Turning the Tables on BRCA-related Breast Cancer

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For women in good health, the discovery of a mutated BRCA1 or BRCA2 gene is not good news. A harmful mutation in that gene may elevate your lifetime risk of developing breast cancer to as high as 80 percent. But for carriers of a BRCA mutation who have developed cancer, there may be a silver lining in that faulty copy. A novel drug treatment being tested at the Abramson Cancer Center, among several other international sites, turns that very mutation against the tumors it begets.

“This is the first time that we have been able to take the genetic reason a person has developed cancer and make it a target,” says Susan Domchek M’05, an associate professor of oncology and hematology and one of the investigators. In a proof-of-concept trial whose results appeared in The Lancet in July, Domchek and her colleagues reported that a six-month course of the therapy either shrank or halted the growth of tumors in 85 percent of subjects who received the higher of two doses tested.

The biological rationale behind it is clever. In order to survive and proliferate, all cells have to repair damage that gets done to their DNA. One of the ways they do so is via properly functioning BRCA1 and BRCA2 alleles. Most people who inherit a mutated version of BRCA from one parent also inherit a normal copy from the other parent. As long as a given cell has one functioning copy, things may be fine. But the loss of that single good allele can lead to genetic instability, since the back-up copy doesn’t work properly. 

That’s why carriers of BRCA1 and BRCA2 mutations are at risk to begin with. “As you get older, there are more hits to your DNA from lots of different things—the sun, alcohol, cigarette smoke, pollution,” says Domchek. “Because of that, the BRCA1 and 2 carriers unfortunately have an accelerated process, because they’ve already lost one good copy, so they only have to lose the second one for cancer to occur.”

But that means the actual cancers in these patients have lost one of the key ways to repair DNA damage and thus maintain themselves. The drug in this study, olaparib, targets another: a protein known as PARP. 
“When you knock out two different ways to repair damage, it places too much stress on the cell,” says Domcheck. “So the [cancer] cells basically fall apart.”

But crucially, healthy cells don’t. “If you give enough of a PARP-inhibitor, even to a normal cell, you’ll eventually do it damage,” Domchek explains. However, previous cell-culture studies have shown that “in order to make a cell die, if it’s a cell with one bad copy [of BRCA1 or BRCA2] and one good copy, you have to give it 1,000 times more drug than a cell where both copies are bad.” In other words, a dose that’s quite lethal to cancer cells poses a relatively minimal threat to the healthy cells nearby.

This study was small—27 patients received a low dose of olaparib and another 27 received a higher dose—and Domchek notes that further studies are needed. “We are hopeful that it will be both better and less toxic” than other drugs currently on the market, she says, “but only trials will tell us.”

In this demonstration trial, “there was no apparent excess toxicity with olaparib at the higher dose,” the authors reported. Furthermore, no patients in the high-dose group withdrew from the study on account of adverse side effects—though as with many chemotherapies, nausea and fatigue were common, if mostly low-grade.  

Forty-one percent of the patients in the higher-dose group showed substantial tumor shrinkage, including one subject whose tumor resolved completely. “If you add in the people who had stable disease for at least 23 to 24 weeks,” says Domchek, “meaning people whose tumors didn’t do anything for 6 months—which by the way is a long time for a cancer patient—that gets you to a clinical benefit rate of 85 percent. That’s just tremendous. If you can tell a patient that the likelihood that their tumor will either shrink or stay the same is 85 percent, well that’s as good as we ever get.”

Her group is now conducting a trial of olaparib on BRCA1- and BRCA2-mutation carriers with a wider variety of cancers. “This has some possibilities in, for instance, pancreatic cancer and prostate cancer as well as breast and ovarian cancer,” says Domchek. “So much more work needs to be done, but still, it’s very exciting.” —T.P.

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