Study Sheds Light on BRCA Mutation Cancer Recurrence and Treatment-Resistance

Researchers in Pennsylvania have offered new insights into why BRCA1/2-mutation-associated breast and ovarian cancers have a high risk of recurrence. The findings may point to more effective methods to treat such cancers.

BRCA1 and BRCA2 proteins are key DNA-repair proteins. Their functional loss leaves some cells highly vulnerable to DNA damage, including damage that triggers cancer. Women with inactivating mutations in the BRCA1 or BRCA2 genes have very high lifetime risks of breast cancer, as well as high risks of ovarian cancer.  BRCA1/2-mutation-associated tumors often can be put into remission with chemo drugs and radiation, which take advantage of the tumors’ lower DNA-repair capacity, but the tumors have a high risk of recurrence within a few years of first-line therapy completion. Scientists understand relatively little about what drives this rate of recurrence.

To help address this knowledge gap, researchers at the University of Pennsylvania’s Basser Center for BRCA at the Abramson Cancer Center compared 67 sets of primary and recurrent BRCA1/2 mutation-associated breast and ovarian tumors. For each set, they compared the DNA mutations, gene activity patterns, and other tumor cell features in the primary tumor to see how these features differed from the recurrent tumor.

“We hypothesized that differences between paired tumors could point to possible mechanisms of tumor evolution allowing recurrence,” said the study’s senior author Katherine Nathanson, MD, the Pearl Basser Professor for BRCA-Related Research in Penn’s Perelman School of Medicine, Deputy Director of the Abramson Cancer Center, and Director of Genetics at the Basser Center for BRCA.

The findings, reported recently in Nature Communications, found multiple features associated with recurrence, including structures that would be expected to improve tumors’ ability to repair treatment-caused DNA damage. “These results suggest key biological features of therapy-resistant recurrences, which point to new possibilities for treating BRCA1/2-mutation cancers,” Nathanson says.

One novel observation was that, especially in BRCA1-mutation recurrent cancers, the tumor cells often have switched to expressing a specific isoform of the BRCA2 protein’s messenger-RNA molecule. This isoform is slightly shorter-than-the normal length BRCA2 RNA. It is translated into the usual BRCA2 protein but is more stable than the normal BRCA2 messenger-RNA and thus would be expected to be associated with an increased level of BRCA2 protein—plausibly as a way of boosting DNA-repair capability.

In general, tumors being treated with strong DNA-damaging drugs and/or radiation may survive that treatment better, and ultimately recur, when they can increase their ability to repair DNA damage. The researchers linked the presence of the shorter form of the BRCA2 RNA not only to cancer recurrence but also to significantly decreased patient survival times.

Similarly, the researchers were surprised to find that whether the tumor had loss of the normal copy of the BRCA1 or BRCA2 gene—termed loss of heterozygosity—could vary through the tumor’s development. Loss of heterozygosity had been generally assumed to be necessary for development of breast and ovarian cancers in germline BRCA1/2 mutation carriers but work from this team and others has shown that it is not always needed. Now, they have found that in 25 percent of cases that loss of heterozygosity can vary between primary and recurrent tumors, a novel finding only possible with matched primary and recurrent tumors. Some tumors progress to not having loss of heterozygosity from having it, as part of tumor progression.  Other tumors go from having loss of heterozygosity to not having it, presumably as a mechanism of therapeutic resistance.

The authors say the discovery of novel markers of therapeutic resistance underscore the importance of profiling the tumor at the time of treatment. Nathanson and her colleagues are continuing to evaluate multiple other factors that contribute to therapeutic response and resistance in patients with BRCA1/2-related tumors.