increased risk (odds ratio, 1.18) of developing contralateral breast cancer. Moreover, in a study by Kollias et al⁹ in which the family history status was known for all patients, there was a stronger correlation between family history and contralateral breast cancer (relative risk, 2.4, P = 0.001) than between prior radiation and contralateral breast cancer (relative risk, 1.1, P = 0.7). This underscores the importance of separate risk analyses for patients with a family history of breast cancer. It would be advantageous if one could analyze specific risk correlations in small patient subsets. However, the study lacks the statistical power to perform this correlation. Larger and more detailed studies are necessary. In the meantime, we believe that the as-low-as-reasonably-achievable principle dictates that it is prudent to consider mechanisms by which we can significantly reduce both scatter and primary beam radiation to the contralateral breast during breast cancer radiotherapy, at least in those groups at high genetic risk. Several groups have recently discussed ways of achieving this goal.^3,10

REFERENCES

1. Obedian E, Fisher DB, Haffty BG: Second malignancies after treatment of early-stage breast cancer: Lumpectomy and radiation therapy versus mastectomy. J Clin Oncol 18: 2406-2412, 2000[Abstract/Free Full Text]

2. Meiser B, Butow P, Friedlander M, et al: Intention to undergo prophylactic bilateral mastectomy in women at increased risk of developing hereditary breast cancer. J Clin Oncol 18: 2250-2257, 2000[Abstract/Free Full Text]

3. Fraass BA, Roberson PL, Lichter AS: Dose to the contralateral breast due to primary breast irradiation. Int J Radiat Oncol Biol Phys 11: 485-497, 1983

4. Pierce LJ, Strawderman M, Narod SA, et al: Effect of radiotherapy after breast-conserving treatment in women with breast cancer and germline BRCA1/2 mutations. J Clin Oncol 18: 3360-3369, 2000[Abstract/Free Full Text]

5. Boice JD Jr, Harvey EB, Blettner M, et al: Cancer of the contralateral breast after radiotherapy for breast cancer. N Engl J Med 326: 781-785, 1992[Abstract]

6. Storm HH, Anderson M, Boice JD, Jr et al: Adjuvant radiotherapy and risk of contralateral breast cancer. J Natl Cancer Inst 84: 145-150, 1992[Free Full Text]

7. Kurtz JM, Amalric R, Brandone H, et al: Contralateral breast cancer and other second malignancies in patients treated by breast conserving therapy with radiation. Int J Radiat Oncol Biol Phys 15: 277-284, 1988[Medline]

8. Broët P, de la Rochefordière A, Scholl SM, et al: Contralateral breast cancer: Annual incidence and risk parameters. J Clin Oncol 13: 1578-1583, 1995[Abstract/Free Full Text]

9. Kollias J, Ellis IO, Elston CW, et al: Clinical and histologic predictors of contralateral breast cancer. Eur J Surg Oncol 25: 584-589, 1999[Medline]

10. Macklis RM, Crownover RL, Crowe J, et al: Reducing scatter radiation to the contralateral breast with a mobile, conformal shield during breast cancer radiotherapy. Am J Clin Oncol 22: 419-425, 1999[Medline]

Response

Yale University School of Medicine New Haven, CT

In Reply:Drs Unnithian and Macklis bring out some important cautionary notes in the interpretation of our recent study comparing breast cancer patients with second malignancies undergoing lumpectomy and radiation with a similar cohort undergoing surgical therapy alone.¹ Caveats in the interpretation of our data include, at the least, the heterogeneity of the population, the lack of a randomized control population and its inherent selection biases, and the limited number of patients at risk for more than 10 to 15 years, when radiation-induced malignancies are likely to occur.

Clearly, our study would not have the power, nor adequate information, to detect excess radiation-induced malignancies among subsets of patients with germline mutations in BRCA1/BRCA2, A-T, P53, or other genes associated with radiation repair or radiation response. However, I would emphasize the need to differentiate those patients with a family history of breast cancer from patients with a documented deleterious mutation in BRCA1/BRCA2, P53, or A-T, with respect to the possibility of an increased risk of radiation-induced malignancies.

I concur with Unnithian and Macklis that patients with a genetic predisposition to breast cancer represent a separate risk group with respect to contralateral disease. Breast cancer patients with deleterious mutations in BRCA1 or BRCA2 have an estimated risk of subsequently developing contralateral breast cancer ranging from 40% to 70%.² Whether the scattered dose from breast or chest wall irradiation or even low doses from routine mammography potentiate this risk is a currently unanswered question worthy of further investigation.

Fortunately, patients with inherited deleterious mutations in BRCA1/BRCA2, P53, A-T, or other genes associated with radiation repair or radiation response represent a minority (5% to 10%) of patients with breast cancer. Further studies are clearly warranted, and substantial limitations in our own study and the currently available literature must be acknowledged. However, the comparable second malignancy rate in irradiated and nonirradiated breast cancer patients provides additional information to clinicians and patients regarding the potential risks and benefits of breast-conserving therapy for the vast majority of patients with early-stage breast cancer.

REFERENCES

1. Obedian E, Fisher DB, Haffty BG: Second malignancies after treatment of early-stage breast cancer: Lumpectomy and radiation therapy versus mastectomy. J Clin Oncol 18: 2406-2412, 2000

2. Ford D, Easton DF, Bishop DT, et al: Risks of cancer in BRCA1-mutation carriers: Breast Cancer Linkage Consortium. Lancet 343: 692-695, 1994[Medline]

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