The University Record, December 4, 2000

Radiation therapy may be safe for women with breast cancer gene mutations

By Kara Gavin
Health System Public Relations

Women with breast cancer who carry a genetic mutation that heightens their risk of the disease might not have to fear having radiation therapy as previously thought, according to a new study led by U-M researchers.

In fact, the results suggest, women with mutations of the BRCA 1 or 2 gene who had breast-conserving surgery after cancer diagnosis may get the same benefit from radiation therapy with no greater incidence of short- or long-term side effects as women with non-hereditary cancer. Some doctors have been concerned that in carriers of the BRCA 1 or 2 mutation, radiation’s ability to damage DNA in normal breast tissue might outweigh its benefit in killing cancer cells.

Radiation oncologist Lori Pierce, the study’s leader, reported on the study Oct. 24 at the annual meeting of the American Society for Therapeutic Radiation Oncology. Pierce and her colleagues from the Comprehensive Cancer Center and several partner institutions published results of the same study in the October issue of the Journal of Clinical Oncology.

“With five years of follow-up data in hand, we see no increased incidence of skin fibrosis, pain, shortness of breath or other side effects, which suggests that DNA repair mechanisms are intact in BRCA 1 and 2 mutation carriers,” Pierce says. “The fear of harm, based on laboratory findings that the BRCA gene product is linked to the cells’ own repair system, may have unnecessarily prevented some women from getting the full range of therapeutic care.”

The retrospective study also found similar high rates of survival, and low rates of cancer recurrence in the affected breast, for 71 women with the BRCA 1 or 2 mutations and 213 without a mutation who had similar diagnoses, surgical procedures and treatments.

But, Pierce cautions, the cancer recurrence data are based on only five years of follow-up. Data on how the women fared after 10 years, due to be available as early as spring of 2002, will be needed to say more certainly whether radiation therapy can continue to reduce the risk of cancer recurrence in the treated breast or the development of new cancers in the same breast.

As many as 10 percent of all breast cancer cases result from inherited factors, while the rest are thought to be sporadic or non-hereditary. In recent years, scientists have pinned down two genes—dubbed BRCA 1 and BRCA 2—that seem to account for most of the inherited cases.

Women who inherit a BRCA 1 or 2 mutation are known to have an increased risk—as high as 55 to 60 percent by age 70—of developing breast or ovarian cancer, probably because they have no genetic “safety net.” In other words, they have no extra normal copy to take over if their one normal copy in a single breast cell undergoes mutation and the cell produces an abnormal form of the protein encoded by the gene.

Even though scientists don’t yet understand the exact workings of the proteins that BRCA 1 and 2 produce, they think they may be tied to the mechanisms cells use to repair damaged DNA. Hence, the controversy over treating these women with radiation.

Since radiation therapy can reduce a woman’s chance of breast cancer recurrence from 35 percent to 40 percent to 10 percent after lumpectomy, the question is an important one. But physicians have worried that therapeutic radiation, no matter how carefully planned and delivered, could cause DNA damage in the remaining normal copy of BRCA 1 or 2 or that carriers of either mutation would show evidence of increased sensitivity to radiation following radiation treatment.

Pierce and her colleagues set out to test these hypotheses by studying the outcome of American and Canadian women with either a BRCA 1 or 2 mutation who underwent radiation following lumpectomy for early-stage breast cancer.

The researchers compared the women’s outcomes and complication rates with the same endpoints in closely matched women with non-hereditary forms of the disease. About half the women in each group had had chemotherapy as well as surgery and radiation.

Since the study was looking for differences in the incidence of any effects of radiation, not just cancer-causing effects, the researchers looked at the women’s records to see how many side effects or complications they had experienced after radiation treatments.

The results showed no differences in the low rates of short-term side effects between the BRCA mutation carriers and sporadic cancer patients. Both groups had similar incidence of skin redness and irritation, and a 1 percent to 2 percent rate of dry cough or shortness of breath and breast discomfort. No significant differences were observed either in the rates of long-term complications such as skin fibrosis, chronic shortness of breath or rib fractures.

Turning to cancer recurrence, the researchers found no significant differences in the rates at which cancer returned to the affected breast after five years of follow-up compared to the sporadic patients. For those whose cancer did come back in the same breast, additional treatment, such as mastectomy, kept it in check. For the other breast, mutation carriers had a higher rate of cancer, as expected.

Finally, the researchers looked at survival after five years. Again, no difference turned up between the two groups in relapse-free survival, cause-specific survival and overall survival.

“While it’s too soon to say that breast-conserving therapy results in long-term rates of cancer control in the treated breast in BRCA 1 or 2 carriers,” Pierce says, “it is clear that radiation is well-tolerated and can be safely given to women who carry either breast cancer mutation. Clinically-indicated adjuvant radiotherapy shouldn’t be omitted in carriers based on toxicity concerns.”