Turner B C, Harrold E, Matloff E, Smith T, Gumbs A A, Beinfield M, Ward B, Skolnick M, Glazer P M, Thomas A, Haffty B G
Department of Therapeutic Radiology, Yale University School of Medicine, New Haven, CT 06520-8040, USA.
J Clin Oncol. 1999 Oct;17(10):3017-24. doi: 10.1200/JCO.1999.17.10.3017.
Breast cancer patients treated conservatively with lumpectomy and radiation therapy (LRT) have an estimated lifetime risk of local relapse (ipsilateral breast tumor recurrence [IBTR]) of 10% to 15%. For breast cancer patients carrying BRCA1 or BRCA2 (BRCA1/2) mutations, the outcome of treatment 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.
Between 1973 and 1994, there were 52 breast cancer patients treated with LRT who developed an IBTR within the prior irradiated breast and who were willing to participate in the current study. From our database, we also identified 52 control breast cancer patients treated with LRT without IBTR. The control patients were individually matched to the index cases with respect to multiple clinical and pathologic parameters. Lymphocyte DNA specimens from all 52 locally recurrent patients and 15 of the matched control patients under age 40 were used as templates for polymerase chain reaction amplification and dye-primer sequencing of exons 2 to 24 of BRCA1, exons 2 to 27 of BRCA2, and flanking intron sequences.
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 ages 40 and 49, and one (3.8%) of 26 older than age 49. In comparison to the six (40%) of 15 of patients under age 40 with IBTR found to have BRCA1/2 mutations, 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 BRCA1/2 mutations was 7.8 years compared with 4.7 years for patients without BRCA1/2 mutations (P =.03). By clinical and histologic criteria, these relapses represented second primary tumors developing in the conservatively treated breast. All patients with BRCA1/2 mutations and IBTR underwent successful surgical salvage mastectomy at the time of IBTR and remain alive without evidence of local or systemic progression of disease.
In this study, we found an elevated frequency of deleterious BRCA1/2 mutations in breast cancer patients treated with LRT who developed late IBTR. The relatively long time to IBTR, as well as the histologic and clinical criteria, suggests that these recurrent cancers actually represent new primary breast cancers. Early onset breast cancer patients experiencing IBTR have a disproportionately high frequency of deleterious BRCA1/2 mutations. This information may be helpful in guiding management in BRCA1 or BRCA2 patients considering breast-conserving therapy.
接受保乳手术和放射治疗（LRT）的乳腺癌患者，其局部复发（同侧乳腺肿瘤复发[IBTR]）的终生风险估计为10%至15%。对于携带BRCA1或BRCA2（BRCA1/2）突变的乳腺癌患者，LRT治疗在IBTR方面的效果尚未确定。在本研究中，我们在一项对接受LRT治疗且发生IBTR的乳腺癌患者的研究中，估计BRCA1/2突变的频率。
1973年至1994年间，有52例接受LRT治疗的乳腺癌患者，在先前接受照射的乳腺内发生了IBTR，且愿意参与本研究。从我们的数据库中，我们还确定了52例接受LRT治疗但未发生IBTR的对照乳腺癌患者。对照患者在多个临床和病理参数方面与索引病例进行了个体匹配。来自所有52例局部复发患者以及15例年龄小于40岁的匹配对照患者的淋巴细胞DNA标本，被用作聚合酶链反应扩增和对BRCA1的第2至24外显子、BRCA2的第2至27外显子以及侧翼内含子序列进行染料引物测序的模板。
LRT治疗后，52例乳腺癌患者中有8例（15%）发生IBTR且携带有害的BRCA1/2突变。按年龄划分，15例年龄小于40岁且发生IBTR的患者中有6例（40%）携带BRCA1/2突变，40至49岁的11例患者中有1例（9.0%），49岁以上的26例患者中有1例（3.8%）。与15例年龄小于40岁且发生IBTR且被发现携带BRCA1/2突变的患者中的6例（40%）相比，15例未发生IBTR且携带BRCA1/2突变的匹配对照患者中只有1例（6.6%）（P = 0.03）。携带BRCA1/2突变的患者发生IBTR的中位时间为7.8年，而未携带BRCA1/2突变的患者为4.7年（P = 0.03）。根据临床和组织学标准，这些复发代表在接受保守治疗的乳腺中发生的第二原发性肿瘤。所有携带BRCA1/2突变且发生IBTR的患者在发生IBTR时均成功接受了挽救性乳房切除术，且仍然存活，无局部或全身疾病进展的证据。
在本研究中，我们发现接受LRT治疗且发生晚期IBTR的乳腺癌患者中，有害BRCA1/2突变的频率升高。发生IBTR的时间相对较长，以及组织学和临床标准，表明这些复发性癌症实际上代表新的原发性乳腺癌。发生IBTR的早发性乳腺癌患者中，有害BRCA1/2突变的频率不成比例地高。该信息可能有助于指导考虑保乳治疗的BRCA1或BRCA2患者的管理。
