NEW YORK – After researchers in Japan saw a heavily pretreated endometrial cancer patient with a BRIP1 mutation respond particularly well to olaparib (AstraZeneca's Lynparza), they wrote last week in the Journal of Clinical Oncology: Precision Oncology that her response may have been due to homologous recombination repair deficiency and worthy of further study.
The insight gleaned from this case could be valuable for future drug development. As of now, the PARP inhibitors on the market — including niraparib (GlaxoSmithKline's Zejula), rucaparib (Clovis Oncology's Rubraca), and olaparib — have been approved as monotherapies for breast and ovarian cancer, but have not been recommended or approved for endometrial cancer.
The patient described in the case report was a 70-year-old woman with serous high-grade endometrial cancer who had received several lines of treatment upon diagnosis, including surgical resection (abdominal hysterectomy, bilateral salpingo-oophorectomy, and omentectomy), followed by two lines of chemotherapy — first, six cycles of carboplatin and paclitaxel, then six cycles of doxorubicin and cisplatin. The authors, led by Kohei Nakamura of the Keio Cancer Center in Tokyo, described the patient's disease as stable following these upfront treatments, but pointed out that she did not have improvement in her para-aortic or left lateral iliac swollen lymph nodes.
Next, the researchers performed next-generation sequencing on the patient's blood and specimen using an in-house assay, which revealed a frameshift BRIP1 pathogenic variant in the tumor. BRIP1, along with BRCA1/2, ATM, ARID1A, and PALB2, are genes that studies have shown to be involved in repairing double-stranded DNA breaks via homologous recombination pathways. The researchers also observed high loss of genetic heterozygosity (LOH) and scattered allelic imbalance, both of which are common among tumors with homologous recombination deficiencies.
These molecular features hobble cancer cells' ability to repair DNA damage, making them more sensitive to PARP inhibitors. As such, the researchers hypothesized that this endometrial cancer patient might benefit from off-label treatment with olaparib.
Although this patient's somatic BRIP1 mutation and high LOH status suggested to the researchers that she had homologous recombination deficiency, unfortunately, they were unable to directly determine this because this type of testing doesn't have insurance coverage in Japan.
After discussing it with the patient, the researchers began off-label treatment with olaparib, given orally in 300 mg pills twice a day, as recommended by the US Food and Drug Administration.
Three months after beginning treatment with olaparib, a CT scan showed that the patient's swollen lymph nodes in her pelvis had disappeared. Then, ultimately, after nine months, she showed a complete response. She had no adverse events.
"Our data suggest that the BRIP1 mutations could indicate the response to PARP inhibition," wrote the researchers. They theorized that potential therapeutic applications of PARP inhibitors like olaparib "might be extended from germline BRCA mutations to target a more diverse group of sporadic tumors, such as those with epigenetic disruption of BRCA1/2 function or genetically or epigenetically acquired aberrations in other important [homologous recombination] pathway constituents."
In the past, PARP inhibitor efficacy was primarily associated with BRCA mutations, but growing understanding of the biology of DNA repair pathways has led researchers to focus more on homologous recombination as a predictive feature. Last year, the FDA approved niraparib for heavily pretreated ovarian cancer patients with homologous recombination deficiency as gauged by Myriad Genetics' companion diagnostic. The myChoice CDx detects large rearrangements and mutations in BRCA1/2 and uses a proprietary algorithm to analyze three processes involved in DNA repair — LOH, telomeric allelic imbalance, and large-scale state transitions — and calculate a genomic instability score.
BRIP1, Nakamura and colleagues pointed out, is closely tied to BRCA1, with the interaction between the two being important for homologous recombination. So, even without a BRCA1 mutation, the BRIP1 mutation may indicate hypersensitivity to PARP inhibition.
More research will be needed to determine the frequency of BRIP1 mutations in endometrial tumors, as well as further exploration of the specific homologous recombination score in future cases. Nonetheless, they concluded that the results of this case study shed light on the potential of PARP inhibitor treatment in BRIP1-mutated endometrial cancer.