BRCA and Synthetic Lethality: Turning a Tumor’s Broken Repair Kit Against It

Key Takeaways:

• In a prospective cohort of nearly 10,000 women carrying BRCA1 or BRCA2 mutations, the cumulative risk of breast cancer by age 80 was 72% for BRCA1 and 69% for BRCA2 carriers, and the cumulative risk of ovarian cancer was 44% and 17%, respectively.
• BRCA1 and BRCA2 repair double-strand DNA breaks by homologous recombination; cells that have lost BRCA function are profoundly sensitive to inhibition of PARP, an enzyme that repairs single-strand breaks, because unrepaired nicks collapse replication forks into breaks the cell cannot fix, a principle called synthetic lethality.
• In the OlympiA trial of 1,836 patients with high-risk, HER2-negative early breast cancer and an inherited BRCA1 or BRCA2 variant, one year of the PARP inhibitor olaparib after standard treatment raised 3-year invasive disease-free survival to 85.9%, compared with 77.1% with placebo.

October is Breast Cancer Awareness Month, and one of the most elegant ideas in modern cancer medicine begins with two genes whose names most people already know. BRCA1 and BRCA2 are caretaker genes. Their proteins repair the most dangerous kind of DNA damage, a double-strand break in which both strands of the helix are severed, by a high-fidelity process called homologous recombination that uses the matching sister chromosome as a template to rebuild the broken sequence correctly. People who inherit one faulty copy of either gene still have a working copy in every cell, so their tissues repair DNA normally, but the reserve is gone. If a single breast or ovarian cell loses its remaining good copy, it can no longer repair double-strand breaks accurately, errors pile up, and cancer becomes far more likely. The size of that risk is striking: in a prospective study following nearly ten thousand carriers, the cumulative chance of breast cancer by age eighty was 72 percent for BRCA1 and 69 percent for BRCA2, and the chance of ovarian cancer was 44 and 17 percent. Understanding PARP inhibitors and BRCA begins with a simple observation about what those tumors have lost, and what they have left.

A cell has more than one repair kit. PARP, short for poly(ADP-ribose) polymerase, is an enzyme that detects single-strand nicks in DNA and recruits the machinery that patches them, a pathway called base excision repair. Normal cells can manage without PARP, and mice lacking it are healthy. But when a cell copies its DNA and the replication machinery runs into an unrepaired nick, the fork collapses and the nick becomes a double-strand break, exactly the kind of damage that requires BRCA-dependent homologous recombination. In 2005, two laboratories published back-to-back papers in Nature showing what happens when both systems fail. Cells lacking BRCA1 or BRCA2 were profoundly sensitive to PARP inhibition, dying through chromosomal instability, cell-cycle arrest, and apoptosis, while BRCA2-deficient tumors could be killed by a PARP inhibitor alone, with no chemotherapy at all. This is synthetic lethality: losing either repair pathway is survivable, but losing both is fatal. And because a carrier’s healthy cells still hold one working BRCA copy and can repair the collapsed forks, the damage falls on the tumor, which has lost both.

How are PARP inhibitors used for BRCA-related breast cancer?

Two decades later, that laboratory insight is standard care for selected patients. In the OlympiA trial, 1,836 people with high-risk, HER2-negative early breast cancer and an inherited BRCA1 or BRCA2 variant, who had already completed surgery and chemotherapy, were randomly assigned to one year of the oral PARP inhibitor olaparib or placebo. At three years, 85.9 percent of those given olaparib were free of invasive disease, compared with 77.1 percent of those given placebo, and there were fewer deaths in the olaparib group. These drugs are not a general cancer preventive and are not for everyone; they are prescribed by oncologists for specific tumors, they carry real side effects, including effects on blood counts, and tumors can eventually find ways around them. The practical lesson for most readers is further upstream. Only a small share of women carry a BRCA1 or BRCA2 mutation, but those who do benefit enormously from knowing it, and knowing it also matters for their relatives. The US Preventive Services Task Force recommends that women with a personal or family history of breast, ovarian, tubal, or peritoneal cancer, or with an ancestry associated with BRCA mutations, be assessed with a brief familial risk tool, and that those who screen positive be referred for genetic counseling and, if appropriate, genetic testing. This Breast Cancer Awareness Month, a careful family history is one of the most useful conversations to have with your physician.

References:

1. Kuchenbaecker, K. B., Hopper, J. L., Barnes, D. R., Phillips, K. A., Mooij, T. M., Roos-Blom, M. J., et al. (2017). Risks of breast, ovarian, and contralateral breast cancer for BRCA1 and BRCA2 mutation carriers. JAMA, 317(23), 2402-2416.
2. Farmer, H., McCabe, N., Lord, C. J., Tutt, A. N., Johnson, D. A., Richardson, T. B., et al. (2005). Targeting the DNA repair defect in BRCA mutant cells as a therapeutic strategy. Nature, 434(7035), 917-921.
3. Bryant, H. E., Schultz, N., Thomas, H. D., Parker, K. M., Flower, D., Lopez, E., et al. (2005). Specific killing of BRCA2-deficient tumours with inhibitors of poly(ADP-ribose) polymerase. Nature, 434(7035), 913-917.
4. Tutt, A. N. J., Garber, J. E., Kaufman, B., Viale, G., Fumagalli, D., Rastogi, P., et al. (2021). Adjuvant olaparib for patients with BRCA1- or BRCA2-mutated breast cancer. New England Journal of Medicine, 384(25), 2394-2405.
5. Owens, D. K., Davidson, K. W., Krist, A. H., Barry, M. J., Cabana, M., Caughey, A. B., et al. (2019). Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer: US Preventive Services Task Force recommendation statement. JAMA, 322(7), 652-665.