No Detriments From Lumpectomy/RT in BRCA 1/2 Carriers

SAN ANTONIO—Breast cancer patients with BRCA 1 or 2 mutations undergoing breast-conserving surgery plus radiotherapy do not have more in-breast recurrences or radiotherapy complications than their counterparts without the germ-line mutation, and they derive particular benefits from prophylactic bilateral oophorectomy, according to 10-year results from a large collaborative database reported at the 26th San Antonio Breast Cancer Symposium (abstract 5).

"The functions of BRCA 1 and 2 are largely unknown, though we do know they are important in maintaining genomic integrity. In vitro studies have shown increased radiation sensitivity in cells deficient in BRCA 1 protein, and BRCA 2 has been shown to be a factor in DNA repair mechanisms," said Lori Pierce, MD, of the University of Michigan, Ann Arbor. These characteristics could conceivably alter treatment outcomes and possibly lead to chronic radiotherapy complications due to alterations in DNA repair, she noted.

The study was based on chart reviews from 12 medical centers of 180 BRCA 1/2 carriers and 496 matched controls with sporadic breast cancer (no more than one postmenopausal relative with breast cancer and no family history of ovarian cancer). All patients were diagnosed with stage I-II disease and treated with breast-conserving surgery plus radiotherapy. Age at diagnosis was 40.5 years in the genetic cohort and 41.4 in the sporadic cohort. Median follow-up was 7.7 and 6.5 years, respectively.

Treatment was comparable between the two cohorts regarding surgery and radiation dose and field. More patients in the genetic group received chemotherapy and more in the sporadic group received tamoxifen. These factors were adjusted for in the multivariate analysis.

Recurrence Rates Similar Overall

In the overall data set, mutation carriers did not have significantly higher rates of local recurrence than persons with sporadic cancers, although there was a trend of slightly worse recurrence rates in the breast and more cancer occurrences outside of the breast among the carriers, Dr. Pierce reported.

Local-only recurrence as the first failure occurred in 22 of 180 genetic patients (12%) and 38 of 496 sporadic patients (7.6%). Analysis of the in-breast tumor recurrences by age, nodal status, and stage also revealed no significant increases among the genetic cohort. Contralateral recurrences, however, were significantly higher among carriers than sporadic patients (P = .0001), she said.

There was also a trend toward some difference in the time of diagnosis of isolated in-breast recurrences, with genetic patients remaining cancer-free longer. Genetic patients were diagnosed at 8.3 years vs 4.5 years in the sporadic group (P = .06).

In patients with isolated local recurrences who underwent surgery, subsequent control rates (local and systemic) were much better in the genetic group, who had no further recurrences, while 29% of sporadic patients had recurrences after this surgery. "All the recurrences in the genetic cohort were successfully salvaged long term. The high salvage rate, the longer time to ipsilateral recurrence, the increased ‘elsewhere’ failures are highly suggestive of new primaries rather than true recurrences," she said.

Oophorectomy Patients

A number of patients in the genetic cohort had prophylactic oophorectomy, and this subset showed a "very striking" improvement in breast tumor control, Dr. Pierce reported. Carriers who underwent oophorectomy had a hazard ratio for tumor control of 0.075 (P = .001). In a comparison of carriers without oophorectomy vs sporadic patients without oophorectomy, a significantly worse 12-fold difference in in-breast tumor control rate was seen for the genetic patients (P = .03).

Carriers who took tamoxifen also achieved some protection, both in in-breast and contralateral tumor control, but the study was underpowered to show significant differences according to this parameter, she said.

In a multivariate analysis, bilateral oophorectomy was found to be the most important independent predictor of in-breast tumor control. The hazard ratio for carriers having oophorectomy was 0.12 (P > .0001), compared with carriers without oophorectomy.

Bilateral oophorectomy was also a highly significant predictor of contralateral recurrences among carriers. Furthermore, compared with sporadic patients, genetic patients without oophorectomy had a 16-fold increased hazard ratio.

"We showed that oophorectomy was associated with a significantly decreased ipsilateral in-breast recurrence rate in mutation carriers. When you look at the non-oophorectomy group, that is where you found genetic status to be an independent predictor for in-breast tumor recurrence," she said.

Finally, Dr. Pierce said, BRCA 1/2 carriers did not have a greater occurrence of radiotherapy complications, including toxicity of the skin, subcutaneous tissue, lung, bone, or heart.