BRCA1/BRCA2 germline mutations in locally recurrent breast cancer patientsafter lumpectomy and radiation therapy: Implications for breast-conservingmanagement in patients with BRCA1/BRCA2 mutations

Purpose: Breast cancer patients treated conservatively with lumpectomy and radiation therapy (LRT) have an estimated lifetime risk of local relapse (i psilateral breast tumor recurrence [IBTR]) of 10% to 15%. For breast cancer patients carrying BRCA1 or BRCA2 (BRCA1/2) mutations, the outcome of treat ment with LRT with respect to IBTR has not been determined. In this study, we estimate the frequency of BRCA1/2 mutations in a study of breast cancer patients with IBTR treated with LRT. Patients and Methods: Between 1973 and 1994, there were 52 breast cancer pa tients treated with LRT who developed an IBTR within the prior irradiated b reast and who were willing to participate in the cur rent study. From our d atabase, we also identified 52 control breast cancer patients treated with LRT without IBTR The control patients were individually matched to the inde x cases with respect to multiple clinical and pathologic parameters. Lympho cyte DNA specimens from all 52 locally recurrent patients and 15 of the mat ched control patients under age 40 were used as templates for polymerase ch ain reaction amplification and dye-primer sequencing of exons 2 to 24 of BR CA1, exons 2 to 27 of BRCA2 and flanking intron sequences. Results: After LRT, eight (15%) of 52 breast cancer patients had IBTR with deleterious BRCA1/2 mutations. By age, there were six (40%) of 15 patients with IBTR under age 40 with BRCA1/2 mutations, one (9.0%) of 11 between age s 40 and 49, and one (3.8%) of 26 older than age 49. in comparison to the s ix (40%) of 15 of patients under age 40 with IBTR found to have BRCA1/2 mut ations, only one (6.6%) of 15 matched control patients without IBTR and had a BRCA1/2 mutation (P = .03). The median time to IBTR for patients with BR CA1/2 mutations was 7.8 years compared with 4.7 years for patients without BRCA1/2 mutations (P = .03). By clinical and histologic criteria, these rel apses represented second primary tumors developing in the conservatively tr eated breast. All patients with BRCA1/2 mutations and IBTR underwent succes sful surgical salvage mastectomy at the time of IBTR and remain alive with out evidence of local or systemic progression of disease. Conclusion: In this study we found an elevated frequency of deleterious BRC A1/2 mutations in breast cancer patients treated with LRT who developed lat e IBTR. The relatively long time to IBTR, as well as the histologic and cli nical criteria, suggests that these recurrent cancers actually represent ne w primary breast cancers. Early onset breast cancer patients experiencing I BTR have a disproportionately high frequency of deleterious BRCA1/2 mutatio ns. This information may be helpful in guiding management in BRCA1 or BRCA2 patients considering breast conserving therapy. (C) 1999 by American Socie ty of Clinical Oncology.